General Information About Plasma Cell Neoplasms

There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.

For more information, see the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in B-Cell Non-Hodgkin Lymphoma Treatment.

Incidence and Mortality

Estimated new cases and deaths from multiple myeloma in the United States in 2024:[1]

• New cases: 35,780.
• Deaths: 12,540.

Clinical Presentation and Evaluation

Table 1. Clinical Presentation of Plasma Cell Neoplasms

Plasma Cell Neoplasm	M Protein Type	Pathology	Clinical Presentation
Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.
MGUS	IgG kappa or lambda; or IgA kappa or lambda	<10% plasma cells in bone marrow	Asymptomatic, with minimal evidence of disease (aside from the presence of an M protein)[2]
Isolated plasmacytoma of bone	IgG kappa or lambda; or IgA kappa or gamma	Solitary lesion of bone; <10% plasma cells in marrow of uninvolved site	Asymptomatic or symptomatic
Extramedullary plasmacytoma	IgG kappa or lambda; or IgA kappa or gamma	Solitary lesion of soft tissue; most commonly occurs in the nasopharynx, tonsils, or paranasal sinuses[3]	Asymptomatic or symptomatic
Multiple myeloma	IgG kappa or lambda; or IgA kappa or gamma	Often, multiple lesions of bone	Symptomatic

Evaluation of patients with monoclonal (or myeloma) protein (M protein)

Idiotypic myeloma cells can be found in the blood of patients with myeloma in all stages of the disease.[4,5] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with MGUS or asymptomatic smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.

The major challenge is to separate the stable asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.[6,7,8]

Patients with an M protein in the serum and/or urine are evaluated by some of the following criteria:

• Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin (Ig) assays; however, specific Ig quantification always overestimates the M protein because normal Ig are included in the result. For this reason, the preference is often that baseline and follow-up measurements of the M protein be done by the same method.[9] Quantitative serum-free light chains (FLC) may be helpful to follow response when an M protein is not apparent.
• Measure and follow the amount of M protein light chains excreted in the urine over 24 hours. Measure the total amount of protein excreted over 24 hours and multiply this value by the percentage of urine protein that is M protein, as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.
• Identify the heavy and light chain of the M protein by immunofixation electrophoresis.
• Measure the hemoglobin, leukocyte, platelet, and differential counts.
• Determine the percentage of marrow plasma cells. Be aware that marrow plasma-cell distribution may vary in different sites. Bone marrow is often sent for cytogenetics and fluorescence in situ hybridization testing for genetic markers of high-risk disease. For more information, see the Genetic factors and risk groups section.
• Measure serum-free kappa and lambda light chains. This is especially useful in cases of oligosecretory plasma-cell dyscrasia or for following cases of light-chain amyloidosis.[10] The FLC ratio of over 100 can predict a greater than 70% progression within 2 years in patients with smoldering myeloma.[11]
• If clinically warranted, obtain needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
• Evaluate renal function with serum creatinine and a creatinine clearance.
• Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light-chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin.

  In most patients with myeloma, the glomeruli function normally allows only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light-chain peak in the globulin region; this tubular pattern is the usual pattern found in patients with myeloma.

• Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins and serum viscosity.
• Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones.
• Obtain a spinal magnetic resonance imaging (MRI) scan (or spinal computed tomography [CT] or positron emission tomography [PET]–CT scan depending on availability) if the skeletal survey is negative.[12,13,14] At diagnosis, whole-body PET scan or MRI of the total spine and pelvis appears to be equally efficacious in the detection of bone lesions.[15,16]
• If amyloidosis is suspected, perform a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.[17]
• Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[18,19]
• The presence of circulating myeloma cells is considered a poor prognostic factor.[20] Primary plasma cell leukemia has a particularly poor prognosis.[21,22]

These initial studies are often compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse.

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and have fewer than 10% of plasma cells in the bone marrow.[2,23,24,25] Patients with smoldering myeloma have similar characteristics but may have more than 10% of plasma cells in the bone marrow.

These types of patients are asymptomatic and do not need to be treated. However, patients with MGUS and risk factors for disease progression must be followed carefully because they are more likely to develop myeloma (most commonly), amyloidosis, lymphoplasmacytic lymphoma, or chronic lymphocytic leukemia. These patients may then require therapy.[25,26,27]

Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[28,29,30] The annual risk of progression of MGUS to a lymphoid or plasma cell malignancy ranges from 0.5% to 1.0% in population-based cohorts.[31,32] This risk ranges from 2% to more than 20% in higher-risk patients.

Risk factors that predict disease progression include the following:

• An abnormal serum-FLC ratio.[31,33]
• Non-IgG class MGUS.
• A high level of serum M protein (≥1.5 g/dL).[31,33]

A Swedish cohort study confirmed that an abnormal serum FLC ratio and a high level of serum monoclonal protein are high-risk factors.[32] The study described the additional risk factor of immunoparesis, which is defined as the reciprocal depression of the other Ig classes (i.e., if a patient has an IgG kappa M protein, the IgM and IgA would be below normal levels with immunoparesis). Incorporation of gene-expression profiles to better assess risk is under clinical evaluation.[34]

Monoclonal gammopathies that cause organ damage, particularly to the kidney, heart, or peripheral nerves, require immediate therapy with the same strategies applied for the conventional plasma-cell dyscrasias.[35] A monoclonal gammopathy causing renal dysfunction—by direct antibody deposition or amyloidosis—is referred to as monoclonal gammopathy of renal significance.[36] Rising serum creatinine, dropping glomerular filtration rates, and increasing urinary–albumin excretion are all parameters that may signify renal damage and are assessed prospectively for high-risk MGUS patients. Although the N-terminal pro-brain natriuretic peptide is a very sensitive marker for amyloid involvement in the heart, the low specificity must be noted. These extra tests are included with the M-protein level, FLC levels, and FLC ratio when following patients with MGUS.[37]

In a retrospective review of 6,399 patients with newly diagnosed multiple myeloma, 44 patients were found to have a biclonal IgG or IgA MGUS. The overall response rate of the myeloma clone to induction therapy was 93%, compared with 64% for the separate-clone MGUS (P = .001).[38][Level of evidence C3] Many MGUS plasma cell clones were unresponsive to available myeloma therapy; this result highlights the need to lower expectations for response in situations in which an MGUS may require therapy because of end-organ damage.

Isolated Plasmacytoma of Bone

The patient has an isolated plasmacytoma of the bone if the following are found:

• A solitary lytic lesion of plasma cells on skeletal survey in an otherwise asymptomatic patient.
• A bone marrow examination from an uninvolved site contains less than 10% plasma cells.[39,40,41] The absence of plasma cells on flow cytometry of the bone marrow suggests a low (<10%) risk of recurrence after radiation therapy of the isolated bone plasmacytoma.[42]

MRI may reveal unsuspected bony lesions that were undetected on standard radiographs. MRI scans of the total spine and pelvis may identify other bony lesions.[43]

Extramedullary Plasmacytoma

A patient has extramedullary plasmacytoma if the following are found:

• Isolated plasma-cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses.
• Negative findings on skeletal x-rays and bone marrow biopsy.[44,45,46]

Multiple Myeloma

Multiple myeloma is a systemic malignancy of plasma cells that typically involves multiple sites within the bone marrow and secretes all or part of a monoclonal antibody.

Prognosis

Multiple myeloma is highly treatable but rarely curable. The median survival in the prechemotherapy era was about 7 months. After the introduction of chemotherapy, prognosis improved significantly with a median survival of 24 to 30 months and a 10-year survival rate of 3%. Even further improvements in prognosis have occurred because of the introduction of newer biological therapies and better salvage options, with median survivals now exceeding 10 years.[47] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[21,48] Racial disparities because of socioeconomic factors, genetics, differences in risk factor exposure, and structural racism are under evaluation.[49]

Multiple myeloma is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. For more information, see the sections on Isolated Plasmacytoma of Bone and Extramedullary Plasmacytoma.

Amyloidosis Associated With Plasma Cell Neoplasms

Multiple myeloma and other plasma cell neoplasms may cause a condition called amyloidosis. Primary amyloidosis can result in severe organ dysfunction, especially in the kidney, heart, or peripheral nerves.[50] Clinical symptoms and signs include the following:

• Fatigue.
• Purpura.
• Enlarged tongue.
• Diarrhea.
• Edema.
• Lower-extremity paresthesia.

Accurate diagnosis of amyloidosis requires histological evidence of amyloid deposits and characterization of the amyloidogenic protein using immunoelectron microscopy.[51] In one series of 745 consecutive patients, 20% of patients with nonamyloid light chain amyloidosis (usually transthyretin) had an innocent monoclonal gammopathy, indicating the significant risk of misdiagnosis.[51]

Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum FLC are poor prognostic factors.[52,53] Proposed staging systems for primary systemic amyloidosis based on these serum levels require independent and prospective confirmation.[52,54] An increase in levels of serum FLC over many years can precede the clinical diagnosis of amyloid light chain amyloidosis.[55] Amyloidosis associated with an IgM monoclonal gammopathy is a rare, but distinct, clinical entity with more frequent neuropathy and adenopathy and less cardiac involvement.[56]

POEMS Syndrome

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare paraneoplastic condition associated with a plasma cell dyscrasia of early or late stage. The acronym describes a constellation of findings often marked by polyneuropathy, organomegaly (usually splenomegaly), endocrinopathy, monoclonal plasma cell dyscrasia, and skin changes.[57] Both sclerotic or lytic bone lesions and lymphadenopathy (with possible Castleman histology) may be identified. Anecdotal reports suggest remissions have been achieved using myeloma-directed therapy.[58,59,60,61,62]

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38. Campbell JP, Heaney JLJ, Pandya S, et al.: Response comparison of multiple myeloma and monoclonal gammopathy of undetermined significance to the same anti-myeloma therapy: a retrospective cohort study. Lancet Haematol 4 (12): e584-e594, 2017.
39. Ozsahin M, Tsang RW, Poortmans P, et al.: Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys 64 (1): 210-7, 2006.
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Stage Information for Plasma Cell Neoplasms

No generally accepted staging system exists for monoclonal gammopathy of undetermined significance, isolated plasmacytoma of bone, or extramedullary plasmacytoma. Of the plasma cell neoplasms, a staging system exists only for multiple myeloma.

Multiple Myeloma

Multiple myeloma is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M protein) in the serum and/or urine, along with various clinical parameters, such as hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. Impaired renal function worsens prognosis regardless of stage.[1]

The stage of the disease at presentation is a strong determinant of survival, but it has little influence on the choice of therapy because almost all patients, except for rare patients with solitary bone tumors or extramedullary plasmacytomas, have generalized disease.

International staging system

The International Myeloma Working Group (IMWG) studied 11,171 patients, 2,901 of whom received high-dose therapy and 8,270 of whom received only standard-dose therapy.[2] The IMWG evaluated 4,445 patients to create a Revised International Staging System (R-ISS) incorporating lactate dehydrogenase levels and interphase fluorescence in situ hybridization (I-FISH) results.[3]

An International Staging System (ISS) was derived and is shown below in Table 2.[2]

Table 2. The International Staging System (ISS) for Multiple Myeloma

Stage	Criteria	Median Survival (mo)
I-FISH = interphase fluorescencein situ hybridization; LDH = lactate dehydrogenase; R-ISS = Revised International Staging System.
I	Beta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL	Not reached
II	Not R-ISS I or III	83
III	Beta-2-microglobulin ≥5.5 mg/L and either high LDH or high-risk chromosomal abnormalities by I-FISH (defined as presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16))	43

Genetic factors and risk groups

Newer clinical investigations are stratifying patients with multiple myeloma into so-called good-risk, intermediate-risk, and high-risk groups, based on genetic aberrations detected by I-FISH.[4,5,6] (See Table 3 below.) This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation.[4] Bone marrow samples are sent for cytogenetic and FISH analysis.[6] Plasma cell leukemia (>2%–5% circulating plasma cells) has a particularly poor prognosis.[7,8,9,10,11,12,13] The otherwise favorable prognosis of hyperploidy is trumped by coexistent adverse cytogenetics.[14]

Table 3. Risk Groups for Multiple Myeloma

Risk Group	Cytogenetic Findings		Disease Characteristics	Median Survival (y)
FISH = fluorescencein situ hybridization; Ig = immunoglobulin.
Good risk	Has any of the following cytogenetic findings:		These patients most often have disease that expresses IgG kappa monoclonal gammopathies, and lytic bone lesions.	10–12[15]
		No adverse FISH or cytogenetics
		Hyperdiploidy
		t(11;14) by FISH
		t(6;14) by FISH
Intermediate risk	Has one of the following formerly deleterious criteria that have been abrogated by standard triplet or quadruplet regimens:[16]		These patients often have IgA lambda monoclonal gammopathies and less bone disease.	5–10
		t(4;14)
		t(14;16)
High risk	Has any of the following cytogenetic findings:		These patients have disease that expresses IgA lambda monoclonal gammopathies (often) and skeletal-related complications (less often).	<5 for high-risk; <3 for ultra-high risk[15]
		del 17p by FISH
		t(14;16) by FISH
		t(4;14)
		t(14;20)
		del 13
		Biallelic delTP53(ultra-high risk)
		1q gain (3 copies), 1 q amp (4 copies, ultra-high risk), monoallelic del (1p32),[17]biallelic del (1p32)[17]
		Plasma cell leukemia

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9. Granell M, Calvo X, Garcia-Guiñón A, et al.: Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica 102 (6): 1099-1104, 2017.
10. Mina R, Joseph NS, Kaufman JL, et al.: Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents. Cancer 125 (3): 416-423, 2019.
11. Royer B, Minvielle S, Diouf M, et al.: Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome. J Clin Oncol 34 (18): 2125-32, 2016.
12. Gonsalves WI, Rajkumar SV, Go RS, et al.: Trends in survival of patients with primary plasma cell leukemia: a population-based analysis. Blood 124 (6): 907-12, 2014.
13. Jelinek T, Bezdekova R, Zihala D, et al.: More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma. J Clin Oncol 41 (7): 1383-1392, 2023.
14. Pawlyn C, Melchor L, Murison A, et al.: Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood 125 (5): 831-40, 2015.
15. Davies FE, Pawlyn C, Usmani SZ, et al.: Perspectives on the Risk-Stratified Treatment of Multiple Myeloma. Blood Cancer Discov 3 (4): 273-284, 2022.
16. Khot A: Del(1p32): prime time in (ultra) high-risk myeloma. Blood 141 (11): 1241-1243, 2023.
17. Schavgoulidze A, Talbot A, Perrot A, et al.: Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor. Blood 141 (11): 1308-1315, 2023.

Treatment Option Overview for Plasma Cell Neoplasms

The major challenge in treating plasma cell neoplasms is separating the stable asymptomatic group of patients who do not require immediate treatment from patients with progressive symptomatic myeloma who may need to be treated immediately.[1,2,3] Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma.

Asymptomatic Plasma Cell Neoplasms (Smoldering Multiple Myeloma)

Asymptomatic patients with multiple myeloma who have no lytic bone lesions and normal renal function may be initially observed safely outside the context of a clinical trial.[1,4,5] Increasing anemia is the most reliable indicator of progression.[5] The following criteria represent the new definition for smoldering myeloma:[3]

• Serum monoclonal protein immunoglobulin (Ig) G or IgA of at least 30 g/L or urinary monoclonal protein of at least 500 mg per 24 hours.
• Clonal bone marrow plasma cells 10% to 60% (>60% represents overt myeloma).
• Absence of amyloidosis or myeloma-defining events as follows:
  • Hypercalcemia greater than 1 mg/dL higher than reference range.
  • Creatinine greater than 2 mg/dL or creatinine clearance less than 40 mL/min.
  • Anemia with hemoglobin less than 10.0 g/dL.
  • Bone lesions (one or more) on skeletal radiography, computed tomography (CT) or positron emission tomography (PET)-CT.
  • Clonal plasma cell percentage in marrow at 60% or more.
  • Involved:uninvolved serum-free light chain (FLC) ratio of 100 or more.
  • More than one focal lesion of at least 5 mm on magnetic resonance imaging (MRI) of the spine.

A prospective randomized clinical trial investigated the role of immediate therapy for patients with smoldering multiple myeloma by specifying high-risk patients with both 10% or more marrow plasma cells and a serum monoclonal (or myeloma) protein (M protein) of at least 3 g/dL.[6] The trial randomly assigned 125 patients to receive lenalidomide plus dexamethasone or observation.

• With a median follow-up of 75 months, lenalidomide plus dexamethasone provided benefit in time to progression compared with observation, with a median time not reached (95% confidence interval [CI], 47 months to not reached) compared with 23 months (95% CI, 16‒31 months) (hazard ratio, 0.24; 95% CI, 0.14‒0.41).[6][Level of evidence B1]
• There was no difference in overall survival (OS) at a median follow-up of 75 months.
• At the beginning of this trial, some of the patients had what would now be considered overt myeloma, based on the updated criteria listed above. This may influence the interpretation of the study because patients with overt myeloma might be responsible for some of the benefits seen with therapy.

Symptomatic Plasma Cell Neoplasms

Patients with symptomatic advanced disease require treatment.

Treatment most often is directed at reducing the tumor cell burden and reversing any complications of disease, such as renal failure, infection, hyperviscosity, or hypercalcemia, with appropriate medical management. The International Myeloma Working Group (IMWG) has published new criteria for identifying patients with active myeloma who require therapy.[3] These criteria include the following:

• Amyloidosis.
• Hypercalcemia greater than 1 mg/dL higher than reference range.
• Creatinine greater than 2 mg/dL or creatinine clearance less than 40 mL/min. Myeloma can cause renal dysfunction via hypercalcemia, amyloidosis, or light chain deposition disease.[7]
• Anemia with hemoglobin less than 10.0 g/dL.
• Bone lesions (one or more) on skeletal radiography, whole-body MRI or spine and pelvis MRI, or PET-CT scans.[8]
• Clonal plasma cell percentage in marrow at 60% or more.
• Involved: uninvolved serum FLC ratio of 100 or more.
• More than one focal lesion of at least 5 mm on skeletal bone survey, or if negative, total-body MRI, or MRI of the spine and pelvis, or PET-CT scan.

Response criteria have been developed for patients on clinical trials by the IMWG.[9] A very good partial response (VGPR) is defined as a reduction of 90% or more in the serum monoclonal protein and a 24-hour urine monoclonal protein of less than 100 mg. Although not incorporated in the IMWG criteria, many trials report near complete response when patients have less than 5% bone marrow plasma cells and unmeasurable serum monoclonal proteins but still have positive serum and/or urine immunofixation. Note that these near complete response patients are incorporated into the VGPR group by the IMWG. Patients who achieve a complete response by IMWG criteria (with a negative immunofixation along with the clear marrow and unmeasurable serum monoclonal proteins) are often said to have attained a stringent complete response if their free kappa/lambda light–chain levels and ratio return to reference ranges. The clinical utility of these various categories must be validated in clinical trials.

Therapy options for patients with symptomatic myeloma can be divided into the following categories:

• Induction therapies.
• Consolidation therapies, which are less applicable for patients of advanced age.
• Maintenance therapies.
• Supportive care, such as bisphosphonates. For more information, see the Pharmacological Therapies for Pain Control section in Cancer Pain.
• Infection prevention, which includes vaccination, antimicrobial prophylaxis, and immunoglobulin replacement (in a small subset of patients), per consensus guidelines from the IMWG.[10]

References:

1. He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003.
2. Kyle RA, Remstein ED, Therneau TM, et al.: Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 356 (25): 2582-90, 2007.
3. Rajkumar SV, Dimopoulos MA, Palumbo A, et al.: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15 (12): e538-48, 2014.
4. Riccardi A, Mora O, Tinelli C, et al.: Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 82 (7): 1254-60, 2000.
5. Bladé J, Dimopoulos M, Rosiñol L, et al.: Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 28 (4): 690-7, 2010.
6. Mateos MV, Hernández MT, Giraldo P, et al.: Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol 17 (8): 1127-36, 2016.
7. Sayed RH, Wechalekar AD, Gilbertson JA, et al.: Natural history and outcome of light chain deposition disease. Blood 126 (26): 2805-10, 2015.
8. Dimopoulos MA, Hillengass J, Usmani S, et al.: Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol 33 (6): 657-64, 2015.
9. Durie BG, Harousseau JL, Miguel JS, et al.: International uniform response criteria for multiple myeloma. Leukemia 20 (9): 1467-73, 2006.
10. Raje NS, Anaissie E, Kumar SK, et al.: Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol 9 (2): e143-e161, 2022.

Treatment of Amyloidosis Associated With Plasma Cell Neoplasms

Treatment Options for Amyloidosis Associated With Plasma Cell Neoplasms

Treatment depends on assessing the extent of systemic damage from the amyloidosis and the underlying plasma cell dyscrasia.[1,2] A rising and elevated level of N-terminal pro brain natriuretic peptide may predict impending cardiac failure in the setting of cardiac amyloidosis, and early treatment should be considered for these patients.[3]

Treatment options for amyloidosis associated with plasma cell neoplasms include the following:

1. Induction therapy.
2. Stem cell rescue.
3. Monoclonal antibody targeting of amyloid deposits (under clinical evaluation).

Induction therapy

As is true for all plasma cell dyscrasias, responses have been reported for patients treated with all the same regimens active in multiple myeloma.[4,5,6,7,8,9,10,11,12] Lower doses of lenalidomide or pomalidomide must be used in patients with renal dysfunction.[13] Patients with amyloidosis respond to treatment with daratumumab, with or without other active agents. Daratumumab is usually combined with other agents used for myeloma.[14,15,16,17,18,19,20] Rapid responses to induction therapy may result in improvement of renal or cardiac function.[21,22]

Evidence (chemotherapy):

1. A prospective trial (NCT03201965) included 388 previously untreated patients with immunoglobulin light-chain amyloidosis (excluding symptomatic myeloma). Patients were randomly assigned to receive to bortezomib, cyclophosphamide, and dexamethasone with or without subcutaneous daratumumab.[23]
   • With a median follow-up of 11.4 months, the hematologic complete response rate was 53% for patients in the daratumumab group and 18.1% for patients in the control group (relative risk, 2.9; 95% confidence interval [CI], 2.1–4.1; P < .001). A landmark analysis at 6 months was also performed.[23][Level of evidence B3]
   • Survival free from organ deterioration or hematologic progression or death favored the daratumumab arm (hazard ratio, 0.58; 95% CI, 0.36–0.93; P = .02).
   • The cardiac and renal responses were doubled for patients in the daratumumab group, but no statistical analysis was provided.

   Daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone is considered a standard regimen for previously untreated patients who are eligible to receive this regimen.

Stem cell rescue

A randomized prospective study of 100 patients with immunoglobulin light-chain amyloidosis compared melphalan plus high-dose dexamethasone with high-dose melphalan plus autologous stem cell rescue.[24] After a median follow-up of 3 years, median overall survival (OS) favored the nontransplant arm (56.9 months vs. 22.2 months; P = .04).[24][Level of evidence A1] The 24% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction.[24,25,26,27,28,29] Between 2007 and 2012, the International Blood and Marrow Transplant Research Program identified 800 patients with amyloidosis who underwent autologous stem cell transplant (SCT); the 5-year OS rate was 77% and transplant-related mortality was 5%, suggesting better selection of patients for transplant.[30][Level of evidence C1] Similarly, in a retrospective review of 672 consecutive patients with amyloidosis who underwent autologous SCT over 20 years, the treatment-related mortality declined to 2.4% between 2010 and 2016 in comparison with 8.6% between 2003 and 2009, and 14.5% between 1996 and 2002.[31][Level of evidence C2] A randomized trial confirming the benefit of autologous transplant is not anticipated.[3,32]

An anecdotal series describes full-intensity and reduced-intensity allogeneic SCT.[33]

Monoclonal antibody targeting of amyloid deposits

The monoclonal antibody CAEL-101 binds to immunoglobulin-associated amyloid in an effort to promote phagocytosis and clearance of the amyloid deposits.

1. In a phase I study (NCT02245867), 27 patients with deep hematologic responses to myeloma therapy, but persistent organ involvement, received CAEL-101.[34]
   • Fifteen of 24 patients (63%) manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue response by serum biomarkers (such as NT-proBNP), renal function, cardiac function, or imaging studies.

   This treatment is not approved by the U.S. Food and Drug Administration and is under clinical evaluation.[34][Level of evidence C3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Gertz MA, Dispenzieri A: Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review. JAMA 324 (1): 79-89, 2020.
2. Palladini G, Merlini G: How I treat AL amyloidosis. Blood 139 (19): 2918-2930, 2022.
3. Merlini G, Wechalekar AD, Palladini G: Systemic light chain amyloidosis: an update for treating physicians. Blood 121 (26): 5124-30, 2013.
4. Kumar SK, Hayman SR, Buadi FK, et al.: Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood 119 (21): 4860-7, 2012.
5. Venner CP, Lane T, Foard D, et al.: Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 119 (19): 4387-90, 2012.
6. Wechalekar AD, Schonland SO, Kastritis E, et al.: A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 121 (17): 3420-7, 2013.
7. Sanchorawala V, Shelton AC, Lo S, et al.: Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood 128 (8): 1059-62, 2016.
8. Palladini G, Milani P, Foli A, et al.: Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies. Blood 131 (5): 525-532, 2018.
9. Manwani R, Cohen O, Sharpley F, et al.: A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib. Blood 134 (25): 2271-2280, 2019.
10. Kastritis E, Leleu X, Arnulf B, et al.: Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol 38 (28): 3252-3260, 2020.
11. Lentzsch S, Lagos GG, Comenzo RL, et al.: Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol 38 (13): 1455-1462, 2020.
12. Dispenzieri A, Kastritis E, Wechalekar AD, et al.: A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia 36 (1): 225-235, 2022.
13. Mikhael J, Manola J, Dueck AC, et al.: Lenalidomide and dexamethasone in patients with relapsed multiple myeloma and impaired renal function: PrE1003, a PrECOG study. Blood Cancer J 8 (9): 86, 2018.
14. Palladini G, Kastritis E, Maurer MS, et al.: Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood 136 (1): 71-80, 2020.
15. Sanchorawala V, Sarosiek S, Schulman A, et al.: Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood 135 (18): 1541-1547, 2020.
16. Nooka AK, Kaufman JL, Hofmeister CC, et al.: Daratumumab in multiple myeloma. Cancer 125 (14): 2364-2382, 2019.
17. Dispenzieri A: AL patients don't dare go without dara. Blood 135 (18): 1509-1510, 2020.
18. Roussel M, Merlini G, Chevret S, et al.: A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood 135 (18): 1531-1540, 2020.
19. Kimmich CR, Terzer T, Benner A, et al.: Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria. Blood 135 (18): 1517-1530, 2020.
20. Royal V, Leung N, Troyanov S, et al.: Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study. Blood 135 (21): 1833-1846, 2020.
21. Basset M, Milani P, Foli A, et al.: Early cardiac response is possible in stage IIIb cardiac AL amyloidosis and is associated with prolonged survival. Blood 140 (18): 1964-1971, 2022.
22. Muchtar E, Dispenzieri A, Wisniowski B, et al.: Graded Cardiac Response Criteria for Patients With Systemic Light Chain Amyloidosis. J Clin Oncol 41 (7): 1393-1403, 2023.
23. Kastritis E, Palladini G, Minnema MC, et al.: Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med 385 (1): 46-58, 2021.
24. Jaccard A, Moreau P, Leblond V, et al.: High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 357 (11): 1083-93, 2007.
25. Dispenzieri A, Kyle RA, Lacy MQ, et al.: Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood 103 (10): 3960-3, 2004.
26. Skinner M, Sanchorawala V, Seldin DC, et al.: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 140 (2): 85-93, 2004.
27. Leung N, Leung TR, Cha SS, et al.: Excessive fluid accumulation during stem cell mobilization: a novel prognostic factor of first-year survival after stem cell transplantation in AL amyloidosis patients. Blood 106 (10): 3353-7, 2005.
28. Madan S, Kumar SK, Dispenzieri A, et al.: High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement. Blood 119 (5): 1117-22, 2012.
29. Cibeira MT, Sanchorawala V, Seldin DC, et al.: Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 118 (16): 4346-52, 2011.
30. D'Souza A, Dispenzieri A, Wirk B, et al.: Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study. J Clin Oncol 33 (32): 3741-9, 2015.
31. Sidiqi MH, Aljama MA, Buadi FK, et al.: Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time. J Clin Oncol 36 (13): 1323-1329, 2018.
32. Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.
33. Schönland SO, Lokhorst H, Buzyn A, et al.: Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid light-chain amyloidosis: a report from the European Group for Blood and Marrow Transplantation. Blood 107 (6): 2578-84, 2006.
34. Edwards CV, Rao N, Bhutani D, et al.: Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 138 (25): 2632-2641, 2021.

Treatment of Monoclonal Gammopathy of Undetermined Significance (MGUS)

Treatment Options for MGUS

Treatment options for MGUS include the following:

1. Watchful waiting.

Watchful waiting

Multiple myeloma, other plasma cell dyscrasia, or lymphoma will develop in 12% of patients by 10 years, 25% of patients by 20 years, and 30% of patients by 25 years.

All patients with MGUS are generally observed to detect increases in monoclonal (M) protein levels and development of a plasma cell dyscrasia. Higher levels of initial M protein levels may correlate with increased risk of progression to multiple myeloma.[1,2] In a large retrospective report, the risk of progression at 20 years was 14% for an initial M protein level of 0.5 g/dL or less, 25% for a level of 1.5 g/dL, 41% for a level of 2.0 g/dL, 49% for a level of 2.5 g/dL, and 64% for a level of 3.0 g/dL.[1]

Treatment is delayed until the disease progresses to the stage that symptoms or signs appear.

Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions, or have improved survival if chemotherapy is started early while they are still asymptomatic as opposed to waiting for progression before treatment is initiated.[3,4,5,6] Newer therapies have not been proven to prevent or delay the progression of MGUS to a plasma cell dyscrasia.[2]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Kyle RA, Therneau TM, Rajkumar SV, et al.: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346 (8): 564-9, 2002.
2. Bird J, Behrens J, Westin J, et al.: UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 147 (1): 22-42, 2009.
3. Bladé J, Dimopoulos M, Rosiñol L, et al.: Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 28 (4): 690-7, 2010.
4. He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003.
5. Riccardi A, Mora O, Tinelli C, et al.: Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 82 (7): 1254-60, 2000.
6. Kyle RA, Remstein ED, Therneau TM, et al.: Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 356 (25): 2582-90, 2007.

Treatment of Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

For more information, see the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in B-Cell Non-Hodgkin Lymphoma Treatment.

Treatment of Isolated Plasmacytoma of Bone

Treatment Options for Isolated Plasmacytoma of Bone

Treatment options for isolated plasmacytoma of bone include the following:

1. Radiation therapy to the lesion.
2. Chemotherapy (if the monoclonal [or myeloma] protein [M protein] increases and other evidence of symptomatic multiple myeloma occurs).

Radiation therapy

About 25% of patients have a serum and/or urine M protein; generally, this disappears after adequate radiation therapy to the lytic lesion.

The survival rate of patients with isolated plasmacytoma of bone treated with radiation therapy to the lesion is greater than 50% at 10 years, which is much better than the survival rate of patients with disseminated multiple myeloma.[1]

Chemotherapy

Most patients will eventually develop disseminated disease and require chemotherapy. Almost 50% of patients will do so within 2 years of diagnosis.[2,3] However, patients with serum paraprotein or Bence Jones protein, who have complete disappearance of these proteins after radiation therapy, may be expected to remain free of disease for prolonged periods.[2,4] Patients with a negative flow cytometry on bone marrow examination for plasma cell infiltration are also unlikely to relapse.[5] Patients who progress to multiple myeloma tend to have good responses to chemotherapy with a median survival of 63 months after progression.[2,4]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 50 (1): 113-20, 2001.
2. Liebross RH, Ha CS, Cox JD, et al.: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys 41 (5): 1063-7, 1998.
3. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.
4. Dimopoulos MA, Goldstein J, Fuller L, et al.: Curability of solitary bone plasmacytoma. J Clin Oncol 10 (4): 587-90, 1992.
5. Paiva B, Chandia M, Vidriales MB, et al.: Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma. Blood 124 (8): 1300-3, 2014.

Treatment of Extramedullary Plasmacytoma

Treatment Options for Extramedullary Plasmacytoma

Treatment options for extramedullary plasmacytoma include the following:

1. Radiation therapy to the isolated lesion with fields that cover the regional lymph nodes, if possible.[1,2]
2. In some cases, surgical resection may be considered, but it is usually followed by radiation therapy.[2]
3. If the monoclonal (or myeloma) protein (M protein) persists or reappears, the patient may need further radiation therapy. In some patients, the plasmacytoma may shrink, but not disappear, and the M protein persists. Close follow-up is generally warranted for these patients. Surgery often is performed if the plasmacytoma is in a site where it can be removed easily (e.g., in the tonsil); the M protein may disappear from the blood or urine. In other cases, persistence or an increasing M protein may herald progression to multiple myeloma.
4. Chemotherapy is required if the disease progresses and causes symptoms.

Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, may need to have skeletal x-rays and bone marrow biopsy (both of which are most often negative) and evaluation for M protein in serum and urine.[1,2,3,4]

About 25% of patients have serum and/or urine M protein; this frequently disappears after adequate radiation.

Extramedullary plasmacytoma is a highly curable disease. Progression-free survival rates range from 70% to 87% at 10 to 14 years after treatment with radiation therapy (with or without previous resection).[1,2,5]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 50 (1): 113-20, 2001.
2. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.
3. Meis JM, Butler JJ, Osborne BM, et al.: Solitary plasmacytomas of bone and extramedullary plasmacytomas. A clinicopathologic and immunohistochemical study. Cancer 59 (8): 1475-85, 1987.
4. Soesan M, Paccagnella A, Chiarion-Sileni V, et al.: Extramedullary plasmacytoma: clinical behaviour and response to treatment. Ann Oncol 3 (1): 51-7, 1992.
5. Strojan P, Soba E, Lamovec J, et al.: Extramedullary plasmacytoma: clinical and histopathologic study. Int J Radiat Oncol Biol Phys 53 (3): 692-701, 2002.

Treatment of Multiple Myeloma

Initial Evaluation

The initial approach to the patient is to evaluate the following parameters:

1. Detection and quantification of a monoclonal (or myeloma) protein (M protein) in the serum or urine, and possible immunoparesis (suppression of the other uninvolved immunoglobulins [Ig]).[1]
2. Detection of more than 10% of plasma cells on a bone marrow examination, along with flow cytometry, cytogenetics, and fluorescence in situ hybridization testing.
3. Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays, or whole-body or spinal and pelvic magnetic resonance imaging (MRI) scans, or focal bone lesions on positron emission tomography-computed tomography (CT) scan.[2,3]
4. Presence of soft tissue plasmacytomas.
5. Serum albumin and beta-2-microglobulin levels.
6. Detection of free kappa and free lambda serum Ig light chain, with calculation of the serum-free light chain ratio.[1,4]
7. Presence of hypercalcemia.
8. Detection of renal dysfunction attributable to the plasma cell dyscrasia (induced by gammopathy or amyloidosis).
9. Presence of anemia.
10. Presence of circulating plasma cells.
11. Presence of hyperviscosity. Asymptomatic patients usually respond to myeloma therapy; plasma exchange is indicated with hemorrhagic or central nervous system manifestations.[5]

Treatment selection is influenced by the age and general health of the patient, previous therapy, and the presence of complications of the disease.[6]

Therapeutic Overview

Despite the introduction of many new therapeutic agents over the past two decades, there is still no confirmed curative approach.

Indolent myeloma

Newly diagnosed patients with indolent disease, historically referred to as smoldering myeloma, can be monitored using a watchful waiting approach.[7] These patients are typically asymptomatic and free of lytic bone lesions, renal dysfunction, hypercalcemia, or significant anemia. Serial measurements of paraprotein parameters can help to confirm stable disease over months or years.[8]

Symptomatic myeloma

Newly diagnosed patients who require therapy fall into two categories: 1) the fit, transplant-eligible patient or 2) the less-fit patient with comorbidities who is not transplant eligible. Patients younger than 65 years are usually considered fit and transplant eligible, while patients older than 75 years are usually not transplant eligible. Comorbidities and performance status are important determinants at all ages, especially between the ages of 65 years and 75 years, to help decide about transplant eligibility. Nomograms exist for geriatric patients to define life expectancy independent of the myeloma diagnosis.[9] Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as autologous stem cell transplant (SCT) consolidation. Most patients also receive a bisphosphonate or RANKL inhibitor to prevent skeletal-related complications.[10,11]

The International Myeloma Working Group has issued guidance for the diagnosis and management of patients with renal impairment.[12]

Fit, transplant-eligible patients

The fit, transplant-eligible patient will receive induction chemotherapy with a four-drug (quadruplet) or three-drug (triplet) approach that includes bortezomib in the absence of a clinical trial. The most commonly used regimens include:

• D-VRd: daratumumab + bortezomib + lenalidomide + dexamethasone.[13,14]
• VRd: bortezomib + lenalidomide + dexamethasone.[15,16,17,18]
• CyBorD: cyclophosphamide + bortezomib + dexamethasone.[19,20] This regimen is preferred in the presence of significant renal dysfunction (creatinine clearance less than 45 cc/min). If the renal function recovers rapidly, some clinicians switch to VRd.

After 4 to 8 months of therapy, responding patients may undergo autologous SCT consolidation.[16,21] The previously mandated autologous SCT consolidation has been questioned because a large, randomized, prospective trial failed to demonstrate an overall survival (OS) benefit.[22] Maintenance therapy is then implemented until the time of relapse.[23,24,25] At relapse, subsequent therapies are given sequentially by using previously successful drugs (if the interval of time since previous exposure is >1 year) or newer drugs not previously tried.

Unfit, transplant-ineligible patients

The less-fit, transplant-ineligible patient will receive induction chemotherapy with a triplet regimen (as described for the fit, transplant-eligible patient) plus the CD38-directed monoclonal antibody, daratumumab, or with a doublet regimen and daratumumab, which might be better tolerated.[26] Therapy is continued until maximal response and then maintenance therapy is given until relapse.[27] At relapse, subsequent therapies are given sequentially (as described for the fit patient).

High risk versus standard risk

Patients with newly diagnosed or relapsing myeloma can be identified as having standard-risk or high-risk disease. This determination is made on the basis of cytogenetics, genetic aberrations detected by fluorescence in situ hybridization, and possibly the genetic expression profile analyses that are in the process of standardization.[28] Plasma cell leukemia at presentation, or as a leukemic evolution of refractory myeloma, is a particularly high-risk, poor-prognosis entity.[29,30,31,32,33] Plasma cell leukemia with an ultra-high poor prognosis is defined by the presence of more than 2% circulating tumor plasma cells by flow cytometry.[34] Higher-risk patients are candidates for clinical trials employing newer agents upfront or for use of newer combination therapies currently used for relapsed disease at the discretion of the clinician.[35,36,37] Beyond induction therapy, high-risk disease can lead to more aggressive strategies, such as tandem transplant or consideration of allogeneic SCT. More intensive maintenance therapies may also be given for high-risk disease; instead of using lenalidomide alone, lenalidomide plus bortezomib has been chosen based on prior trials using thalidomide.[38] These more aggressive strategies have been implemented because of poor responsiveness to standard regimens and the worse prognosis of high-risk patients. Ultimately, randomized prospective trials are needed to establish improved outcomes with these newer approaches for high-risk patients.

Measurable Residual Disease

The assessment of measurable residual disease (MRD) is mandatory for the assessment of efficacy in clinical trials.[39,40,41,42] Does MRD testing outside of the trial setting yield meaningful clinical improvement in patient outcomes by informing selection or duration of therapy? Achievement of MRD negativity after induction therapy (with or without consolidation therapy) is associated with improved progression-free survival (PFS) and improved OS.[43,44,45,46,47,48,49,50,51] While MRD negativity may be useful for the design of clinical trials, there are no data suggesting that this interim marker improves outcomes by altering subsequent therapy. Similarly, there are no data to suggest that sustained MRD negativity can allow deintensification or discontinuation of maintenance therapy.[52,53]

Induction Therapy

Patients with myeloma who are symptomatic or require therapy because of progression or adverse laboratory findings require induction therapy. Ideally, induction therapy should reduce tumor burden, provide symptomatic relief, and prevent further end-organ damage.

Fit, transplant-eligible patients

Two randomized prospective trials have evaluated the D-VRd regimen for induction therapy in fit, transplant-eligible patients.

1. A prospective trial included 709 transplant-eligible patients with newly diagnosed myeloma. Patients were randomly assigned to receive either D-VRd or VRd. All patients received an autologous SCT and subsequent lenalidomide maintenance therapy.[54]
   • With a median follow-up of 47.5 months, the 4-year PFS rate was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.30–0.59; P < .001).[54][Level of evidence B1]
   • The complete response rate was 87.9% in the D-VRd group and 70.1% in the VRd group (P < .001). The percentage of patients who achieved MRD-negative status favored D-VRd (75.2% vs. 47.5%; P < .001).
   • The most common grade 3 or 4 adverse event was neutropenia, which occurred in 62% of patients who received D-VRd and 51% of patients who received VRd.
2. The phase II GRIFFIN trial (NCT02874742) enrolled 207 patients with newly diagnosed transplant-eligible multiple myeloma. Patients were randomly assigned to receive induction therapy with either D-VRd or VRd. Patients then received an autologous SCT, two more cycles of the induction regimen, and 2 years of maintenance therapy with Dara-R (daratumumab and lenalidomide) or lenalidomide alone depending on the original randomization.[13]
   • With a median follow-up of 22.1 months at the clinical cutoff, the percentage of patients with a stringent complete response was 62.6% in the D-VRd group and 45.4% in the VRd group (odds ratio [OR], 1.98; 95% CI, 1.12–3.49; P = .0177).[13][Level of evidence B3]
   • The rate of patients achieving a complete response or better was 79.8% in the D-VRd group and 60.8% in the RVd group (OR, 2.53; 95% CI, 1.33–4.81; P = .0045).[14][Level of evidence B3]
   • The MRD-negative rate was 62.5% in the D-VRd group and 27.2% in the VRd group (P < .0001).
   • A Markov model using MRD status to predict PFS suggested improved quality of life and lower cost over 10 years with the use of daratumumab in the first-line setting.[55]

A more intensive regimen of induction therapy, consolidation therapy, and maintenance therapy was investigated in patients with high-risk cytogenetic abnormalities.

1. In the multicenter phase II OPTIMUM trial (NCT03188172), 412 newly diagnosed patients were screened to identify 103 patients with ultra–high-risk (UHR) myeloma or plasma cell leukemia.[56] UHR myeloma was defined by the presence of at least two specified genetic risk markers (t(4;14), t(14;16), t(14;20), del (1P), gain (1Q), and del 17P)) and/or SKY92 gene expression risk signature. All patients were treated with Dara-CVRd (daratumumab plus cyclophosphamide, bortezomib, lenalidomide, and dexamethasone) induction for 6 cycles (or until maximum response), autologous SCT consolidation, and Dara-VRd consolidation followed by Dara-R maintenance.[57]
   • With a median follow-up of 41.2 months, the 30-month PFS rate was 77% (95% CI, 69%–81%) for patients who received the study treatment versus 40% (95% CI, 31%–49%) for an historical control group who received KCRD (carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone).[56][Level of evidence C2] The 30-month OS rate was 84% (95% CI, 76%–91%) for patients who received the OPTIMUM regimen and 74% (95% CI, 66%–82%) for the historical control KCRD regimen.[56][Level of evidence C1]
   • The study design did not prove that Dara-CVRd is the preferred regimen for patients with UHR myeloma, but it is a feasible regimen for further randomized trials in this patient population.

In transplant-eligible patients, alkylators such as melphalan are avoided upfront to prevent stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting.[58] Bortezomib is given subcutaneously, which helps to avoid the neuropathies that were much more severe with intravenous administration.[59,60,61] Bortezomib is also preferred for patients with renal impairment.[62] Patients on a bortezomib-containing regimen need prophylaxis for herpes zoster (usually with valacyclovir or acyclovir). Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT) or pulmonary embolism, requiring additional prophylactic medication.[63,64] Because lenalidomide is metabolized erratically in patients with renal failure, clinicians may choose the CyBorD regimen,[19,20] but this selection is empiric and not based on randomized trial results. For patients without extra risk factors for DVT, aspirin (81 mg daily) suffices, but stronger anticoagulants should be considered for patients with multiple risk factors who receive lenalidomide (or other similar immunomodulating agents such as pomalidomide or thalidomide). Lower doses of lenalidomide must be used for patients with renal dysfunction.[65]

Unfit, transplant-ineligible patients

Triplet therapies such as VRd and CyBorD can be used in patients in with adequate fitness and minimal concurrent morbidities. When triplets are deemed too difficult, doublets with Vd (bortezomib plus dexamethasone) or Rd (lenalidomide plus dexamethasone) can be used, or even a triplet such as VMP as described in the section for fit patients.[15,26] Therapy options have changed with the advent of daratumumab, the CD38-directed monoclonal antibody. This biological therapy has been studied with the aforementioned doublets and triplets in both phase II and phase III trials.

1. In a prospective randomized trial (NCT02252172) of 737 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus lenalidomide and dexamethasone was compared with Rd alone.[66]
   • With a median follow-up of 56.2 months, the 60-month OS rate was 66.3% (95% CI, 60.8%–71.3)% for patients who received daratumumab and 53.1% (95% CI, 47.2%–58.6%) for patients who received Rd alone (HR, 0.68; 95% CI, 0.53–0.86; P = .0013).[66][Level of evidence A1]
   • With a median follow-up of 56.2 months, the 60-month PFS rate was 52.5% for patients who received daratumumab (95% CI, 46.7%−58.0%) and 28.7% for patients who received Rd alone (95% CI, 23.1%−34.6%) (HR, 0.53; 95% CI, 0.43−0.66; P < .0001).[66]
   • Results for the percentage of patients falling below the threshold for MRD (<1 tumor cell per 10⁵ white cells) favored the daratumumab combination, 24.2% versus 7.3% (P < .001).
   • The daratumumab combination resulted in significant and sustained reductions of pain scores and improved quality of life in the EuroQOL 5-dimensional descriptive visual system.[67][Level of evidence A3]
2. In a prospective randomized trial in 706 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus VMP was compared with VMP alone.[68]
   • With a median follow-up of 40.1 months, the 3-year OS rate favored the daratumumab-combination group at 78% (95% CI, 73.2%−83.0%) versus 67.9% in the VMP-alone group (95% CI, 62.6%−72.6%) (HR, 0.60; 95% CI, 0.46−0.80; P = .003).[68][Level of evidence A1]
   • With a median follow-up of 40.1 months, the 3-year PFS rate favored the daratumumab-combination group at 50.7% (95% CI, 45.1%−55.9%) versus 18.5% in the VMP group (95% CI, 14.4%−23.1%) (HR, 0.42; 95% CI, 0.34−0.51; P < .0001).[68][Level of evidence B1]
   • Patients without MRD favored daratumumab 22.3% (threshold of one tumor cell per 10⁵ white cells) versus 6.2% in the control group (P < .001).

   Immunologic reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (this dosing schedule is not approved by the U.S. Food and Drug Administration).

3. In a prospective randomized trial of 955 patients with newly diagnosed multiple myeloma who were ineligible for transplant, the combination of carfilzomib plus melphalan and prednisone was compared with the combination of bortezomib plus melphalan and prednisone.[69]
   • With a median follow-up of 23 months, there was no difference in median PFS (22.3 vs. 22.1 months; HR, 0.91; 95% CI, 0.75−1.10; P = .159) or in median OS (HR, 1.1; 95% CI, 0.82−1.4).[69][Level of evidence A1]
4. In a prospective trial, 1,087 patients with standard-risk or intermediate-risk myeloma who deferred transplant for induction therapy were randomly assigned to receive carfilzomib plus lenalidomide and dexamethasone or bortezomib plus lenalidomide and dexamethasone.[70]
   • With a median follow-up of 26 months, there was no difference in median PFS (34.6 vs. 34.4 months; HR, 1.04; 95% CI, 0.83−1.31; P = .742) or in median OS (HR, 0.98; 95% CI, 0.71−1.36; P = .923).[70][Level of evidence A1]
5. Many other phase II and phase III trials, published in preliminary abstract form, show results similar to the trial that combined daratumumab with melphalan and prednisone, and used daratumumab with other triplets and doublets in both previously untreated and previously treated patients.[71,72] Further follow-up is required to establish OS benefits. Mature OS data are required to better assess the cost-effectiveness of daratumumab in the first-line setting.[73]

Consolidation Therapy

Autologous bone marrow or peripheral stem cell transplant

Evidence (autologous bone marrow or peripheral SCT):

The failure of conventional therapy to cure myeloma has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hematopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hematopoietic recovery made it possible for investigators to test very large doses of chemotherapy.

Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:

• The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[74]
• Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hematopoietic stem cells impossible.[58]
• Younger patients in good health tolerate high-dose therapy better than older patients with a poor performance status.[75,76,77] However, fit patients older than 70 to 75 years can receive autologous SCT consolidation.[78,79]

Single autologous bone marrow or peripheral stem cell transplant

Evidence (single autologous bone marrow or peripheral SCT):

1. While some prospective randomized trials showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplant after induction chemotherapy compared with chemotherapy alone,[25,80,81,82][Level of evidence A1] other trials have not shown any survival advantage.[83,84,85,86,87,88][Level of evidence A1]
2. In a prospective randomized trial (NCT01208662), 722 patients aged 65 years or younger with newly diagnosed multiple myeloma received either VRd for three cycles followed by autologous SCT consolidation and two more cycles of VRd or VRd alone for eight cycles. Both groups received maintenance lenalidomide given continuously in the absence of disease relapse or unacceptable side effects.[89] At relapse, patients who received VRd only (without autologous SCT) were re-induced and offered transplant if they were still responding.
   • With a median follow-up of 76.0 months, the median PFS was shorter for patients in the nontransplant arm (42.0 months) than for patients in the transplant arm (67.5 months) (HR, 1.53; 95% CI, 1.23–1.91; P < .001).[89][Level of evidence B1]
   • The 5-year OS rate was not significantly different: 79.2% for patients in the nontransplant arm versus 80.7% for patients in the transplant arm (HR, 1.10; 95% CI, 0.73–1.65; P > 0.99).
   • Rates of grade 3 or 4 hematologic adverse events were significantly higher in the transplant arm (41.9%) than in the nontransplant arm (26.1%) (P < .001). Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were only reported in the transplant arm (10 cases).
   • Only 28% of patients who received RVd originally received autologous SCT at any time after the end of study treatment.
3. Three meta-analyses of almost 3,000 patients showed no survival advantage.[22,90,91][Level of evidence A1]
4. A meta-analysis was performed for all randomized clinical trials conducted between 2000 and 2021 that compared up-front autologous SCT with standard-dose therapy/consolidation. A total of 3,307 citations were screened: six trials were selected for PFS analysis and four trials were selected for OS analysis (2,959 patients).[92]
   • With a median follow-up of 3.1 to 7.8 years, patients with high-risk cytogenetics (t(4;14), t(14;16), and/or del(17p)) had a significant OS benefit from autologous SCT versus standard-dose therapy (HR, 0.66; 95% CI, 0.45–0.97; P = .03).[92][Level of evidence A2] No survival benefit was seen for patients with standard-risk cytogenetics.
   • Patients with high-risk disease (approximately 20% of the total) showed a significant PFS benefit from autologous SCT versus standard-dose therapy (HR, 0.52; 95% CI, 0.33–0.83). Patients with standard-risk disease also showed a PFS benefit from autologous SCT (HR, 0.65; 95% CI, 0.56–0.76).[92]

Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.[25,80,81,82,93] The role of autologous SCT has changed, from a mandated standard consolidation for those patients healthy enough to undergo it toward a therapeutic option, like any other, that offers approximately 2 years of increased PFS on average with defined toxicities. Incorporating, eliminating, delaying, or even replacing autologous SCT in the future (perhaps with chimeric antigen receptor T cells or bispecific antibodies) will be the subject of ongoing and upcoming clinical trials. Subgroups of patients may have a particular benefit from autologous SCT. Patients with a t(11;14) translocation may show differential benefit, as found in a retrospective review of 3,538 total patients in a dataset from the Center of International Blood and Marrow Transplant Research.[94] One meta-analysis of only four randomized clinical trials suggested an OS benefit for up-front autologous SCT in patients with high-risk cytogenetics.[92]

Tandem autologous bone marrow or peripheral stem cell transplant followed by autologous or allogeneic transplant

Another approach to high-dose therapy has been the use of two sequential infusions of high-dose therapy with stem cell support (tandem transplants).[95,96,97,98,99]

Evidence (tandem autologous bone marrow or peripheral SCT):

1. A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single autologous hematopoietic cell transplant with tandem autologous hematopoietic cell transplant.
   • There was no difference in OS (HR, 0.94; 95% CI, 0.77–1.14) or in event-free survival (EFS) (HR, 0.86; 95% CI, 0.70–1.05).[100][Level of evidence A2]
2. A prospective randomized trial of 758 patients who completed induction therapy in less than 12 months compared autologous SCT plus lenalidomide maintenance, tandem autologous SCT, and autologous SCT plus VRd maintenance.[101]
   • There was no difference in 38-month PFS (53.9%−58.5%) and OS (81.8%−85.4%) rates among these three randomized groups.[101][Level of evidence A1]
3. Five different groups have compared single or tandem autologous transplants with one autologous transplant followed by a reduced-intensity conditioning allograft from a human leukocyte antigen (HLA)-identical sibling; treatment assignment was based on the presence or absence of an HLA-identical sibling. The results have been discordant for survival in these nonrandomized trials.[102,103,104,105][Level of evidence C1]
4. Six clinical trials compared the outcomes of patients receiving tandem autologous transplant with those of patients receiving a reduced-intensity allogeneic SCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity allogeneic SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[106,107][Level of evidence A1]

A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants.[108] None of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.

Allogeneic bone marrow or peripheral stem cell transplant

Evidence (allogeneic bone marrow or peripheral SCT):

Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses after the infusion of donor lymphocytes.[109]

Favorable prognostic features included the following:

• Low tumor burden.
• Responsive disease before transplant.
• Application of transplant after first-line therapy.

Myeloablative allogeneic SCT has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality.[109,110,111] In one anecdotal series of 60 patients who underwent allogeneic SCT, six of the patients relapsed between 6 and 12 years, suggesting that late relapses still occur with this type of consolidation.[112]

The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[111] Since the introduction of lenalidomide and bortezomib, a trial exploring donor versus no donor comparison of autologous SCT versus autologous SCT and nonmyeloablative allogeneic SCT in 260 untreated patients showed no difference in PFS or OS.[113][Level of evidence C1] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[104,114][Level of evidence C1]

Six clinical trials compared the outcomes of patients receiving tandem autologous transplant with those of patients receiving a reduced-intensity autologous SCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity autologous SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[106,107][Level of evidence A1] Anecdotal long-term survivals have been reported for patients with therapy-related MDS, AML, acute lymphoblastic leukemia, or chronic myelomonocytic leukemia treated with allogeneic SCT.[115]

Salvage autologous bone marrow or peripheral stem cell transplant after relapse from first transplant

After relapsing more than 24 months after autologous SCT, 174 patients received reinduction therapy and were then randomly assigned to receive either high-dose melphalan and salvage autologous SCT or oral weekly cyclophosphamide.[116] With a median follow-up of 52 months, the median OS was superior for salvage autologous SCT: 67 months (95% CI, 55–not estimable) versus 52 months (42–60) (HR, 0.56; 0.35–0.90; P = .017).[116,117][Level of evidence A1]

In a retrospective review of 233 patients with refractory myeloma or relapsed and refractory myeloma who underwent a salvage autologous SCT, 81% of patients achieved a partial response (PR) or better.[118][Level of evidence C3]

Maintenance Therapy

Myeloma patients who respond to treatment show a progressive fall in the M protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. No clinical trial has directly compared a consolidation approach with a maintenance approach to assess which is better in prolonging remission and, ultimately, survival.[119] Most clinical trials employ one or both.[120,121] Maintenance trials with glucocorticosteroids [122,123] and with interferon [124] showed very minor improvements in remission duration and survival but with toxicities that outweighed the benefits. The efficacy and tolerability of thalidomide, lenalidomide, bortezomib, and ixazomib in the induction and relapse settings has made these agents attractive options in maintenance trials.[119]

Maintenance therapy (lenalidomide, ixazomib, daratumumab alone or in combination)

Evidence (maintenance therapy [lenalidomide, ixazomib, daratumumab alone or in combination]):

1. A prospective randomized trial of 460 patients with newly diagnosed multiple myeloma who had completed induction therapy and autologous SCT compared lenalidomide maintenance with placebo.[125]
   • With a median follow-up of 91 months, the median OS for the lenalidomide maintenance group was 113.8 months (95% CI, 100.4−not reached) versus 84.1 months for the placebo group (range, 73.8−106.0 months; HR, 0.61; 95% CI, 0.46−0.80; P = .0004).[125][Level of evidence A1]
   • This translated to a 5-year OS rate of 76% (95% CI, 70%−81%) for the lenalidomide group versus 64% (95% CI, 58%−70%) for the placebo group.
2. A prospective randomized trial evaluated lenalidomide maintenance in 1,917 patients newly diagnosed with or without transplant.[126]
   • With a median follow-up of 31 months, lenalidomide showed improved median PFS, 39 months (95% CI, 36−42) versus 20 months (range, 18−22) (HR, 0.46; 95% CI, 0.41−0.53; P < .0001), but lenalidomide failed to significantly improve the 3-year OS rate, 78.6% (95% CI, 75.6%−81.6%) versus 75.8% (72.4%−79.2%) (HR, 0.87; 95% CI, 0.73−1.05; P = .15).[126][Level of evidence B1]
3. A meta-analysis included 1,208 patients with newly diagnosed disease who underwent an autologous SCT.[127]
   • With a median follow-up of 79.5 months, OS was not reached for the lenalidomide maintenance group versus 86 months for the placebo or observation group (HR, 0.75; 95% CI, 0.63‒0.90; P = .001).[127][Level of evidence A2]
4. A meta-analysis of 7,730 patients in randomized clinical trials investigated lenalidomide or thalidomide maintenance in patients with newly diagnosed myeloma, with or without transplant.[128]
   • The immunomodulatory maintenance therapy significantly improved PFS (HR, 0.62; 95% CI, 0.57−0.67; P < .001), but failed to significantly improve OS (HR, 0.93; 95% CI, 0.85−1.01; P = .082).[128][Level of evidence B1]
5. A meta-analysis of 5,073 patients in randomized clinical trials investigated maintenance therapy in patients with newly diagnosed myeloma.[129]
   • Lenalidomide (with or without prednisone) significantly improved PFS (HR, 0.47; 95% CI, 0.39−0.55), but also failed to significantly improve OS (HR, 0.76; 95% CI, 0.51−1.16).[129][Level of evidence B1]
6. A randomized, prospective trial of lenalidomide maintenance versus no maintenance after induction with melphalan and prednisone or melphalan, prednisone, and lenalidomide included patients aged 65 years and older who were not eligible for transplant.[27]
   • The results showed a 66% reduction in the rate of progression (HR, 0.34; P < .001), which translated to an EFS of 31 months versus 14 months in favor of maintenance lenalidomide.[27][Level of evidence B1]
7. A randomized prospective trial (CASSIOPEIA [NCT02541383]) evaluated daratumumab maintenance versus no maintenance for patients with newly diagnosed myeloma. Patients had already received bortezomib, thalidomide, and dexamethasone with or without daratumumab as induction before autologous SCT.[130]
   • With a median follow-up of 35.4 months after maintenance randomization, the median PFS was not reached in the daratumumab arm and was 46.7 months (40.0–not evaluable) with observation only (HR, 0.53; 95% CI, 0.42–0.68; P < .0001).[130][Level of evidence B1]
8. A randomized prospective trial evaluated ixazomib maintenance versus no maintenance for patients with newly diagnosed myeloma who were not undergoing autologous SCT after induction therapy.[131]
   • With a median follow-up of 41 months, the median PFS favored ixazomib maintenance at 17.4 months versus 9.4 months (HR, 0.66; 95% CI, 0.54–0.80; P < .001).[131][Level of evidence B1]
9. A prospective trial (NCT02659293) evaluated maintenance therapy in patients with newly diagnosed melanoma who had received induction therapy and autologous SCT. Patients were randomly assigned to receive maintenance therapy with either 3 years of carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone.[132]
   • With a median follow-up of 33.8 months, the median PFS was 59.1 months for patients who received the triplet maintenance therapy and 41.4 months for patients who received lenalidomide alone (HR, 0.51; 95% CI, 0.31–0.86; P = .012).[132][Level of evidence B1]
   • Toxicity and efficacy data are not mature.[132]

All the trials and meta-analyses of lenalidomide maintenance showed a significant improvement in PFS, while OS was improved in one trial and one meta-analysis, both after autologous SCT. All of these trials showed an increase in myelodysplasia or acute leukemia from 3% to 7% for lenalidomide, consistent with other studies of lenalidomide. This increased risk is mostly seen in patients with previous exposure to alkylating agents. Doses of 5 mg to 15 mg a day have been used either continuously or with 1 week off every month. Genetic profiling may identify groups of patients who benefit from lenalidomide maintenance. Among 556 patients in the Myeloma XI trial (NCT01554852), those with del(1p), del(17p), and t(4;14) had a median PFS of 57.3 months with lenalidomide maintenance and 10.9 months with observation.[133] For patients unable to receive lenalidomide maintenance, ixazomib is a reasonable alternative. The combination of daratumumab plus lenalidomide is being evaluated in the GRIFFIN trial.[14] Although maintenance therapy with carfilzomib, lenalidomide, and dexamethasone resulted in improved PFS when compared with lenalidomide alone, the preliminary toxicity and efficacy results must mature before implementing this regimen.[132]

Proteasome inhibitor maintenance therapy

Evidence (proteasome inhibitor maintenance therapy):

1. In a prospective randomized trial of 656 newly diagnosed patients with at least a PR after standard induction therapy followed by autologous SCT, ixazomib (the oral proteasome inhibitor) was compared with placebo.[134]
   • With a median follow-up of 31 months, the ixazomib maintenance improved medial PFS, 26.5 months (95% CI, 23.7−33.8) versus 21.3 months (18.0−24.7) (HR, 0.72; 95% CI, 0.58−0.89; P = .0023).[134][Level of evidence B1] There was no increase in second malignancies with the proteasome inhibitor (3% for both groups).
2. In 511 previously untreated patients not eligible for transplant and aged 65 years or older, a randomized comparison of bortezomib, melphalan, prednisone, thalidomide and subsequent maintenance using bortezomib plus thalidomide versus bortezomib, melphalan, and prednisone (with no maintenance) showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.
   • With a median follow-up of 47 months, the 3-year PFS rate was 55% versus 33% (P < .01), and the 5-year OS rate was 59% versus 46% (P = .04).[135][Level of evidence A1]
   • Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during the induction or by the use of maintenance therapy with bortezomib and thalidomide.

Summary: After autologous SCT, patients are offered lenalidomide maintenance therapy based on the consistent PFS and occasional OS benefits previously described. But short-term and long-term toxicities, and financial toxicities, may prevent implementation.[136,137] High-risk patients, especially those with del(17p) or t(14;16), may require bortezomib maintenance (with or without lenalidomide), but this approach is not evidence-based and confirmatory clinical trials are required.[138,139]

Management and Prevention of Myeloma Bone Disease

Myeloma bone disease is a consequence of increased osteoclastic activity and agents that inhibit osteoclasts are an important component of myeloma therapy.[11] The bisphosphonates pamidronate and zoledronate are used most often, via intravenous infusion, but the RANKL monoclonal antibody inhibitor denosumab, given subcutaneously, is also effective, especially when renal dysfunction precludes the use of bisphosphonates.[10,11]

Zoledronate (bisphosphonate)

Evidence (zoledronate):

1. A randomized, prospective trial of 1,970 patients compared intravenous zoledronate with oral clodronate in newly diagnosed patients receiving induction chemotherapy with or without consolidation.[140]
   • With a median follow-up of 3.7 years, zoledronate improved median OS from 44.5 months to 50.0 months (HR, 0.84; 95% CI, 0.74–0.96; P = .0118).[140][Level of evidence A1]
   • In this trial, both bisphosphonates were continued until time of relapse. As expected, skeletal-related events were also reduced in the zoledronate group (27% vs. 35%; P = .004).[141,142]
2. The improvement of median OS with zoledronate was confirmed in a Cochrane network meta-analysis.[143][Level of evidence A2] This meta-analysis also showed that 6 to 15 patients need treatment with bisphosphonates to prevent one skeletal-related event.
3. A clinical trial of zoledronate given once a month compared with zoledronate given every 12 weeks showed noninferiority for the 12-week regimen in 1,822 patients with bone metastases from breast cancer, prostate cancer, or multiple myeloma.[144] However, this study included only 278 patients with myeloma, and evaluation of this subgroup was insufficiently powered to establish noninferiority for the 12-week regimen. Nonetheless, this trial is used as justification for implementing a 12-week schedule at the start of therapy or as soon as maximal response has been reached.
4. Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[145,146] For more information about osteonecrosis of the jaw, see Oral Complications of Cancer Therapies. These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.[147] Bisphosphonates are usually given intravenously on a monthly basis for 2 years and then extended at the same schedule or at a reduced schedule (i.e., once every 3–4 months), if there is evidence of active myeloma bone disease.[148,149] On the aforementioned randomized trial,[141] which showed OS advantage, patients received bisphosphonates monthly until time of relapse.

Pamidronate (bisphosphonate)

Evidence (pamidronate):

1. A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduced pathological fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treatment group vs. 51% in the placebo group after 21 months of therapy; P = .015).[150][Level of evidence B1] For more information about bisphosphonate therapy, see the Pharmacological Therapies for Pain Control section in Cancer Pain.
2. A double-blind, randomized, controlled trial of 504 patients with newly diagnosed multiple myeloma compared 30 mg of pamidronate to 90 mg of pamidronate. The study found that there was no difference in skeletal-related events, but there was less osteonecrosis (2 events vs. 8 events) seen in the low-dose group.[151][Level of evidence B3]
3. A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications (both were given for 2 years).[152][Level of evidence B1]

Denosumab (RANKL inhibitor)

Evidence (denosumab):

1. In a prospective randomized double-blind trial, 1,718 patients with newly diagnosed myeloma and at least one documented lytic bone lesion received either zoledronate or denosumab.[10]
   • The study met its primary end point of noninferiority for denosumab compared with zoledronate (HR, 0.98; 95% CI, 0.85‒1.14; P = .01 for noninferiority).[10]
   • Denosumab is significantly more expensive than the bisphosphonates, which are available in generic form.

Unlike bisphosphonates, the reversible mechanism of action for denosumab may result in rebound fractures if it is discontinued, although this theoretical concern for patients with myeloma may be mitigated by continuous maintenance therapy.[153]

Radiation therapy for bone lesions

Lytic lesions of the spine generally require radiation if any of the following are true:

1. They are associated with an extramedullary (paraspinal) plasmacytoma.
2. A painful destruction of a vertebral body occurred.
3. CT or MRI scans present evidence of spinal cord compression.[154]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy.

Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.[155]

Bisphosphonates are useful for slowing or reversing the osteopenia that is common in patients with myeloma.[150]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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93. Pineda-Roman M, Barlogie B, Anaissie E, et al.: High-dose melphalan-based autotransplants for multiple myeloma: the Arkansas experience since 1989 in 3077 patients. Cancer 112 (8): 1754-64, 2008.
94. Badar T, Hari P, Dávila O, et al.: African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States. Cancer 127 (1): 82-92, 2021.
95. Barlogie B, Tricot GJ, van Rhee F, et al.: Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135 (2): 158-64, 2006.
96. Barlogie B, Tricot G, Rasmussen E, et al.: Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107 (7): 2633-8, 2006.
97. Barlogie B, Zangari M, Bolejack V, et al.: Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma 6 (6): 469-74, 2006.
98. Bruno B, Rotta M, Patriarca F, et al.: Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 113 (14): 3375-82, 2009.
99. Rotta M, Storer BE, Sahebi F, et al.: Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 113 (14): 3383-91, 2009.
100. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al.: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 101 (2): 100-6, 2009.
101. Stadtmauer EA, Pasquini MC, Blackwell B, et al.: Autologous Transplantation, Consolidation, and Maintenance Therapy in Multiple Myeloma: Results of the BMT CTN 0702 Trial. J Clin Oncol 37 (7): 589-597, 2019.
102. Moreau P, Garban F, Attal M, et al.: Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood 112 (9): 3914-5, 2008.
103. Bruno B, Rotta M, Patriarca F, et al.: A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356 (11): 1110-20, 2007.
104. Gahrton G, Iacobelli S, Björkstrand B, et al.: Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood 121 (25): 5055-63, 2013.
105. Rosiñol L, Pérez-Simón JA, Sureda A, et al.: A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 112 (9): 3591-3, 2008.
106. Armeson KE, Hill EG, Costa LJ: Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant 48 (4): 562-7, 2013.
107. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al.: Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol 6: 2, 2013.
108. Naumann-Winter F, Greb A, Borchmann P, et al.: First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev 10: CD004626, 2012.
109. Reynolds C, Ratanatharathorn V, Adams P, et al.: Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 27 (8): 801-7, 2001.
110. Arora M, McGlave PB, Burns LJ, et al.: Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 35 (12): 1133-40, 2005.
111. Lokhorst H, Einsele H, Vesole D, et al.: International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 28 (29): 4521-30, 2010.
112. Sahebi F, Shen Y, Thomas SH, et al.: Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long-term follow-up study. Br J Haematol 160 (2): 199-206, 2013.
113. Lokhorst HM, van der Holt B, Cornelissen JJ, et al.: Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 119 (26): 6219-25; quiz 6399, 2012.
114. Giaccone L, Storer B, Patriarca F, et al.: Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 117 (24): 6721-7, 2011.
115. Vasudevan Nampoothiri R, Pasic I, Law AD, et al.: Allogeneic hematopoietic stem cell transplantation in patients with therapy-related hematologic malignancies developing after multiple myeloma. Eur J Haematol 108 (5): 430-436, 2022.
116. Cook G, Ashcroft AJ, Cairns DA, et al.: The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol 3 (7): e340-51, 2016.
117. Ahmedzai SH, Snowden JA, Ashcroft AJ, et al.: Patient-Reported Outcome Results From the Open-Label, Randomized Phase III Myeloma X Trial Evaluating Salvage Autologous Stem-Cell Transplantation in Relapsed Multiple Myeloma. J Clin Oncol 37 (19): 1617-1628, 2019.
118. Veltri LW, Milton DR, Delgado R, et al.: Outcome of autologous hematopoietic stem cell transplantation in refractory multiple myeloma. Cancer 123 (18): 3568-3575, 2017.
119. Ludwig H, Durie BG, McCarthy P, et al.: IMWG consensus on maintenance therapy in multiple myeloma. Blood 119 (13): 3003-15, 2012.
120. Benboubker L, Dimopoulos MA, Dispenzieri A, et al.: Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371 (10): 906-17, 2014.
121. Palumbo A, Gay F, Cavallo F, et al.: Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol 33 (30): 3459-66, 2015.
122. Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007.
123. Berenson JR, Crowley JJ, Grogan TM, et al.: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99 (9): 3163-8, 2002.
124. The Myeloma Trialists' Collaborative Group: Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113 (4): 1020-34, 2001.
125. Holstein SA, Jung SH, Richardson PG, et al.: Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol 4 (9): e431-e442, 2017.
126. Jackson GH, Davies FE, Pawlyn C, et al.: Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20 (1): 57-73, 2019.
127. McCarthy PL, Holstein SA, Petrucci MT, et al.: Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol 35 (29): 3279-3289, 2017.
128. Wang Y, Yang F, Shen Y, et al.: Maintenance Therapy With Immunomodulatory Drugs in Multiple Myeloma: A Meta-Analysis and Systematic Review. J Natl Cancer Inst 108 (3): , 2016.
129. Gay F, Jackson G, Rosiñol L, et al.: Maintenance Treatment and Survival in Patients With Myeloma: A Systematic Review and Network Meta-analysis. JAMA Oncol 4 (10): 1389-1397, 2018.
130. Moreau P, Hulin C, Perrot A, et al.: Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol 22 (10): 1378-1390, 2021.
131. Dimopoulos MA, Špička I, Quach H, et al.: Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. J Clin Oncol 38 (34): 4030-4041, 2020.
132. Dytfeld D, Wróbel T, Jamroziak K, et al.: Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol 24 (2): 139-150, 2023.
133. Panopoulou A, Cairns DA, Holroyd A, et al.: Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial. Blood 141 (14): 1666-1674, 2023.
134. Dimopoulos MA, Gay F, Schjesvold F, et al.: Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 393 (10168): 253-264, 2019.
135. Palumbo A, Bringhen S, Rossi D, et al.: Overall survival benefit for bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients. [Abstract] Blood 120 (21): A-200, 2012.
136. Olszewski AJ, Dusetzina SB, Eaton CB, et al.: Subsidies for Oral Chemotherapy and Use of Immunomodulatory Drugs Among Medicare Beneficiaries With Myeloma. J Clin Oncol 35 (29): 3306-3314, 2017.
137. Olszewski AJ, Dusetzina SB, Trivedi AN, et al.: Prescription Drug Coverage and Outcomes of Myeloma Therapy Among Medicare Beneficiaries. J Clin Oncol 36 (28): 2879-2886, 2018.
138. Mikhael JR: Maintenance Lenalidomide After Transplantation in Multiple Myeloma Prolongs Survival-In Most. J Clin Oncol 35 (29): 3269-3271, 2017.
139. van de Donk NWCJ, Yong K: Oral proteasome inhibitor maintenance for multiple myeloma. Lancet 393 (10168): 204-205, 2019.
140. Morgan GJ, Davies FE, Gregory WM, et al.: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376 (9757): 1989-99, 2010.
141. Morgan GJ, Child JA, Gregory WM, et al.: Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol 12 (8): 743-52, 2011.
142. Morgan GJ, Davies FE, Gregory WM, et al.: Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood 119 (23): 5374-83, 2012.
143. Mhaskar R, Redzepovic J, Wheatley K, et al.: Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev (3): CD003188, 2010.
144. Himelstein AL, Foster JC, Khatcheressian JL, et al.: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317 (1): 48-58, 2017.
145. Badros A, Weikel D, Salama A, et al.: Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24 (6): 945-52, 2006.
146. Kademani D, Koka S, Lacy MQ, et al.: Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 81 (8): 1100-3, 2006.
147. Lacy MQ, Dispenzieri A, Gertz MA, et al.: Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 81 (8): 1047-53, 2006.
148. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al.: Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 27 (30): 5015-22, 2009.
149. Terpos E, Sezer O, Croucher PI, et al.: The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 20 (8): 1303-17, 2009.
150. Berenson JR, Lichtenstein A, Porter L, et al.: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16 (2): 593-602, 1998.
151. Gimsing P, Carlson K, Turesson I, et al.: Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Lancet Oncol 11 (10): 973-82, 2010.
152. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003.
153. Chakraborty R, Majhail NS, Anwer F: Denosumab vs Zoledronic Acid for Bone-Targeted Therapy in Multiple Myeloma: What Are the Unanswered Questions? JAMA Oncol 5 (8): 1095-1096, 2019.
154. Rades D, Hoskin PJ, Stalpers LJ, et al.: Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys 64 (5): 1452-7, 2006.
155. Catell D, Kogen Z, Donahue B, et al.: Multiple myeloma of an extremity: must the entire bone be treated? Int J Radiat Oncol Biol Phys 40 (1): 117-9, 1998.

Treatment of Relapsed or Refractory Multiple Myeloma

Treatment Options for Relapsed or Refractory Multiple Myeloma

Relapses occur for almost all patients after induction therapy, consolidation with autologous stem cell transplant (SCT), and maintenance therapy. During initial therapy, some patients respond poorly or their disease progresses. The general strategy is to give new therapies sequentially as required. In fit patients, reinduction therapy with response may be consolidated with an autologous SCT or allogeneic SCT in some cases. Sometimes, when relapse occurs 1 year or more after initial therapy, the same drugs can be administered a second time.

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and a survival prognosis that is as good as that for responding patients.[1,2] When the stable nature of the disease becomes established, these patients can discontinue therapy until the myeloma begins to progress again. Other patients with primary refractory myeloma and progressive disease require a change in therapy. For more information, see the Treatment of Multiple Myeloma section.

For patients who respond to their initial therapy, the myeloma growth rate, as measured by the monoclonal (or myeloma) protein-doubling time, increases progressively with each subsequent relapse, and remission durations become shorter and shorter. Marrow function becomes increasingly compromised as patients develop pancytopenia and enter a refractory phase; occasionally, the myeloma cells dedifferentiate and extramedullary plasmacytomas develop. The myeloma cells may still be sensitive to chemotherapy, but the regrowth rate during relapse is so rapid that progressive improvement is not observed.

Combinations of drugs or single agents may be given sequentially as required. The goal is to avoid symptoms and adverse consequences of relapsing disease. However, the onset of therapy may be delayed because of slow disease progression and good performance status.

Treatment options for relapsed or refractory multiple myeloma include the following:

1. Monoclonal antibodies.
   • Daratumumab.
   • Elotuzumab.
   • Isatuximab.
2. Proteasome inhibitors.
   • Bortezomib.
   • Carfilzomib.
   • Ixazomib.
3. Chimeric antigen receptor (CAR) T-cell therapy.
4. Bispecific antibody therapy.
   • Teclistamab.
   • Talquetamab.
   • Elranatamab.
5. Immunomodulatory agents.
   • Pomalidomide.
   • Lenalidomide.
   • Thalidomide.
6. Chemotherapy (cytotoxic agents).
7. Selinexor.
8. Venetoclax.
9. BRAF/MEK inhibitors.
10. Corticosteroids.

Monoclonal antibodies

Daratumumab

Daratumumab is a monoclonal antibody targeting CD38 that can be given on its own but is usually given in combination with other drugs. Although it is given as an infusion, the subcutaneous formulation has equivalent efficacy and fewer adverse events.[3]

Evidence (daratumumab):

1. In the prospective CASTOR trial (NCT02136134), 498 previously treated patients were randomly assigned to receive either daratumumab, bortezomib, and dexamethasone (DVd) or bortezomib and dexamethasone (Vd).[4]
   • With a median follow-up of 72.6 months, the median overall survival (OS) was 49.6 months for patients in the DVd group and 38.5 months for patients in the Vd group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.59–0.92; P = .0075).[4][Level of evidence A1]
2. In the prospective POLLUX trial (NCT02076009), 569 previously treated patients were randomly assigned to receive either daratumumab, lenalidomide, and dexamethasone (DRd) or lenalidomide and dexamethasone (Rd).[5,6]
   • With a median follow-up of 79.7 months, the median OS was 67.6 months for patients in the DRd group and 51.8 months for patients in the Rd group (HR, 0.73; 95% CI, 0.58–0.91; P = .0044).[6][Level of evidence A1]
3. In a prospective trial (NCT03158688), 466 previously treated patients were randomly assigned in a 2:1 ratio to receive either daratumumab, carfilzomib, and dexamethasone or carfilzomib and dexamethasone.[7]
   • With a median follow-up of 27.8 months, the median progression-free survival (PFS) was 28.6 months (95% CI, 25.6–29.5) in the daratumumab group and 15.2 months (11.1–19.9) in the control arm (log-rank P < .0001).[8][Level of evidence B1]
4. In a prospective randomized trial, 1,304 previously treated patients received either daratumumab plus pomalidomide and dexamethasone (DPd) or pomalidomide and dexamethasone (Pd) alone.[9]
   • With a median follow-up of 16.9 months, the median PFS was 12.4 months (95% CI, 8.3–19.3) for patients who received DPd and 6.9 months (95% CI, 5.5–9.3) for patients who received Pd (HR, 0.63; 95% CI, 0.47–0.85; P = .0018).[9][Level of evidence B1]
5. Several phase I and phase II trials evaluated daratumumab as a single agent for relapsed or refractory multiple myeloma.[10,11,12]
   • With a median follow-up of 12 to 17 months, the overall response rate was 31% and 36%, with minimal response or stable disease in about 40% of patients.[10,11,12][Level of evidence C3]

In every prospective randomized trial to date, adding daratumumab to other active myeloma combination therapies showed improved responses and PFS when compared with the combination therapies alone.

Elotuzumab

Elotuzumab is a monoclonal antibody directed at SLAMF7 (signaling lymphocytic activation molecule F7).

Evidence (elotuzumab):

1. A prospective trial (ELOQUENT-3 [NCT02654132]) included 117 patients who had relapsed or refractory disease after both lenalidomide and a proteasome inhibitor. Patients were randomly assigned to receive either elotuzumab, pomalidomide, and dexamethasone (EPd) or Pd.[13]
   • With a median follow-up of 45 months, the median OS was 29.8 months (22.9–45.7) for patients who received EPd compared with 17.4 months (13.8–27.7) for patients who received Pd (HR, 0.59; 95% CI, 0.37–0.93; P = .0217).[13][Level of evidence A1]
2. In a prospective randomized trial (ELOQUENT-2 [NCT01239797]) of 646 patients with relapsed or refractory myeloma, elotuzumab was combined with lenalidomide and dexamethasone and compared with Rd alone.[14][Level of evidence A1]
   • With a median follow-up of 70.6 months, the 5-year PFS rate was 17% in the elotuzumab group and 11% in the Rd group (HR, 0.73; 95% CI, 0.60–0.89; P = .0014). The 5-year OS rate was 40% in the elotuzumab group and 33% in the Rd group (HR, 0.82; 95.4% CI, 0.68–1.00; P = .0408).[14]

Isatuximab

Isatuximab is a monoclonal antibody directed against CD38.

Evidence (isatuximab):

1. In a prospective randomized trial of 387 patients with relapsed or refractory disease, Pd was given with or without isatuximab.[15]
   • With a median follow-up of 35.3 months, the median OS was 24.6 months (95% CI, 20.3–31.3) for patients who received isatuximab plus PD and 17.7 months (95% CI, 14.4–26.2) for patients who received Pd alone (HR, 0.76; 95% CI, 0.57–1.01; 2-sided P = .056).
   • Similarly, the median PFS was 17.5 months (95% CI, 14.9–19.2) for the isatuximab group and 12.9 months (95% CI, 10.1–16.6) for the Pd group (HR, 0.76; 95% CI, 0.58–0.99; P = .020).[15][Level of evidence B1]
2. In a prospective randomized trial of 302 patients with relapsed or refractory disease, the combination of carfilzomib and dexamethasone was given with or without isatuximab.
   • With a median follow-up of 20.7 months, the 2-year PFS rate was 68.9% (95% CI, 60.7%–75.8%) for patients who received isatuximab group and 45.7% (95% CI, 35.2%–55.6%) for patients who received carfilzomib and dexamethasone alone (HR, 0.53; 99% CI, 0.32–0.89; 2-sided P = .0014).[16][Level of evidence B1]

There are no data comparing isatuximab with daratumumab, both of which target CD38. There are no data proving that isatuximab has efficacy in patients with disease that is resistant to daratumumab.

Proteasome inhibitors

Bortezomib

Bortezomib is the first-in-class proteasome inhibitor that is given subcutaneously on a weekly basis for 3 of every 4 weeks; the subcutaneous route is preferred to the intravenous (IV) route because it causes significantly less neuropathy and no loss of responsiveness.[17,18,19] Bortezomib is metabolized and cleared by the liver, and it appears to be active and well tolerated in patients with renal impairment.[20,21] More than 6 months after completion of bortezomib induction therapy, bortezomib can be given again with a 40% overall response rate, according to a meta-analysis of 23 phase II studies.[22][Level of evidence C3]

Evidence (bortezomib):

1. A prospective randomized study of 669 patients with relapsed myeloma compared bortezomib given by IV with high-dose oral dexamethasone.[23]
   • With a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR, 0.77; P = .027) even though the trial allowed crossover after relapse.[23][Level of evidence A1]
2. A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[24]
   • With a median follow-up of 7.0 months, 1-year OS rates were better in patients who received the combination (82% vs. 75%; P = .05).[24][Level of evidence A1]
3. A prospective, randomized trial of 260 newly diagnosed patients aged 65 years and older compared bortezomib, melphalan, and prednisone (VMP) with bortezomib, thalidomide, and prednisone (VTP).[25]
   • With a median follow-up of 72 months, the median OS favored the VMP arm, 63 months versus 43 months for the VTP group (HR, 0.67; 95% CI, 0.49–0.91; P = .01).[25][Level of evidence A1]

Carfilzomib

Carfilzomib is a second-generation proteasome inhibitor that is given by IV (unlike the subcutaneous route for bortezomib). Most studies have employed twice-weekly administration, but once-weekly administration appears at least equally efficacious and safe.[26]

Evidence (carfilzomib):

1. A randomized prospective trial included 578 patients with relapsed or refractory myeloma.[26]
   • The median PFS of patients who received carfilzomib once a week was significantly better, 11.2 months (95% CI, 8.6‒13.0 months), than twice a week, 7.6 months (95% CI, 5.8‒9.2 months) (HR, 0.69; 95% CI, 0.54‒0.83; P = .0029).[26][Level of evidence B1]
2. In a prospective randomized trial of 792 patients with relapsed or refractory myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone was compared with Rd.[27]
   • With a median follow-up of 67.1 months, median OS in the carfilzomib arm was 48.3 months (95% CI, 42.4‒52.8) versus 40.4 months (95% CI, 33.6‒44.4) (HR, 0.79; 95% CI, 0.67‒0.95; one-sided P = .009).[27][Level of evidence A1]
   • In a preplanned subgroup analysis, patients with high-risk cytogenetics (i.e., t(4;14), t(14;16), del(17p)) also had improved PFS for the triplet (23 months vs. 14 months; HR, 0.70; 95% CI, 0.43−1.16; one-sided P = .083) and response rates, but the carfilzomib combination did not abrogate the worse prognosis.[28][Level of evidence B3]
3. A prospective, randomized study (NCT01568866) of 929 patients compared carfilzomib and dexamethasone with bortezomib and dexamethasone.[29]
   • With a median follow-up of 37 months, the median OS was 47.6 months (95% CI, 42.5–not evaluable) for the carfilzomib combination compared with 40.0 months (95% CI, 32.6–42.3) for the bortezomib combination (HR, 0.79; 95% CI, 0.65–0.96; P = .020).[29][Level of evidence A1]
4. Cardiovascular adverse events such as heart failure, chest pain, and acute coronary syndrome (grade 3 or higher) occurred in 25% of patients, especially in the first 3 months of therapy.[30,31]
5. A systematic review and meta-analysis demonstrated that renal adverse events occurred in 21% of patients of patients who received carfilzomib, and 8.3% had grade 3 to 5 toxicities. Acute kidney injury was the most common renal toxicity.[32]

Ixazomib

Ixazomib is a second-generation proteasome inhibitor that is given orally on a weekly basis for 3 of every 4 weeks.

Evidence (ixazomib):

1. In a prospective, randomized trial involving 722 patients with relapsed or refractory myeloma, ixazomib combined with lenalidomide and dexamethasone was compared with a placebo combined with lenalidomide and dexamethasone.[33,34]
   • With a median follow-up of 2 years, the median PFS was 20.6 months in the ixazomib group versus 14.7 months for the placebo group (HR, 0.66; 95% CI, 0.47–0.93; P = .016).[33][Level of evidence B1]
   • Improved PFS was also seen for high-risk patients (defined by fluorescence in situ hybridization and cytogenetics).[34][Level of evidence B1]
   • No grade 3 or 4 neuropathy was seen in any patient treated with ixazomib.
   • With a median follow-up of 85 months, there was little difference in the median OS at 53.6 months for the ixazomib group and 51.6 months for the placebo group (HR, 0.939; P = 0.49).[35][Level of evidence B1 based on PFS, as noted above]
2. A prospective randomized trial (NCT01850524) included 705 patients with newly diagnosed, transplant-eligible multiple myeloma. The study compared ixazomib combined with lenalidomide and dexamethasone with a placebo combined with lenalidomide and dexamethasone.[36]
   • With a median follow-up of 53.3 to 55.8 months for each arm, the median PFS was 35.3 months in the ixazomib group versus 21.8 months in the placebo group (HR, 0.830; 95% CI, 0.676–1.018; P = .073).[36][Level of evidence B3] This difference did not meet statistical significance for PFS.

CAR T-cell therapy

CAR T-cell therapy is a cellular therapy for refractory and/or multiply relapsed myeloma. This therapy consists of autologous T cells transduced with an anti–B-cell maturation antigen (BCMA). This therapy has shown a 50% to 65% complete remission rate and a median PFS of 18 to 20 months in patients from highly selected nonrandomized series.[37,38,39,40,41,42,43][Level of evidence C3] On the basis of durable responses in these nonrandomized series, the U.S. Food and Drug Administration (FDA) approved the BCMA-directed CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel (cilta-cel) for patients with relapsed or refractory disease after four or more prior lines of therapy including lenalidomide or pomalidomide, bortezomib, and an anti-CD38 monoclonal antibody.[44] A review of the management of moderate-to-severe immune-related adverse events suggests immediate use of corticosteroids and supportive hospital care.[45] Other molecular targets and expanded clinical approaches are being investigated,[37,46][Level of evidence C3] even after prior noncellular anti-BCMA therapies.

Evidence (CAR T-cell therapy):

1. A randomized prospective trial included 419 patients with relapsed myeloma after one to three prior lines of treatment who also had lenalidomide-refractory disease. Patients received either CAR T-cell therapy with cilta-cel or standard-of-care at the discretion of physicians.[47]
   • With a median follow-up of 15.9 months, the 12-month PFS rate was 75.9% (95% CI, 69.4%–81.1%) in the cilta-cel group and 48.6% (95% CI, 41.5%–55.3%) in the standard-of-care group (HR, 0.26; 95% CI, 0.18–0.38; P < .001).[47]
   • No difference in OS was reported. Grade 3 or higher cytokine-release syndrome occurred in 1.1% of patients in the CAR T-cell therapy group, and no patients had grade 3 or higher neurotoxicity.

   CAR T-cell therapy is a reasonable option for patients with lenalidomide-refractory disease after one to three prior lines of therapy. However, the FDA approval for CAR T-cell therapy still mandates four lines of prior therapy.[44]

Bispecific antibody therapy

Bispecific antibodies target both CD3, which is on the surface of T cells, and either BCMA or GPRC5D (G protein–coupled receptor family C group 5 member D), both of which concentrate on the surface of myeloma cells.[44,48]

Teclistamab

Teclistamab is a T-cell-redirecting bispecific antibody.

Evidence (teclistamab):

1. In a phase I/II study (NCT03145181 and NCT04557098), teclistamab was given to 165 patients with relapsed or refractory myeloma who received at last four prior systemic treatments.[49]
   • With a median follow-up of 14.1 months, the overall response rate was 63.0%, with a complete response rate of 39.4%. The median PFS was 11.3 months (95% CI, 8.8–17.1).[49][Level of evidence C3]
   • Side effects included cytokine release syndrome in 72% of patients (grade 3 or 4 in only one patient) and hematologic toxicity (grade 3 or 4) in 61% of patients, including febrile neutropenia (44.8%).
2. Teclistamab was given to 157 patients with relapsed or refractory myeloma in a phase I study.[50][Level of evidence C3]
   • A total of 40 patients received the recommended phase II dose. With a median follow-up of 6.1 months, the overall response rate among these patients was 65%, with 58% achieving a very good partial response or better.
   • Side effects included cytokine release syndrome in 70% of patients (all grade 1 or 2) and hematologic toxicity (grade 3 or 4) in 40% of patients.

Talquetamab

Talquetamab is a T-cell-redirecting bispecific antibody that targets GPRC5D, a receptor highly expressed on plasma cells, along with CD3.

Evidence (talquetamab):

1. In a phase II study, talquetamab was given to 232 patients with relapsed or refractory myeloma who had received at least four prior systemic treatments.[51]
   • At a median follow-up of 11.7 months, the overall response rate was 73.6% (95% CI, 63%–82.4%). Approximately 85% of responders were still in remission by 9 months.[51,52][Level of evidence C3]
   • Cytokine release syndrome occurred in up to 89% patients and was grade 1 or 2 in all but one case. Skin-related events and dysgeusia occurred in 60% to 70% of patients.

Elranatamab

Elranatamab is a T-cell directing bispecific antibody targeting BCMA and CD3.

Evidence (elranatamab):

1. Elranatamab was given to 187 patients with relapsed or refractory myeloma who received at least four prior lines of therapy.[53]
   • With a median follow-up of 14.7 months, the objective response rate was 61% (95% CI, 51.8%–69.6%) and 35% of patients achieved a complete response. The 15-month PFS rate was 50.9% (95% CI, 40.9%–60.0%).[53][Level of evidence C3]

Summary: Patients with myeloma who have received at least four prior lines of therapy and are experiencing a slow relapse are often referred for CAR T-cell therapy because delays in production of the agent are less problematic, and because time receiving therapy is fixed and short-term, allowing a long duration therapy-free time after a response.[44] Patients who experience a quick relapse may benefit from an "off-the-shelf" bispecific antibody that results in similar response rates and durability of response, but this approach comes with the downside of required continual therapy.[44] The choice of bispecific antibody cannot be made based on any clinical evidence because of the lack of comparative trials. However, using products with different targets sequentially seems logical.

Immunomodulatory agents

Pomalidomide

Pomalidomide is a third-generation immunomodulatory agent. Pomalidomide is associated with some myelosuppression and an increased incidence of thromboembolic events, as noted with lenalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), but very little peripheral neuropathy compared with other agents.

Evidence (pomalidomide):

1. A prospective trial (ELOQUENT-3 [NCT02654132]) included 117 patients who had relapsed or refractory disease after both lenalidomide and a proteasome inhibitor. Patients were randomly assigned to receive either EPd or Pd.[13]
   • With a median follow-up of 45 months, the median OS was 29.8 months (22.9–45.7) for patients who received EPd compared with 17.4 months (13.8–27.7) for patients who received Pd (HR, 0.59; 95% CI, 0.37–0.93; P = .0217).[13][Level of evidence A1]
2. In a prospective trial of 559 patients with relapsed or refractory myeloma and previous treatment with lenalidomide, patients were randomly assigned to receive either pomalidomide plus bortezomib and dexamethasone or Vd.[54]
   • With a median follow-up of 15.9 months, the median PFS was 11.2 months (95% CI, 9.7−13.7) in the pomalidomide combination group and 7.1 months (95% CI, 5.9−8.9) in the Vd group (HR, 0.61; 95% CI, 0.49−0.77; P < .001).[54][Level of evidence B1]
3. For 302 patients with relapsed or refractory disease, Pd (40 mg weekly) was compared with a higher-dose dexamethasone regimen (40 mg daily for 4 days every 8 days).[55]
   • With a median follow-up of 10.0 months, the PFS was superior for the pomalidomide arm, at 4.0 months versus 1.9 months (HR, 0.48; 95% CI, 0.39–0.60; P < .0001)[55][Level of evidence B1]

Lenalidomide

Lenalidomide is a second-generation immunomodulatory agent. Lenalidomide is associated with increased incidence of thromboembolic events, as noted with pomalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), myelosuppression (more than pomalidomide), and neuropathy (less than thalidomide, but more than pomalidomide).[56,57,58,59,60]

A meta-analysis of 3,254 patients from seven randomized trials showed that lenalidomide was associated with an increased risk of hematologic second primary malignancies (3.1% in patients who received lenalidomide vs. 1.4% in those who did not; HR, 3.8; 95% CI, 1.15–12.62; P = .029).[61] This risk was confined to the combination of lenalidomide and melphalan (HR, 4.86; 95% CI, 2.79–8.46; P = .0001) but was not higher for lenalidomide with either cyclophosphamide or dexamethasone.[61] A retrospective review of almost 4,000 patients with relapsed or refractory disease who received lenalidomide in 11 clinical trials suggested an increased incidence of nonmelanoma skin cancers.[62]

As a result of predominant renal clearance, lenalidomide doses need to be reduced for patients with impaired renal function (creatinine clearance, 30–50: 10 mg every day; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis).[63] Uncontrolled trials have added clarithromycin (500 mg twice a day) to lenalidomide and dexamethasone, with reports of increased response rates.[64] Controlled studies are required to establish the value of this approach.

Evidence (lenalidomide):

1. Two prospective randomized and placebo-controlled studies of 351 and 353 patients with relapsed myeloma compared lenalidomide plus high-dose dexamethasone versus high-dose dexamethasone alone.[65,66]
   • With a median follow-up of 16 to 26 months, the median OS was 29.6 months or more (not reached in one trial) versus 20.2 months to 20.6 months in the control group (HR, 0.66; 95% CI, 0.45‒0.96; P = .03 in one study [65] and P < .001 in the other study).[66][Level of evidence A1]
2. A prospective, randomized study of 1,623 patients with transplant-ineligible, previously untreated myeloma compared lenalidomide and dexamethasone given until disease progression with a 72-week induction regimen with melphalan, prednisone, and thalidomide (MPT) for 72 weeks.[57]
   • With a median follow-up of 46 months, there was improved OS for the lenalidomide group, with 4-year OS rates of 52% versus 38% (HR, 0.72; 95% CI, 0.54–0.96; P = .02).[57][Level of evidence A1]

Thalidomide

Thalidomide is a first-generation immunomodulatory agent that is not often used because of its sedative and constipating effects, its significant and potentially debilitating neuropathy, and its thrombogenic effect (thromboprophylaxis is required).[67,68] Very little myelosuppression is seen with this agent.

Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses.[69] By using a low dose (50 mg by mouth every day), significant sedation, constipation, and neuropathy may be avoided. Thromboprophylaxis with aspirin, warfarin, or low-molecular-weight heparin is required; the choice of therapy depends on preexisting risk factors.[60]

Evidence (thalidomide):

1. A meta-analysis of 1,685 previously untreated patients considered six randomized prospective trials comparing thalidomide, melphalan, and prednisone versus melphalan and prednisone alone.[70]
   • The addition of thalidomide improved median OS from 32.7 months to 39.3 months (HR, 0.83; 95% CI, 0.73–0.94; P = .004).[70][Level of evidence A1]

Chemotherapy (cytotoxic agents)

Regimens:

• Melphalan and prednisone.[71,72]
• Vincristine + doxorubicin (infusion) + dexamethasone (VAD).[73,74]
• Cyclophosphamide (+ bortezomib + dexamethasone in the CyBorD regimen).[75,76]
• Pegylated liposomal doxorubicin (in a modified VAD regimen) [77,78] or combined with bortezomib and dexamethasone.[79]

Evidence (chemotherapy):

1. A meta-analysis of randomized prospective trials compared melphalan and prednisone with combinations of other cytotoxic agents. No differences were noted in PFS or OS.[72][Level of evidence A1]
2. The VAD regimen has shown activity in previously untreated patients and in relapsed patients, with response rates ranging from 60% to 80%.[73,74][Level of evidence C3] Because of logistics problems delivering a 96-hour infusion of doxorubicin, substitution with pegylated liposomal doxorubicin provides comparable response rates.[77,78]

Chemotherapy alone has been used to obtain a clinical remission after exhausting most of the new regimens, allowing improvement in performance status that may permit subsequent use of clinical trials investigating alternative therapies.

Selinexor

Selinexor is a selective inhibitor of nuclear export compounds that blocks exportin 1 (which activates tumor suppressor proteins), inhibits nuclear factor κB, and reduces oncoprotein mRNA translation.

Selinexor (evidence):

1. A randomized prospective trial included 402 patients with relapsed or refractory disease. Patients received either selinexor plus bortezomib and dexamethasone (SVd) or Vd.[80]
   • With a median follow-up of 13.2 months (SVd) or 16.5 months (Vd), the median PFS was 13.9 months (95% CI, 11.7–not evaluable) for patients who received SVd and 9.5 months (95% CI, 8.1–10.8) for patients who received Vd (HR, 0.70; 95% CI, 0.53–0.93; P = .0075).[80][Level of evidence B1]
   • Patients who received the selinexor combination had more thrombocytopenia (39% vs. 17%) and fatigue (13% vs. 1%).
2. In a phase IIB multicenter study, 122 patients with multiply resistant myeloma refractory to a proteasome inhibitor, an immunomodulatory agent, and daratumumab received oral selinexor and dexamethasone.[81] High-risk cytogenetics were present in 53% of patients. Patients had received a median of seven previous regimens.
   • A partial response or better was observed in 26% of patients (95% CI, 19%−35%), with a median duration of response of 4.4 months. The median PFS was 3.7 months; median OS was 8.6 months.[81][Level of evidence C3]
3. In a phase II study of 42 patients with relapsed or refractory disease, patients received SVd.[82]
   • A partial response or better was observed in 63% of patients, with a median PFS of 9.0 months.[82][Level of evidence C3]

Selinexor has significant side effects, including nausea, vomiting, fatigue, diarrhea, weight loss, poor appetite, and cytopenias. A descriptive retrospective study of 437 patients enrolled in clinical trials focused on aggressive medical support for these side effects.[83]

Venetoclax

Venetoclax is a selective BCL-2 inhibitor that induces apoptosis in myeloma cells, particularly in those with t(11;14), which expresses high levels of bcl2.

Evidence (venetoclax):

1. In a phase I study of 66 heavily pretreated patients with relapsed or refractory myeloma, 30 patients harbored a t(11;14) translocation.[84]
   • Among all 66 patients, the overall response rate was 21%, and 15% of patients achieved very good partial response or better. For those with t(11;14), the overall response rate was 40%, with 27% achieving a very good partial response or better.[84][Level of evidence C3]
2. In a prospective trial (BELLINI [NCT02755597]), 291 patients with relapsed or refractory myeloma were randomly assigned to receive venetoclax plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone.[85]
   • With a median follow-up of 18.7 months, the median PFS was 22.4 months for patients on the venetoclax arm versus 11.5 months for patients on the placebo arm (HR, 0.63; 95% CI, 0.44–0.90; P = .01).
   • OS favored the placebo arm because of treatment-related sepsis (HR, 2.03; 95% CI, 1.04–3.95; P = .034).[85][Level of evidence A1]
   • A prespecified analysis of 35 patients with t(11;14) translocation (20 patients who received venetoclax and 15 patients who received placebo) resulted in the median PFS not being reached for patients on the venetoclax arm versus 9.5 months for patients on the placebo arm (HR, 0.11; 95% CI, 0.02–0.56; P = .004).[85][Level of evidence B1]

BRAF/MEK inhibitors

Although activating BRAF mutations are rarely found in patients with newly diagnosed myeloma, these mutations appear in multiple-relapsing disease. Twelve such patients with a BRAF V600E mutation who received encorafenib and binimetinib had an overall response rate of 83.3%, a median PFS of 5.6 months, and an OS rate of 55% at 24 months.[86][Level of evidence C3]

Corticosteroids

Dexamethasone dosage has been evaluated in two prospective randomized trials.

1. A prospective, randomized study (ECOG-E4A03) of 445 previously untreated patients with myeloma compared lenalidomide and high-dose dexamethasone (40 mg on days 1–4, 9–12, and 17–20, every 28 days) with lenalidomide and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22, every 28 days).[56]
   • With a median follow-up of 36 months, the 2-year OS rate favored the low-dose dexamethasone arm (87% vs. 75%; P = .006), despite no difference in PFS.[56][Level of evidence A1]
   • The increased deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity.
   • Deep venous thromboses (DVTs) were also more frequent in the high-dose arm (25% vs. 9%). Patients in the low-dose dexamethasone arm with lenalidomide experienced less than 5% DVT with aspirin alone.
2. A prospective randomized trial of melphalan and prednisone versus melphalan and high-dose dexamethasone showed no difference in PFS or OS, but there was an increase in infection in the high-dose dexamethasone arm.[87]

On the basis of these trials, all ongoing trials and regimens use the low-dose dexamethasone schedule in combination with other therapeutic agents: 40 mg dexamethasone (oral or IV) weekly in fit patients, or 20 mg (oral or IV) in less-fit patients at higher risk for complications.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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67. Palumbo A, Cavo M, Bringhen S, et al.: Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 29 (8): 986-93, 2011.
68. Delforge M, Bladé J, Dimopoulos MA, et al.: Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11 (11): 1086-95, 2010.
69. Palumbo A, Facon T, Sonneveld P, et al.: Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111 (8): 3968-77, 2008.
70. Fayers PM, Palumbo A, Hulin C, et al.: Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood 118 (5): 1239-47, 2011.
71. Gregory WM, Richards MA, Malpas JS: Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 10 (2): 334-42, 1992.
72. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 16 (12): 3832-42, 1998.
73. Segeren CM, Sonneveld P, van der Holt B, et al.: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105 (1): 127-30, 1999.
74. Anderson H, Scarffe JH, Ranson M, et al.: VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71 (2): 326-30, 1995.
75. Reece DE, Rodriguez GP, Chen C, et al.: Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 26 (29): 4777-83, 2008.
76. Knop S, Liebisch H, Wandt H, et al.: Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: results of an interim analysis of the German DSMM Xia trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-8516, 2009.
77. Dimopoulos MA, Pouli A, Zervas K, et al.: Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 14 (7): 1039-44, 2003.
78. Rifkin RM, Gregory SA, Mohrbacher A, et al.: Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer 106 (4): 848-58, 2006.
79. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al.: Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 27 (30): 5015-22, 2009.
80. Grosicki S, Simonova M, Spicka I, et al.: Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet 396 (10262): 1563-1573, 2020.
81. Chari A, Vogl DT, Gavriatopoulou M, et al.: Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med 381 (8): 727-738, 2019.
82. Bahlis NJ, Sutherland H, White D, et al.: Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood 132 (24): 2546-2554, 2018.
83. Gavriatopoulou M, Chari A, Chen C, et al.: Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials. Leukemia 34 (9): 2430-2440, 2020.
84. Kumar S, Kaufman JL, Gasparetto C, et al.: Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 130 (22): 2401-2409, 2017.
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86. Giesen N, Chatterjee M, Scheid C, et al.: A phase 2 clinical trial of combined BRAF/MEK inhibition for BRAFV600E-mutated multiple myeloma. Blood 141 (14): 1685-1690, 2023.
87. Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007.

Key References for Plasma Cell Neoplasms (Including Multiple Myeloma)

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of plasma cell neoplasms and multiple myeloma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for plasma cell neoplasms and multiple myeloma. Listed after each reference are the sections within this summary where the reference is cited.

• Facon T, Kumar SK, Plesner T, et al.: Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 22 (11): 1582-1596, 2021. [PUBMED Abstract]

  Cited in:

  • Treatment of Multiple Myeloma
• Moreau P, Masszi T, Grzasko N, et al.: Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 374 (17): 1621-34, 2016. [PUBMED Abstract]

  Cited in:

  • Treatment of Relapsed or Refractory Multiple Myeloma
• Morgan GJ, Davies FE, Gregory WM, et al.: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376 (9757): 1989-99, 2010. [PUBMED Abstract]

  Cited in:

  • Treatment of Multiple Myeloma
• Palumbo A, Avet-Loiseau H, Oliva S, et al.: Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 33 (26): 2863-9, 2015. [PUBMED Abstract]

  Cited in:

  • Stage Information for Plasma Cell Neoplasms
• Sonneveld P, Chanan-Khan A, Weisel K, et al.: Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. J Clin Oncol 41 (8): 1600-1609, 2023. [PUBMED Abstract]

  Cited in:

  • Treatment of Multiple Myeloma
  • Treatment of Relapsed or Refractory Multiple Myeloma
• Rajkumar SV, Dimopoulos MA, Palumbo A, et al.: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15 (12): e538-48, 2014. [PUBMED Abstract]

  Cited in:

  • General Information About Plasma Cell Neoplasms
  • Treatment Option Overview for Plasma Cell Neoplasms

Latest Updates to This Summary (06 / 12 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage Information for Plasma Cell Neoplasms

Revised Table 3, Risk Groups for Multiple Myeloma (cited Davies et al. and Khot as references 15 and 16, respectively).

Treatment Option Overview for Plasma Cell Neoplasms

Revised the list of therapy options for patients with symptomatic myeloma to add infection prevention, which includes vaccination, antimicrobial prophylaxis, and immunoglobulin replacement (in a small subset of patients), per consensus guidelines from the International Myeloma Working Group (cited Raje et al. as reference 10).

Treatment of Multiple Myeloma

The Fit, transplant-eligible patients subsection was extensively revised.

Added text to state that genetic profiling may identify groups of patients who benefit from lenalidomide maintenance. Among 556 patients in the Myeloma XI trial, those with del(1p), del(17p), and t(4;14) had a median progression-free survival of 57.3 months with lenalidomide maintenance and 10.9 months with observation (cited Panopoulou et al. as reference 133).

Treatment of Relapsed or Refractory Multiple Myeloma

Revised text about the results of the ELOQUENT-2 study that compared elotuzumab and lenalidomide with lenalidomide and dexamethasone in 646 patients with relapsed or refractory melanoma (cited Dimopoulos et al. as reference 14).

Added text to state that the U.S. Food and Drug Administration (FDA) approved the B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel for patients with relapsed or refractory disease after four or more prior lines of therapy including lenalidomide or pomalidomide, bortezomib, and an anti-CD38 monoclonal antibody (cited Holstein et al. as reference 44).

Revised text to state that CAR T-cell therapy is a reasonable option for patients with lenalidomide-refractory disease after one to three prior lines of therapy. However, the FDA approval for CAR T-cell therapy still mandates four lines of prior therapy.

Added Bispecific antibody therapy as a new subsection.

Added BRAF/MEK inhibitors as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about treatment of plasma cell neoplasms (including multiple myeloma). It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment is:

• Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389362]

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Last Revised: 2024-06-12