Multiple Myeloma

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Practice Essentials

Multiple myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow, resulting in an overabundance of monoclonal paraprotein (M protein), destruction of bone, and displacement of other hematopoietic cell lines.[1] MM is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. See the image below.



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Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). ....

Signs and symptoms

MM can range from asymptomatic to severely symptomatic with complications requiring emergent treatment. Presenting signs and symptoms of MM include the following:

See Presentation for more detail.

Diagnosis

MM is often discovered through routine blood screening when patients are being evaluated for unrelated problems. In one third of patients, the condition is diagnosed after a pathologic fracture occurs, usually involving the axial skeleton.

Examination for MM may reveal the following:

In patients with MM and amyloidosis, the characteristic examination findings include the following:

Testing

The International Myeloma Workshop guidelines for standard investigative workup in patients with suspected MM include the following[1] :

Routine laboratory tests include the following:

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend a wider plasma cell FISH panel that includes del(13), del (17p13), t(4;14), t(11;14), t(14;16), t(14:20), 1q21 gain/1q21amplification, and 1p deletion. The NCCN also recommends measuring N-terminal pro B-type natriuretic peptide (NT-proBNP/BNP).[2]

Imaging studies

See Workup for more detail.

Management

Treatment choices are guided by the results of the diagnostic workup, which determine the initial classification of the patient's illness into one of the following disorders in the spectrum of MM:

Radiation therapy is the primary therapy for solitary plasmacytoma with or without marrow involvement. Surgery may be required if the lesion causes structural instability or neurologic compromise.[2]

Active surveillance or watchful waiting is recommended for patients with SMM or asymptomatic MM. However, patients at high risk of progression to active MM may benefit from early intervention.

Newly diagnosed patients with MM should be referred to a hematopoietic cell transplant (HCT) center to assess whether they are eligible for HCT and/or high-dose therapy. Transplant-eligible patients are initially treated with primary therapy (induction) followed by high-dose chemotherapy with autologous HCT.[2]  

Treatment regimens

Treatment regimens for symptomatic MM are generally based on the following patient categories:

Triplet regimens are the standard. All contain dexamethasone and many include lenalidomide. Clinicians treat many patients with high-dose therapy and HCT. Maintenance therapy is typically with lenalidomide, sometimes in combination with other agents (eg, carfilzomib, daratumumab).

For MM that relapses after more than 6 months, the regimen used for primary induction therapy can be repeated. For relapses that occur sooner,  a number of regimens are available, including chimeric antigen receptor (CAR) T-cell therapies. Regimen selection varies with early relapse (1-3 prior therapies) versus late relapse (> 3 prior therapies). Newer agents for relapses after ≥4 prior therapies include selinexor, teclistamab, elranatamab, and talquetamab. 

See Treatment and Medication for more detail.

Pathophysiology

The development of MM is commonly preceded by MGUS, a premalignant condition that results when plasma cells undergo mutations that restore their capacity for proliferation. In MGUS, these clonal plasma cells take up less than 10% of bone marrow. The serum protein value is less than 3 g/dL, and myeloma-related end-organ damage is absent. An intermediate disease stage between MGUS and MM, termed smoldering MM, is characterized by an M protein level of 3 g/dL or more and over 10% clonal plasma cells in bone marrow, but no symptoms of myeloma-related end-organ damage.[3]   .

A variety of cytogenetic abnormalities are found in MGUS and MM. Almost half of cases are hyperdiploid, usually with extra copies of the odd-numbered chromosomes (exception of chromosomes 1, 13, and 21). Most of the remainder are nonhyperdiploid and are characterized by a primary translocation involving the immunoglobulin heavy-chain (IgH) gene at 14q32.[3] In addition, virtually all cases involve dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. This genetic heterogeneity contributes to the rapid emergence of drug resistance in MM.[4]

Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.[5] This discovery has resulted in the expansion of treatment options.

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)-6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes (see below).

Skeletal processes

Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processes

The most common mechanisms of kidney injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[6, 7] Renal conditions that may be observed include the following:

Neurologic processes

The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processes

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with overproduction of IgG1, IgG3, or IgA. Sludging in the capillaries can result in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

Etiology

The precise etiology of MM has not yet been established. Roles have been suggested for a variety of factors, including genetic causes, environmental or occupational causes, MGUS, radiation, chronic inflammation, and infection.

Genetic causes

MM has been reported in two or more first-degree relatives and in identical twins, although no evidence suggests a hereditary basis for the disease. A study by the Mayo Clinic found MM in eight siblings from a group of 440 patients; these eight siblings had different heavy chains but the same light chains.

Some studies have shown that abnormalities of certain oncogenes, such as c-myc, are associated with development early in the course of plasma cell tumors and that abnormalities of oncogenes such as N-ras and K-ras are associated with development after bone marrow relapse. Abnormalities of tumor suppressor genes, such as TP53, have been shown to be associated with spread to other organs.[8]

Ongoing research is investigating whether human leukocyte antigen (HLA)-Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma.

Environmental or occupational causes

Case-controlled studies have suggested a significant risk of developing MM in individuals with significant occupational exposures in the agriculture, food, and petrochemical industries. An increased risk has been reported in farmers, especially in those who use herbicides and insecticides (eg, chlordane), and in people exposed to benzene and other organic solvents. There is conflicting evidence regarding long-term (> 20 y) exposure to hair dyes and possible increased risk of developing MM.[9]

MGUS/Smoldering multiple myeloma (SMM)

Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of three criteria:

MGUS is seen in 2-3% of the elderly White population. It is divided into the following three subtypes:

Patients with non-IgM MGUS have a risk of progression to MM at a rate of 1% per year. For these patients, risk factors for progression to MM are as follows:

Patients with IgM MGUS have a risk of progression to Waldenström macroglobulinemia and less frequently lymphoma or amyloid light chain (AL) amyloidosis. IgM MGUS rarely progresses to MM. Light-chain MGUS has a tendency to progress to light-chain MM, AL amyloidosis, or light-chain deposition disease.

A study by Wadhera et al examined secondary MGUS that developed in patients with MM. Of 1942 patients with MM, 128 (6.6%) developed a secondary MGUS at a median of 12 months from the diagnosis of MM. Overall survival was superior in patients with MM who developed secondary MGUS compared with the rest of the cohort.[10]

Smoldering MM is present when the serum M protein concentration is > 3 g/dL or the bone marrow plasma cell concentration is > 10% but there is no evidence of end-organ damage. Risk factors for progression of SMM to MM include any of the following:

The time to progression decreases with increasing numbers of risk factors, as follows:

Radiation

Radiation may play a role in some patients. An increased risk has been reported in atomic-bomb survivors exposed to more than 50 Gy: In 109,000 survivors of the atomic bombing of Nagasaki during World War II, 29 died from MM between 1950 and 1976. Some more recent studies, however, do not confirm that these survivors have an increased risk of developing MM.

A study of workers at the Oak Ridge Diffusion Plant in eastern Tennessee showed only a weak correlation of risk of MM to uranium exposure.[11]

Chronic inflammation

A relationship between MM and preexisting chronic inflammatory diseases has been suggested, but studies of a possible relationship between autoimmune diseases and MM risk have reported contradictory results. A Mendelian randomization study concluded that genetic susceptibility to primary sclerosing cholangitis might be causally related to a modestly increased risk of MM, but found no evidence of increased risk related to type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary biliary cirrhosis, or juvenile idiopathic arthritis.[12]

Infection

Human herpesvirus 8 (HH8) infection of bone marrow dendritic cells has been found in patients with MM and in some patients with MGUS.

Epidemiology

MM accounts for 10% of all hematologic cancers.[13, 14]  The American Cancer Society estimates that in the United States, approximately 36,110 new cases of MM (20,030 in men and 16,080 in women) will be diagnosed in 2025.[15] The lifetime risk of getting MM is approximately 1 in 108 for men and 1 in 133 for women (overall, 0.8%).[15, 16] Approximately 12,030 deaths from MM (6540 in men and 5490 in women) are expected to occur in the US in 2025.[15] Rates for new MM cases rose slightly over the last decade, from 7.0 per 100,000 persons in 2011 to 7.1 per 100,000 persons in 2021, while death rates declined slightly, from 3.4 to 2.8 per 100,000 from 2012 to 2022.[16]

In the US, the annual incidence of MM per 100,000 persons is 8.1 cases in White men, 5.1 cases in White women, 17.1 cases in Black men, and 13.0 cases in Black women. For Hispanics, the rates are 7.9 in men and 5.8 in women. Rates are lowest for Asians/Pacific Islanders, at 5.1 in men and 3.3 in women.[16]  According to a study of the ethnic disparities among patients with MM, Hispanics had the youngest median age at diagnosis (65 years) and Whites had the oldest (71 years). Asians had the best overall survival rates, while Hispanics had the worst.[17]

The median age at diagnosis of MM is 69 years. Less than 14% of patients are younger than 55 years, and only about 3% are younger than 45 years.[16]

Prognosis

MM is a heterogeneous disease, with survival ranging from 1 year to more than 10 years. Median survival in unselected patients with MM is 3 years. The 5-year relative survival rate is 61.1%.[16] Survival is higher in younger people and lower in the elderly.[8, 18]

The tumor burden and the proliferation rate are the two key indicators for the prognosis in patients with MM. Many schemas have been published to aid in determining the prognosis. One schema uses C-reactive protein (CRP) and beta-2 microglobulin (which is an expression of tumor burden) to predict survival, as follows[19] :

Poor prognostic factors include the following:

The prognosis by treatment is as follows:

Infections are an important cause of early death in MM. In a United Kingdom study, 10% of patients died within 60 days after diagnosis of MM, and 45% of those deaths were due to infection.[20] In a Swedish study, 22% of patients died of infection within the first year after diagnosis. The risk of both bacterial infections (eg, meningitis, septicemia, pneumonia) and viral infections (eg, herpes zoster, influenza) was seven times higher in patients with MM than in matched controls. The Swedish investigators also found that the risk of infections has increased in recent decades, and they argue that the use of more intensive treatment measures for MM (ie, newer drugs and high-dose chemotherapy with transplantation) has contributed to the increased risk.[21]

Patient Education

Patient education is very important in the management of MM. The International Myeloma Foundation (IMF) offers educational resources, a quarterly newsletter, and conferences. Patients or physicians can contact the IMF by phone at (800) 452-CURE (800-452-2873) in the United States and Canada or on the internet at International Myeloma Foundation.

Patient education should address, at a minimum, the following questions:

History

Presenting signs and symptoms of multiple myeloma (MM) include bone pain, pathologic fractures, weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord compression, and acute kidney injury. In approximately 30% of cases, MM is discovered through routine blood screening when patients are being evaluated for unrelated problems. Typically, a large gap between the total protein and the albumin levels observed on an automated chemistry panel suggests a problem (ie, protein minus albumin equals globulin).

Two thirds of patients complain of bone pain, commonly with lower back pain. This bone pain is frequently located in the back, long bones, skull, and/or pelvis. In one third of patients, MM is diagnosed after a pathologic fracture occurs; such fractures commonly involve the axial skeleton.

Patients may also complain of nonspecific constitutional symptoms related to hyperviscosity and hypercalcemia.

Bone pain

Bone pain is the most common presenting symptom in MM. Most case series report that 70% of patients have bone pain at presentation. The lumbar spine is one of the most common sites of pain.

Pathologic fractures and bone lesions

Pathologic fractures are very common in MM; 93% of patients have more than one site of bony involvement. A severe bony event is a common presenting issue.

Spinal cord compression

The symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities. Because spinal cord compressions in MM occur at multiple levels, comprehensive evaluation of the spine is warranted. Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis.

Bleeding

Occasionally, a patient may come to medical attention for bleeding resulting from thrombocytopenia. Rarely, monoclonal protein may absorb clotting factors and lead to bleeding.

Hypercalcemia

Confusion, somnolence, bone pain, constipation, nausea, and thirst are the presenting symptoms of hypercalcemia. This complication may be present in as many as 30% of patients with MM at presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in MM, its occurrence does not adversely affect survival.

Infection

Abnormal humoral immunity and leukopenia may lead to infection. Pneumococcal organisms are commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more common in patients with MM.

Hyperviscosity

Hyperviscosity may be associated with a number of symptoms, including generalized malaise, infection, fever, paresthesia, sluggish mentation, and sensory loss. Patients may report headaches and somnolence, and they may bruise easily, experience epistaxis, and have hazy vision. Patients with MM typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum. Occasionally, patients may have such a high volume of monoclonal protein that their hyperviscosity results in complications such as stroke or myocardial ischemia or infarction.

Neurologic symptoms

Carpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with MM. Some peripheral neuropathies have been attributed to MM. Long-term neurologic function is directly related to the rapidity of the diagnosis and the institution of appropriate therapy for MM.

Anemia

Anemia, which may be quite severe, is the most common cause of weakness in patients with MM.

Physical Examination

On head, ears, eyes, nose, and throat (HEENT) examination, fundoscopy may show exudative macular detachment, retinal hemorrhage, or cotton-wool spots. Pallor from anemia may be present. Ecchymoses or purpura from thrombocytopenia may be evident.

Bony tenderness is not uncommon in MM, resulting from focal lytic destructive bone lesions or pathologic fracture. Pain without tenderness is typical. Pathologic fractures may be observed. In general, painful lesions that involve at least 50% of the cortical diameter of a long bone or lesions that involve the femoral neck or calcar femorale are at high (50%) risk for a pathologic fracture. The risk of fracture is lower in upper-extremity lesions than in lower-extremity lesions. Even a small cortical defect can decrease torsional strength by as much as 60% (stress riser effect).

Neurologic findings may include a sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), neuropathy, myopathy, a Tinel sign, or a Phalen sign due to carpel tunnel compression secondary to amyloid deposition.

Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not uncommon. Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions.

On evaluation of the abdomen, hepatosplenomegaly may be discovered. Cardiovascular system examination may reveal cardiomegaly secondary to immunoglobulin deposition.

Amyloidosis may develop in some patients with MM. The characteristic physical examination findings that suggest amyloidosis include the following:

The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition. The swelling feels hard and rubbery. Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules.

Macroglossia may occur secondary to amyloid deposition in the tongue and is a common finding in patients with amyloidosis (see the image below).



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Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Skin lesions that have been described as waxy papules or nodules may occur on the torso, ears, or lips.

Post-proctoscopic peripalpebral purpura strongly suggests amyloidosis. The term originated in the time when rectal biopsy was the initial procedure of choice for diagnosing amyloidosis, and the hemodynamic effect of the procedure—comparable to a prolonged Valsalva maneuver—would lead to burst capillaries in patients with amyloid infiltration of the vessels around the eyes, Patients also may develop these raccoonlike dark circles around their eyes as a result of coughing, vomiting, or forced expiration during spirometric testing).

Complications

Kidney failure and insufficiency are seen in 25% of patients with MM,[22]  and may reflect any of the following:

Anemia, neutropenia, or thrombocytopenia is due to bone marrow infiltration of plasma cells. Thrombosis and Raynaud phenomenon due to cryoglobulinemia may be present.

Bone disease may result in the following:

Radiculopathy and/or cord compression may occur because of skeletal destruction and nerve compression.

Bacterial infection may develop; it is the leading cause of death in patients with myeloma. The highest risk is in the first 2-3 months of chemotherapy.

Purpura, retinal hemorrhage, papilledema, coronary ischemia, seizures, and confusion may occur as a result of hyperviscosity syndrome.

Hypercalcemia may cause polyuria and polydipsia, muscle cramps, constipation, and a change in the patient’s mental status.

Approach Considerations

The workup in patients suspected to have multiple myeloma (MM) includes the following[1, 2, 26, 27, 28] :

Consider the risk of acute kidney injury, especially in the setting of contrast medium injection for imaging studies. Take care to limit patients’ exposure and maintain hydration.

Blood Studies

Perform a complete blood count (CBC) to determine if the patient has anemia, thrombocytopenia, or leukopenia. The CBC and differential may show pancytopenia. The reticulocyte count is typically low. Peripheral blood smears may show rouleaux formation.

The erythrocyte sedimentation rate (ESR) and C-reactive protein level are typically increased. Coagulation studies may yield abnormal results.

Obtain a comprehensive metabolic panel to assess levels of the following:

The National Comprehensive Cancer Network recommends measuring N-terminal pro B-type natriuretic peptide (NT-proBNP/BNP).[2] Elevated levels indicate increased risk of poor outcome.

Urine Studies

Obtain a 24-hour urine collection for quantification of protein and creatinine clearance. Quantification of proteinuria is useful for the diagnosis of MM (> 1 g of protein in 24 h is a major criterion) and for monitoring the response to therapy. Creatinine clearance can be useful for defining the severity of the patient’s kidney impairment.

Urinary protein electrophoresis is performed for detection of Bence Jones proteins of the Bence Jones protein (ie, lambda light chains), followed by immunofixation electrophoresis for confirmation.

Electrophoresis and Immunofixation

Serum protein electrophoresis (SPEP) is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed). Urine protein electrophoresis (UPEP) is used to identify the presence of the Bence Jones protein in urine. Immunofixation is used to identify the subtype of protein (ie, IgA lambda).

National Comprehensive Cancer Network (NCCN) guidelines also recommend the use of serum free light chain assay and plasma cell fluorescence in situ hybridization (FISH) for del 13, del 17p13, t(4;14), t(11;14), 1q21 amplification as part of the initial diagnostic workup.[2]

Chemical screening, including calcium and creatinine SPEP, immunofixation, and immunoglobulin quantitation, may show azotemia, hypercalcemia, an elevated alkaline phosphatase level, and hypoalbuminemia. A high lactate dehydrogenase (LDH) level is predictive of an aggressive lymphomalike course.

SPEP is a useful screening test for detecting M proteins. An M component is usually detected by means of high-resolution SPEP. The kappa-to-lambda ratio has been recommended as a screening tool for detecting M-component abnormalities. An M-component serum concentration of 30 g/L is a minimal diagnostic criterion for MM. In about 25% of patients, M protein cannot be detected by using SPEP.

Routine urinalysis may not indicate the presence of Bence Jones proteinuria. Therefore, a 24-hour urinalysis by means of UPEP or immunoelectrophoresis may be required. UPEP or immunoelectrophoresis can also be used to detect an M component and kappa or lambda light chains. The most important means of detecting MM is electrophoretic measurement of immunoglobulins in both serum and urine.

Quantitative Immunoglobulin Levels (IgG, IgA, IgM)

Suppression of nonmyelomatous immunoglobulin is a minor diagnostic criterion for MM. The level of MM protein (ie, M protein level), as documented by the immunoglobulin level, can be useful as a marker to assess the response to therapy.

Beta-2 Microglobulin and C-Reactive Protein

Beta-2 microglobulin is a surrogate marker for the overall body tumor burden. The level of beta-2 microglobulin is increased in patients with renal insufficiency without MM, which is one reason that it is a useful prognosticator in MM.[19] (See Prognosis.) Patients with MM and impaired renal function have a worse prognosis.

C-reactive protein (CRP) is a surrogate marker of interleukin-6 (IL-6) activity. IL-6 is often referred to as the plasma cell growth factor. Like beta-2 microglobulin, CRP is useful for prognostication.[19] (See Overview/Prognosis.)

Serum Viscosity

Check the serum viscosity in patients with central nervous system (CNS) symptoms, nosebleeds, or very high M protein levels. These findings may indicate hyperviscosity syndrome.

Imaging Studies

Lytic bone lesions are classified as a myeloma-defining event, and skeletal imaging studies are a mandatory part of the initial workup for multiple myeloma (MM). Lytic lesions appear as multiple, rounded, punched-out areas, most often in the skull (see the image below), vertebral column, ribs, and/or pelvis. Less common but not rare sites of involvement include the long bones.



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Radiograph of the skull demonstrating a typical lytic lesion in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematolo....

Historically, a skeletal survey with plain radiography was used to assess bone involvement in MM, but whole-body low-dose CT—alone or in combination with PET— has proved significantly more sensitive and is currently recommended by International Myeloma Working Group (IMWG), European Hematology Association–European Society for Medical Oncology (EHA-ESMO), and National Comprehensive Cancer Network (NCCN) guidelines.[29, 2, 27] However, a plain-radiography skeletal survey is acceptable if those other modalities are unavailable.[29]  

IMWG and EHA-ESMO guidelines consider fluorodeoxyglucose (FDG) PET/CT an alternative to whole-body CT.[29, 27]  NCCN guidelines list FDG-PET/CT as the preferred modality for initial imaging.[2]

If the CT or FDG-PET/CT studies are negative or inconclusive, all the guidelines recommend whole-body noncontrast MRI; if whole-body MRI is not available, MRI of the spine and pelvis may be used. A negative finding on MRI helps to distinguish smoldering MM from MM by confirming the absence of focal bone marrow lesions.[29, 2, 27]

For follow-up of smoldering MM, annual imaging with noncontrast MRI, FDG-PET/CT, low-dose CT can be used. IMWG guidelines suggest that clinicians may consider alternating whole-body MRI with whole-body CT in this setting, as the two modalities have complementary findings.[29]

FDG-PET/CT, low-dose CT, and whole-body noncontrast MRI are also used for follow-up of MM and assessing response to treatment.[2, 29, 27]

Do not use bone scans to evaluate MM. Cytokines secreted by MM cells suppress osteoblast activity; therefore, typically, no increased uptake is observed. On technetium bone scanning, more than 50% of lesions can be missed.[29]

Also see the topic Multiple Myeloma Imaging.

Bone Aspiration and Biopsy

MM is characterized by an increased number of bone marrow plasma cells. Plasma cells show low proliferative activity, as measured by using the labeling index. This index is a reliable parameter for the diagnosis of MM. High values are strongly correlated with progression of the disease.

Obtain bone marrow aspirate and biopsy samples from patients with MM to calculate the percentage of plasma cells in the aspirate (reference range, up to 3%) and to look for sheets or clusters of plasma cells in the biopsy specimen. Bone marrow biopsy enables a more accurate evaluation of malignancies than does bone marrow aspiration.

Histologic Findings

Plasma cells are 2-3 times larger than typical lymphocytes; they have eccentric nuclei that are smooth (round or oval) in contour with clumped chromatin and have a perinuclear halo or pale zone (see the image below). The cytoplasm is basophilic.



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Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). ....

Many MM cells have characteristic, but not diagnostic, cytoplasmic inclusions, usually containing immunoglobulin. The variants include Mott cells, Russell bodies, grape cells, and morula cells. Bone marrow examination reveals plasma cell infiltration, often in sheets or clumps (see the image below). This infiltration is different from the lymphoplasmacytic infiltration observed in patients with Waldenstrom macroglobulinemia.



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Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hem....

Analysis of bone biopsy specimens may reveal plasmacytic, mixed cellular, or plasmablastic histologic findings. Approximate median survival by histologic type is as follows:

Cytogenetic Analysis

Cytogenetic analysis of the bone marrow may contribute significant prognostic information in multiple myeloma. In newly diagnosed MM, cytogenetic abnormalities that are considered to confer high risk of progression include the following[2] :

The most significant cytogenetic abnormality appears to be deletion of 17p13. This abnormality is associated with shorter survival, more extramedullary disease, and hypercalcemia. This locus is the site of the TP53 tumor suppressor gene. Chromosome 1 abnormalities and MYC defects are also significant prognostic factors in multiple myeloma.

Although not as well defined as in other hematologic malignancies, such as acute leukemia, risk-adapted therapy based on cytogenetic abnormalities is at the forefront of myeloma research.

Staging

Staging is a cumulative evaluation of all of the diagnostic information garnered and is a useful tool for stratifying the severity of patients’ disease. Currently, two staging systems for multiple myeloma are in use: the Salmon-Durie system, which has been widely used since 1975; and the International Staging System, developed by the International Myeloma Working Group and introduced in 2005.[30, 31]  Revisions of the International Staging System, published in 2015 and 2022, added genetic information to the standard laboratory tests.[32, 28]  See also Multiple Myeloma Staging.

Salmon-Durie staging system

The Salmon-Durie classification of MM is based on three stages and additional subclassifications.

In stage I, the MM cell mass is less than 0.6 × 1012 cells/m2, and all of the following are present:

In stage II, the MM cell mass is 0.6-1.2 × 1012 cells/m2 or more. The other values fit neither those of stage I nor those of stage III.

In stage III, the MM cell mass is >1.2 × 1012 cells/m2, and all of the following are present:

Subclassification A includes relatively normal kidney function (serum creatinine  < 2 mg/dL), whereas subclassification B includes abnormal kidney function (serum creatinine > 2 mg/dL)

Median survival is as follows:

Disease in subclassification B has a significantly worse outcome (eg, 2-12 mo survival in 4 separate series).

International Staging System

The International Staging System (ISS) of the International Myeloma Working Group is also based on three stages.

Stage I consists of the following:

Stage II consists of the following:

Stage III consists of the following:

Median survival is as follows:

Revised International Staging System

In the 2015 revision of the ISS (R-ISS), stage I comprises all of the following[32] :

Stage II consists of all other possible combinations of ISS criteria, chromosomal abnormalities, and LDH other than those of stage I or III.

Stage III consists of the following:

Second Revised International Staging System

The second revision of the International Staging System (R2-ISS), which has been validated only in newly diagnosecomprises four stages.[28] R2-ISS assigns a numerical value to each risk factor based on its influence on overall survival, as follows: 

Stage I - Low risk (0 points):

Stage II - Low-intermediate risk (0.5 to 1 point):

Stage III - Intermediate-high risk :

Stage IV - High risk

Survival

With R2-ISS, median overall survival (OS) and progression-free survival (PFS) are as follows[28] :

Approach Considerations

Overall, the treatment of multiple myeloma (MM) is complex: options include a variety of drug combinations, including quadruplet and triplet regimens; autologous stem cell transplantation; and chimeric antigen receptor (CAR) T-cell therapies for relapsed or refractory MM; along with adjunctive radiation and surgical care as needed.[33] Recommended treatment strategies vary, depending on whether the patient is fit and in good or well-controlled health; or less fit with significant comorbidities or of advanced age (≥80 years); and whether the disease is standard risk or high risk.[34]  

The approach to newly diagnosed MM is as follows:

Smoldering multiple myeloma (SMM) is managed with surveillance in most cases. WIth high-risk SMM, however, treatment with lenalidomide may be considered, as it may significantly prolong time to progression.[35, 36]

Although advances in treatment have dramatically improved survival in recent decades, MM remains incurable. The term functional cure has been proposed for patients who survive long enough to die from other causes, but that can be measured only in retrospect.[37]

Adjunctive therapy for MM includes radiation therapy to target areas of pain, impending pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (primary and secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture). Evidence suggests that it may be effective in treating bone pain and in decreasing the likelihood of lesion recurrence.[38, 39, 40]

Adjunctive therapy may also include any of the following, as appropriate:

For a summary of treatment approaches to MM, see Multiple Myeloma Treatment Protocols.

Smoldering Multiple Myeloma

Smoldering MM may follow one of three paths: an estimated 25% of cases never progress to symptomatic disease, while some progress slowly and others develop into over MM in less than 2 years. Risk models for progression have been developed but remain imperfect, so close surveillance remains the standard of care.[37]

National Comprehensive Cancer Network (NCCN) guidelines, while advising clinical trial participation, recommend observation every 3 to 6 months in patients with low-risk smoldering MM and every 3 months in high-risk cases, as clinically indicated, along with imaging studies annually or as needed.[2]  

Laboratory studies and procedures

The NCCN-recommended laboratory tests for surveillance of smoldering MM include the following[2] :

Vaxman and Gertz suggest a variable schedule for surveillance, with the following tests performed every 3 to 6 months[37] :

The following tests would be performed every 12 months:

If the hemoglobin concentration decreases, these authors recommend the following:

If  progression is suspected, patients should undergo bone marrow biopsy and bone marrow aspiration, with fluorescence in situ hybridization, single-nucleotide polymorphism array, next-generation sequencing, or multi-parameter flow cytometry.[2, 37]

Imaging studies

The NCCN recommends imaging studies annually or as needed. These may be with noncontrast whole-body magnetic resonance imaging, low-dose computed tomography, or fluorodeoxyglucose positron emission tomography (FDG-PET/CT); ideally, studies should be with the same technique as the one used at diagnosis.[2]

In patients with suspected smoldering MM whose initial whole-body MRI is negative, the International Myeloma Working Group (IMWG) recommends follow-up with annual MRI scans. For those whose MRI shows a single unequivocal focal lesion, The IMWG recommends alternating whole-body MRI and whole-body low-dose CT every 6 months. The risk that smoldering MM will progress to MM decreases over time. Consequently, the IMWG advises that if, after 5 years of monitoring, no signs of progression have occurred, regular imaging can be reduced or stopped, especially in patients without high-risk features.[29]

Lenalidomide

Patients with high-risk smoldering MM may be considered for lenalidomide treatment.[2] In a phase III trial of patients with high-risk SMM, the PETHEMA group found evidence of benefit from treatment with lenalidomide versus observation. After a median follow-up of 40 months, study patients who were randomized to lenalidomide and dexamethasone induction followed by lenalidomide maintenance demonstrated significantly prolonged median time to progression (median not reached vs 21 months) and higher 3-year survival rate (94% vs. 80%).[35]

Lenalidomide as single-agent therapy (without dexamethasone induction) may also slow progression of SMM to MM. A phase III trial in 182 patients found that after 3 years, SMM had not progressed to MM in 91% of patients receiving lenalidomide, compared with 66% of those who underwent observation only.  Many patients stopped taking lenalidomide early due to adverse effects (eg, fatigue, neutropenia); however, preliminary results suggest that even a short course of treatment may be beneficial.[36]

Chemotherapy and Immunotherapy

The first step before starting therapy in MM is to determine whether a patient is a candidate for autologous stem cell transplantation (ASCT). Eligibility depends primarily on the patient’s age and comorbidities. Typically, age of 65 years is used as a cut-off point for transplant eligibility. Thus, treatment for MM is best looked at in terms of the following three categories of patients:

Young, newly diagnosed patients who are potential transplant candidates

For induction, patients in good or well-controlled health receive approximately 3–4 cycles of therapy. Historically, the gold standard regimen was melphalan plus prednisone (MP); however, MP and other two-drug (doublet) regimens have fallen out of favor for induction therapy,[41] and are more often used for patients whose poor performance status or frailty makes them ineligible for transplant, although a third drug can be added if their performance improves.[2] Current guidelines favor a four-drug (quadruplet) or three-drug (triplet) regimen for induction. The most commonly used regimens include the following[34] :

The CyBorD regimen is preferred for patients with significant kidney insufficiency. If kidney function recovers rapidly, some clinicians switch to VRd.

After induction therapy, ASCT candidates undergo stem cell harvest. Frontline ASCT can then be performed, or the patient may resume induction therapy, with ASCT delayed until first relapse.[33]  Maintenance therapy is typically with lenalidomide, to which carfilzomib or daratumumab may be added.[2]

Assessing response

Originally, gauging response to MM treatment was based on declines in serum and urine levels of monoclonal proteins and assessment of bone marrow. In 2016, the International Myeloma Working Group published response criteria that also include more sensitive laboratory and imaging techniques.[42]  The criteria classify response as follows:

In addition, the International Myeloma Working Group established criteria for minimal residual disease in patients with complete response.[42]

Regimens with thalidomide

Thalidomide has proved effective against MM. Currently, however, its use is generally limited to inclusion in combination regimens for aggressive MM, such as dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/bortezomib (VTD-PACE).[2]

The toxicity of thalidomide is predominantly sensory neuropathy. In addition, because of the drug’s teratogenicity, close monitoring is required to avoid inadvertent administration during pregnancy.

Regimens with lenalidomide

An analogue of thalidomide, lenalidomide (Revlimid) has become a standard component of MM therapy. Lenalidome received US Food and Drug Administration (FDA) approval in 2006 for use in patients with MM who have received at least one prior therapy. FDA approval was expanded in 2015 to include the use of lenalidomide, in combination with dexamethasone, for treatment of newly diagnosed MM, based on results of the FIRST trial,[43, 44]  and further expanded in 2017 to include maintenance therapy following ASCT.[45]

Patients tolerate lenalidomide therapy well, and nausea is usually minimal. Patients typically experience total alopecia, but other adverse effects (eg, peripheral neurotoxicity, constipation) are usually mild. Pancytopenia is expected, but is not severe enough to require hospitalization for infection or transfusion unless the patient also has some other cause of bone marrow suppression. More serious adverse effects include venous or arterial thrombosis and increased isk of second primary malignancies after ASCT.[37]

Because of the significantly increased risk for thrombotic events, many physicians incorporate anticoagulation strategies in their management. A study by Palumbo et al determined that aspirin and low-dose warfarin had similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths in patients with myeloma receiving thalidomide-based regimens compared with low-molecular weight heparin, except in elderly patients.[46] In addition, the NCCN recommends that clinicians consider harvesting peripheral blood stem cells before patients have prolonged exposure to lenalidomide.[2]

Regimens with bortezomib

Bortezomib (Velcade), a proteosome inhibitor, has shown striking activity against MM. Objective responses as high as 27.7% in patients with relapsed and heavily pretreated MM[47] led to its approval by the FDA in 2003.

A phase 3 study by Durie et al in 525 patients with previously untreated MM reported that the addition of bortezomib to lenalidomide and dexamethasone improved median progression-free survival from 30 to 43 months, improved median overall survival from 64 to 75 months, and improived overall response rates from 722% to 82%.[48] This regimen has been shown to be active not only before but also after ASCT. Following high-dose therapy and ASCT, the rate of very good partial response or better continued to favor bortezomib plus dexamethasone. This benefit was observed independent of beta-2 microglobulin or adverse cytogenetic risk groups.

A phase 2 study of the CyBorD regimen in 33 patients with newly diagnosed MM reported that in the 28 patients who completed all four cycles of therapy, the complete or near-complete response (CR/nCR) rate was 46% and very good partial response or better (≥VGPR) rate was 71%. Twenty three patients underwent ASCT, with CR/nCR in 70% and ≥VGPR in 74% through day 100.[49]

Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and kidney failure. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia. Despite these results, the exact timing of bortezomib administration in the treatment plan of patients with newly diagnosed MM is still evolving through ongoing research.

Bortezomib can be administered by either the intravenous (IV) or the subcutaneous (SC) route in 2012. A study by Moreau et al found that the efficacy of SC bortezomib is not inferior to that of standard IV administration. Moreau also observed a better safety profile with SC administration: in particular, the incidence of grade 2 or greater peripheral neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher peripheral neuropathy occurred in 6% of patients with SC administration vs 16% for IV administration.[50] Starting therapy with SC administration may be considered for patients with pre-existing peripheral neuropathy and those at high risk for it.

Regimens with daratumumab

Daratumumab is a monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of hematopoietic cells, including clonal plasma cells in MM. Binding to CD38 induces rapid tumor cell death through multiple mechanisms.

In 2019, the FDA approved daratumumab with bortezomib, thalidomide, and dexamethasone (VTD) for newly diagnosed patients with MM who are eligible for ASCT. Approval was based on results from the phase III CASSIOPEIA study (n=1085) that demonstrated the benefit of adding daratumumab to VTD before and after ASCT.[51]  The randomized phase II GRIFFIN trial, in newly diagnosed transplant-eligible patients with MM, confirmed that adding daratumumab to lenalidomide, bortezomib, and dexamethasone (RVD) for induction and consolidation therapy significantly improved stringent complete response (67% vs 48% for RVD alone; P=0.0079) and 4-year progression-free survival (PFS: 87.2% vs 70% for RVD); HR=0.45; P=0.032).[52]

Combining daratumumab with hyaluronidase, which allows SC administration, received FDA approval in July 2024 as induction and consolidation therapy in newly diagnosed patients eligible for ASCT, in combination with bortezomib, lenalidomide, and dexamethasone (VRd). Approval was based on results from the phase 3 PERSEUS trial (n=709), in which the addition of daratumumab resulted in ∼60% reduction in the risk of disease progression or death compared with VRd alone, at a median follow-up of 47.5 months.[53]

High-risk patients who are potential transplant candidates

Patients are considered at high risk if their MM meets any of the following criteria:

This group represents about 25% of those with newly diagnosed MM, with an expected median survival of 2 years or less. Although these patients respond to traditional therapies for induction, their disease tends to relapse rapidly. Options in these cases include the following regimens[2, 33] :

Once a response has been achieved, then patients can be brought to ASCT.

Newly diagnosed patients who are not transplant candidates

All of the regimens used in transplant candidates may be used in patients who are not being considered for transplantation. In contrast to the 3-4 cycles used for induction in transplant-eligible patients, transplant-ineligible patients are typically scheduled for 9-12 cycles.[33]

National Comprehensive Cancer Network NCCN) guidelines list the following as preferred regimens in this setting[2] :

The open-label, randomized, phase 3 MAIA trial, in patients with newly diagnosed MM who were ineligible for ASCT demonstrated an improvement in PFS with the addition of daratumumab to lenalidomide and low-dose dexamethasone. The rate of complete response or better was 47.6% in the daratumumab group and 24.9% in the control group. A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white blood cells).[54]

In September 2024, isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (VRd) was approved for treatment of newly diagnosed MM in patients who are ineligible for ASCT. Approval was supported by the open-label, randomized, phase 3 IMROZ trial. At nearly 60 months of follow-up, PFS was 63.2% in patients taking isatuximab plus VRd compared with 45.2% with VRd (P < 0.001).[55]

Maintenance therapy

In spite of advances in treatment, MM remains an incurable disease. To improve OS in these patients, a number of trials have evaluated the role of maintenance therapy in both transplant-eligible and transplant-ineligible patients.

Given its favorable toxicity profile and efficacy at low doses, lenalidomide has been adopted for maintenance therapy. Two large trials, CALGB 100104 and IFM 05-02, have evaluated the role of lenalidomide in maintenance therapy, using slightly different protocols and having somewhat different outcomes.[56, 57] Patients in both studies received induction treatment followed by ASCT. In the IFM 05-02 study, however, all patients received 2 months of consolidation treatment with lenalidomide before being randomized to lenalidomide or placebo.

Both studies showed a significant improvement in time to progression (46 vs 27 months in CALGB study and 41 vs 23 months in IFM study). However, CALGB 100104 study showed significant improvement in OS (85 % vs 77 %), whereas IFM 05-02 did not show an improvement in OS. Both studies showed an increased incidence of hematologic toxicity and second primary malignancies, particularly acute myelogenous leukemia/myelodysplastic syndrome in the lenalidomide arm.

The reason for the difference in the two studies in terms of OS benefit is not very clear. Since all the patients in the IFM trial received 2 months of consolidation treatment with lenalidomide following ASCT, it is possible that only short period of maintenance therapy, rather than continuous maintenance therapy, is required to achieve all the OS benefit seen in the CALGB trial.

A meta-analysis shows the benefit of maintenance lenalidomide, with a 51% reduction in the risk of recurrence.[58] This benefit outweighs the risk of second primary malignancies seen in the trials of lenalidomide maintenance.

A number of trials have also evaluated bortezomib in maintenance therapy. All of them have showed benefit in PFS but no clear OS benefit. Bortezomib given once a week in maintenance seems to be better tolerated and associated with lesser neuropathy.[59, 60, 60]  For maintenance therapy in high-risk MM, two-drug regimens are typically recommended (eg, bortezomib plus lenalidomide).[2, 33]

Although trials have shown the benefit of maintenance therapy after ASCT, the risk of second primary malignancies and the need for continuous treatment should be kept in mind. Individual patient characteristics should be taken in consideration before recommending maintenance therapy.

Patients with refractory disease or relapse

Patients who have a relapse after initial disease control may be treated with any of the agents not already utilized. If the relapse occurs longer than 6 months after the initial therapy, then the initial regimen can be used again. For relapses that occur sooner, the selection of regimens varies depending on the number of prior therapies and the regimens used. Triplet regimens are the standard, but patients who are considered unable to tolerate three drugs can be started with a 2-drug regimen, with a third drug added once their performance status improves.[2]

Bortezomib

Bortezomib has a well-established role as salvage therapy, based on a phase 3 randomized trial showing a response rate of 38% versus 18% in patients receiving dexamethasone only.[47] Median PFS was 6.22 months in the bortezomib arm versus 3.49 months in the dexamethasone-only group.

Panobinostat

Panobinostat (Farydak) is a histone deacetylase (HDAc) inhibitor approved in 2015. It is indicated in combination with bortezomib and dexamethasone for treatment of MM in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. The FDA approval was based on efficacy and safety data in a prespecified subgroup analysis of the phase III PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial, in which patients treated with panobinostat (n = 94) had a median PFS of 10.6 months, compared with 5.8 months for patients in the placebo arm (n= 99) (hazard ratio= 0.52 [95% confidence interval: 0.36, 0.76]).[61]

Carfizomib

In 2012, the FDA approved carfilzomib (Kyprolis) for the treatment of patients with MM who have received at least two prior therapies including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of therapy completion. The approval was based on a phase 2b, single-arm, multicenter clinical study of 266 patients with relapsed MM with other therapies. The study assessed for overall response rate (ORR), which was 22.9% over a median duration of 7.8 months.[62]

In 2015, the FDA expanded carfilzomib’s indication for MM based on data from the ASPIRE study, conducted in patients with relapsed MM who had received 1-3 prior lines of therapy. In ASPIRE, median PFS for patients treated with carfilzomib combined with lenalidomide and dexamethasone was 26.3 months, compared with 17.6 months in those treated with lenalidomide and low-dose dexamethasone alone.[63]

In 2016, the FDA approved carfilzomib in combination with dexamethasone for relapsed or refractory MM in patients who have received 1-3 prior lines of therapy. Approval was based on the ENDEAVOR study (n=929) where a statistically significant improvement in median PFS was observed with carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone in patients with relapsed MM (26.3 mo vs 17.6 mo; P=0.0001).[64] On interim analysis, median overall survival was 47.6 months in the carfilzomib group versus 40.0 months in the bortezomib group (hazard ratio 0.791, one-sided P=0.010).[65]

Daratumumab

Daratumumab gained approval from the FDA in 2015 for patients with MM who had received at least three prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or whose disease is refractory to both a PI and an IMiD. The approval was based on the phase 2 MMY2002 (SIRIUS) study that showed treatment with single-agent daratumumab resulted in an ORR of 29.2% in patients who received a median of five prior lines of therapy, including a PI and an IMiD.[66]

Stringent complete response (sCR) was reported in 2.8%, very good partial response (VGPR) was reported in 9.4%, and partial response (PR) was reported in 17% of patients. For responders, the median duration of response was 7.4 months. At baseline, 97% of patients were refractory to their last line of therapy, 95% were refractory to both a PI and an IMiD, and 77% were refractory to alkylating agents.[66] These data are supported by similar results from a phase I/II trial.[67]

Two phase 3 trials, CASTOR and POLLUX, have demonstrated an OS benefit with daratumumab-containing regimens in relapsed/refractory MM. In CASTOR, on median follow-up of 72.6 months, median OS was 49.6 months with daratumumab, bortezomib, and dexamethasone versus 38.5 months with bortezomib and dexamethasone (P = 0.0075).[68] In POLLUX, on median follow-up of 79.7 months, median OS was was 67.6 months with daratumumab, lenalidomide, and dexamethasone versus 51.8 months with lenalidomide and dexamethasone (P = 0.0044).[69]

Ixazomib

Ixazomib (Ninlaro) is a reversible proteasome inhibitor. It preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome. Ixazomib is indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy. Approval was based on data from the phase 3 TOURMALINE-MM1 trial, an international, randomized, double-blind clinical trial of 722 patients with treatment-refractory or recurrent multiple myeloma. It compared ixazomib with placebo the patients who also received lenalidomide and dexamethasone. Median progression-free survival was improved by 35% with ixazomib compared with placebo (20.6 vs 14.7 months; P = 0.012).[70]

Elotuzumab

Elotuzumab (Empliciti) is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocytic activation molecule family member 7) protein. SLAMF7 is expressed on myeloma cells and natural killer cells and plasma cells. Elotuzumab facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity. It is indicated for use in combination with lenalidomide and dexamethasone for MM in patients who have received 1-3 prior therapies.

Approval was based on the ELOQUENT-2 trial, a randomized, open-label clinical study that included 646 participants with MM who had experienced relapse or who had not responded to previous treatment. The addition of elotuzumab to the combination of lenalidomide and dexamethasone extended PFS to 19.4 months, as compared with 14.9 months in patients treated with lenalidomide and dexamethasone (P< 0.001). Additionally, the overall response rate (including complete and partial responses) was 78.5%, compared with 60.1% in patients receiving lenalidomide and dexamethasone (P< 0.001).[71]

The ELOQUENT-3 trial studies 117 patients with MM that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor. Patients received elotuzumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone alone (control group). Median PFS was 10.3 months in the elotuzumab group and 4.7 months in the control group. The overall response rate was 53% in the elotuzumab group compared with 26% in the control group.[72]

Isatuximab

The FDA has approved the anti-CD38 monoclonal antibody isatuximab (Sarclisa) for three indications:

Thalidomide

Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its antiangiogenic properties have become increasingly apparent as a critical step in the proliferation and spread of malignant neoplasm.[76]

Lenalidomide

An important prospective placebo-controlled trial of the addition of lenalidomide to dexamethasone in relapsed MM demonstrated spectacular results.[77] The major response rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a significant improvement in time to progression (11.1 months in the lenalidomide plus dexamethasone group vs 4.7 months in the placebo group). Overall survival was significantly improved.[77]

Pomalidomide

A study by Lacy et al found that pomalidomide overcame resistance in MM that was refractory to both lenalidomide and bortezomib.[78] In 2013, pomalidomide was approved by the FDA for use in patients with MM who have received at least two previous therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy.[79, 80]

This approval was supported by a phase 2 study comparing pomalidomide plus low-dose dexamethasone with pomalidomide alone in patients with relapsed MM refractory to their last therapy who had received lenalidomide and bortezomib. Of the 221 patients who were evaluable for response, 29.2% in the pomalidomide plus low-dose dexamethasone arm achieved a partial response or better, compared with 7.4% in the pomalidomide-alone arm.[79] The median duration of response for the former was 7.4 months; the median had not been reached for the latter.

In another study, Miguel et al found that the combination of pomalidomide with low-dose dexamethasone yielded a longer median PFS in 455 patients with refractory or relapsed and refractory MM than high-dose dexamethasone alone.[81] In the open-label, randomized study patients received 28-day cycles of either pomalidomide (4 mg/day on days 1-21) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) or only high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20). At follow-up (median, 10 months), median PFS was 4.0 months for the combination therapy group, compared with 1.9 months for the monotherapy group, for a hazard ratio of 0.48. Rates of most adverse events were similar in the two groups.[81]

Selinexor

The first selective inhibitor of nuclear export (SINE), selinexor, was approved by the FDA in 2019. Selinexor acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell cycle arrest, and apoptosis of cancer cells. Selinexor is indicated in combination with dexamethasone for adults with relapsed or refractory MM who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The multicenter, single-arm, open-label STORM trial analyzed selinexor plus dexamethasone. STORM part 2 included 122 patients with relapsed/refractory MM who previously had 3 or more treatments. FDA approval was based on results from the 83 patients from the STORM trial whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. This group had a 25.4% overall response rate, 1% stringent complete response rate, 5% very good partial response, and 19% partial response rate.[82, 83]  

Teclistamab

In 2022, the FDA granted accelerated approval to teclistamab (Tecvayli) for adults with relapsed or refractory MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Teclistamab is the first of a new class of agents: it is a bispecific T-cell engaging antibody that binds to CD3 receptors on the surface of T-cells and to B-cell maturation antigen (BCMA) expressed on the surface of MM cells and some healthy B-lineage cells.

Efficacy was based on a single-arm, multicohort, open-label, multicenter study, MajesTEC-1. Patients (n=165) had previously received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and had not received prior BCMA-targeted therapy. Patients received weekly SC teclistamab (at a dose of 1.5 mg/kg) after receiving step-up doses of 0.06 mg and 0.3 mg/kg. The overall response rate was 63%, with 39.4% having a complete response or better. The median duration of response was 18.4 and the median duration of progression-free survival was 11.3 months.[84]

Elranatamab

In August 2023, the FDA granted accelerated approval to elranatamab (Elrexfio) for relapsed or refractory MM in adults who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Like teclistamab, elranatamab is a bispecific BCMA-directed CD3 T-cell engager.

Approval was based on MagnetisMM-3, an open-label, single-arm, multicenter study in which the objective response rate in treated patients receiving the recommended dose was 57.7%. On median follow-up of 11.1 months in responders, the median duration of response (DOR) was not reached and the DOR rate at 6 months was 90.4% and at 9 months was 82.3%[85]

Talquetamab

Also in August 2023, the FDA granted accelerated approval to talquetamab (Talvey) for relapsed or refractory MM in adults who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Talquetamab is a bispecific antibody against CD3 and GPRC5D; it redirects T cells to mediate killing of myeloma cells that express GPRC5D.

Efficacy was evaluated in MMY1001 (MonumenTAL-1), a single-arm, open-label, multicenter study that included 187 patients who had previously received at least four prior systemic therapies. Overall response rate (ORR) in patients receiving 0.4 mg/kg weekly was 73% and median duration of response (DOR)  was 9.5 months. ORR in 87 patients receiving 0.8 mg/kg biweekly was 73.6% and median DOR was not estimable. An estimated 85% of responders maintained response for at least 9 months.[86]

Transplantation

Using the patient’s own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense therapy for MM. After harvesting the stem cells from the patient, physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then “rescue” the patient by reinfusing the harvested cells. This process of myeloablative therapy, followed by the reinfusion of stem cells, is termed autologous stem cell transplantation (ASCT). In ASCT, the reinfused stem cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.

A study by Moreau et al determined that achievement of very good partial response (VGPR) after induction therapy is an important prognostic factor in patients undergoing autologous stem cell transplantation.[87] VGPR was significantly improved with bortezomib-dexamethasone induction therapy.

A study by Harousseau et al also concluded that this combination significantly improved postinduction and posttransplantation complete response/near response rate at at least VGPR rates compared with VAD.[88] Cavo et al also concluded that this combination represents a new standard of care for patients with multiple myeloma who are eligible for transplant.[89]

In MM patients with progressive or relapsing disease following ASCT, treatment with the combination of bortezomib, thalidomide and dexamethasone is more effective than treatment with thalidomide and dexamethasone alone, although triple therapy is associated with a greater risk of grade 3 neurotoxicity.[90]

Tandem transplantation

Tandem (double) ASCT has been proposed as a way of overcoming the incomplete response to a single transplant. However, trials of tandem ASCT have yielded inconclusive results.[33, 91, 92, 93]  The most recent trial, published in 2019, found that tandem ASCT did not improve PFS or OS.[49] Tandem ASCT may be considered in selected patients with high-risk disease who do not achieve a complete response after the first transplant, but preferably its use should be limited to clinical trials.[33]

Allogeneic transplantation

In highly selected patients with MM, such as those with high-risk disease and poor response after ASCT, physicians may use allogeneic transplantation. In this approach, physicians administer myeloablative therapy and infuse stem cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably a human leukocyte antigen (HLA)-identical sibling.The advantage of this approach over autologous transplantation is that the patient is not at risk of being reinfused with MM cells. In addition, the donor’s immune system may fight the recipient’s cancer (ie, graft vs myeloma effect). Unfortunately, the donor’s immune system may also attack the recipient’s body (ie, graft versus host disease).

The use of allogeneic transplantation in MM patients remains largely investigational, for several reasons. First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with MM are older than the ideal age for allogeneic transplantation. Second, studies have had mixed outcomes. A meta-analysis of three studies involving 491 patients with high-risk MM concluded that ASCT followed by allogeneic transplantation appeared to result in improved PFS and complete response rates compared with tandem ASCT, but did not significantly  improve OS. In addition, the risks of transplant-related and non-relapse mortality were higher.[94]

Chimeric antigen receptor (CAR) T-Cell Therapy

Two chimeric antigen receptor (CAR) T-cell therapies using B-cell maturation antigen (BCMA) have been approved for use in patients with relapsed or refractory MM: ciltacabtagene autoleucel and idecabtagene vicleucel. Research is addressing the limitations and challenges of CAR T-cell therapy, including inevitable relapse and adverse effects such as cytokine release syndrome and neurotoxicity.[95, 96]

Ciltacabtagene autoleucel

In 2022, the FDA approved ciltacabtagene autoleucel (Carvykti), a CAR-T cell therapy featuring two BCMA-targeting single-domain antibodies, for relapsed or refractory MM in adults who were previously treated with ≥4 prior therapies. In April 2024, it was approved for earlier use, in patients after at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, in MM refractory to lenalidomide.[97]

Approval was based on the findings from the open-label, single-arm, phase 1b/2 CARTITUDE-1 study, which enrolled patients who had received a median of 6 prior treatment regimens. Treated patients had 98% overall response rate. Stringent complete responses rates were 78% (95% CI, 68.8-86.1) at 18-month follow-up and 83% at 22-month follow-up. At a median of 18 months follow-up, median duration of response was 21.8 months.[97, 98]

Idecabtagene vicleucel

Idecabtagene vicleucel (Abecma) is a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy.[99] In April 2024, the FDA approved it for relapsed or refractory MM after at least 2 prior lines of therapy (it was originally approved in 2021 for use after 4 or more), including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Approval was based on the KarMMA study, a multicenter, open-label study in patients with relapsed or refractory MM who had received at least 3 prior lines of therapy. At a median follow-up of 13.3 months, 94 of the 128 patients (73%) had a response; 42 of the 128 (33%) had a complete response or better, and 79% of those had minimal residual disease (MRD)–negative status. The median PFS was 8.8 months. Common adverse effects included neutropenia, anemia, thrombocytopenia, and cytokine release syndrome.[100]

Radiation Therapy

MM is extremely sensitive to radiation. Physicians use radiation to treat symptomatic lesions, to stabilize bones at risk for fracture, and to treat spinal cord compression.

If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be initiated. Radiation treatment can result in additional early bone loss due to inflammation, and weight bearing should be limited for the first 4-6 weeks.

Prevention and Treatment of Skeletal-Related Events

Agents used for prevention and treatment of skeletal-related events (SREs) in patients with MM include the bisphosphonates zoledronic acid and pamidronate, and the monoclonal antibody denosumab. Bisphosphonates are specific inhibitors of osteoclastic activity and are used to treat bone resorption. They also have a role in the secondary prevention of bony complications in MM, including hypercalcemia, pathologic fracture, and spinal cord compression. Zoledronic acid may be significantly more potent than pamidronate. A study by Morgan et al revealed the anticancer properties of zoledronic acid in addition to its ability to reduce skeletal-related events in MM.[101]

Denosumab targets and binds to receptor activator of nuclear factor kappa-Β ligand (RANKL). Osteoclast-activating factors, such as RANKL, are implicated in an increased risk for SREs with MM. In a phase 3 trial that compared denosumab with zoledronic acid in patients (n=1718) with bone metastases, denosumab was noninferior for delaying SREs and was associated with a significantly lower risk of kidney toxicity (10% vs 17%, respectively).[102]  Further exploratory analysis revealed that the following three patient groups had significantly longer progression-free survival with denosumab:

No difference in PFS was observed with denosumab versus zoledronic acid in patients not intending to undergo ASCT, patients ≥70 years old, or patients with creatinine clearance ≤60 mL/min.[103]

Guidelines

In 2021, the International Myeloma Working Group (IMWG) released updated practice guidelines for the management of MM-related bone disease.[104]  The recommendations include the following:

In 2017, the American Society of Clinical Oncology (ASCO) issued an update to its clinical practice guideline on the role of bone-modifying agents in MM.[40] ASCO recommendations include the following:

ASCO recommendations for patients with kidney impairment include the following:

ASCO recommendations regarding duration of therapy include the following:

Osteonecrosis of the jaw

Osteonecrosis of the jaw is a rare but severe adverse effect of bisphosphonate therapy. Level 1 evidence (ie, systematic reviews or randomized controlled trials) indicate that approximately 1% of cancer patients exposed to zoledronic acid develop osteonecrosis of the jaw.[105] Dental extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.

A position paper by the American Association of Oral and Maxillofacial Surgeons describes the differential diagnosis, prevention, and treatment of medication-related osteonecrosis of the jaw. Consultation with an appropriate dental professional is advised before prescribing a bisphosphonate.[105]

Adjunctive Therapy for Complications

Potential complications of MM include the following:

Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in MM.

To treat pathologic fractures, physicians should orthopedically stabilize (typically, pin) the bone and irradiate these lesions. Careful attention to a patient’s bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates or denosumab may be useful to prevent fractures.[40, 106, 107]  (See Treatment/Prevention and Treatment of Skeletal-Related Events.)

Spinal cord compression is one of the most severe complications of MM. The resulting neurologic dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed. Patients who may have spinal cord compression need a rapid evaluation, which may necessitate urgent transfer to a center equipped with MRI for diagnosis or with a radiation oncologist for urgent therapy.

Patients with spinal cord compression due to MM should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to restore or stabilize neurologic function. Surgery may be indicated. (See Surgical Care.)

Erythropoietin may ameliorate anemia resulting from either MM itself or from chemotherapy, and it has been shown to improve quality of life.[108] However, a systematic review failed to demonstrate a survival advantage for the use of erythropoietin agents in the treatment of patients with cancer-related anemia.[109]

Acute kidney injury related to MM is typically managed with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis.[7] Hydration (to maintain a urine output of > 3 L/d), management of hypercalcemia, and avoidance of nephrotoxins (eg, intravenous contrast media, aminoglycoside antibiotics) are also key factors. Conventional therapy may take weeks to months to show a benefit.

Kidney impairment resulting from MM is associated with a very poor prognosis. A case series demonstrated that patients with kidney failure from MM may benefit from autologous stem cell transplants, and as many as one third may demonstrate improvement in their kidney function with this approach.[110] A report by Ludwig et suggests that bortezomib-based therapy may restore kidney function in MM patients with kidney failure.[6]

Guidelines on the management of MM complications by the European Myeloma Network include the following recommendations[111] :

Surgical Care

Surgical therapy for MM is limited to adjunctive treatment. It consists of prophylactic fixation of pending fractures, decompression of the spinal cord when indicated, and treatment of pathologic fractures.

Prophylactic treatment of impending fractures and the treatment of pathologic fractures may involve bracing. In general, bracing is not effective for the long bones, though it may be effective for treating spinal involvement without neurologic compromise.

Intramedullary fixation is the procedure of choice when surgery is necessary. If the metaphysis or joint surface is involved, resection of the diseased bone and reconstruction with a total joint or, more typically, a hemiarthroplasty is indicated. Modular implants may be required. Severe destruction of the diaphysis may require reconstruction with combinations of methylmethacrylate, intramedullary nails, or resection and prosthetic replacement.

Surgical treatment of pathologic vertebral fractures may involve spinal instrumentation or vertebral augmentation with vertebroplasty (percutaneous injection of a cement mixture) or kyphoplasty (inserting a balloon into the vertebra and filling it with cement). (See Percutaneous Vertebroplasty and Kyphoplasty.) A review of 23 clinical studies in patients with MM reported that vertebroplasty and kyphoplasty are safe and effective in this population, providing pain relief and reducing pain-associated disability and fracture incidence.[113]

Dietary Measures

Patients with MM who are receiving bisphosphonate therapy should include adequate calcium in their diet.

The dietary supplement curcumin, which has anti-inflammatory properties, may slow the progression of smoldering multiple myeloma.[114]

Physical Activity

Patients with MM should be encouraged to be physically active to the extent appropriate for their individual bone status. Physical activity may help maintain bone strength.

In general, patients with activity-related pain in the femur or the tibia should be given a walker or crutches until a radiographic workup has been completed. Radiation therapy elicits an inflammatory response, and for the first 6 weeks or so, bony resorption may actually weaken the target bone. Given that prophylactic treatment of an impending fracture is usually easier than reconstruction of a pathologic fracture, clinicians should have a low threshold for initiating protected weight bearing.

Consultations

Patients with MM often benefit from the expertise of an orthopedic surgeon who is versed in oncologic management because prophylactic fixation of impending pathologic fractures is occasionally warranted.

From the orthopedic perspective, because patients with MM have significant systemic comorbidities—including potentially severe hematologic, infectious, and metabolic diseases—the orthopedic surgeon treating the skeletal disease in a patient with myeloma should work in conjunction with the radiation oncologists and the medical oncologists.

Long-Term Monitoring

Patients with MM may require hospitalization for the treatment of pain or bony pathology.

Patients with MM are at high risk of infection, especially from encapsulated organisms. Vaccinations against pneumococcal organisms and influenza are recommended. Consider vaccinating patients against Haemophilus influenzae type b. Use of the herpes zoster vaccine should be considered.

The following laboratory results are helpful in the follow-up care of patients with MM:

Guidelines Summary

The following organizations have published guidelines on multiple myeloma (MM):

Management of Complications

The NCCN, American Society of Clinical Oncology (ASCO), and International Myeloma Workshop clinical guidelines for prevention of venous thromboembolism agree that patients with multiple myeloma who are receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive prophylactic anticoagulation therapy with either aspirin or low molecular weight heparin (LMWH) for lower-risk patients and LMWH for higher-risk patients.[115, 116, 117]

A joint American Society of Hematology (ASH) and ASCO clinical practice guideline on the use of erythropoiesis-stimulating agents (ESAs) in cancer was updated in 2019. The specific recommendations for patients with multiple myeloma receiving concurrent chemotherapy include the following[115] :

Guidelines on the management of multiple myeloma complications by the European Myeloma Network include the following recommendations[111] :

A guideline from the European Myeloma Network includes the following recommendations for vaccination in multiple myeloma[112] :

Medication Summary

Multiple myeloma (MM) is treated with several categories of medications. Chemotherapeutic agents, corticosteroids, and monoclonal antibodies are used to reduce the disease burden, and bisphosphonates are used to promote bone healing and to provide secondary prophylaxis against skeletal-related events (eg, hypercalcemia, bone fracture, spinal cord compression, need for radiation, and need for surgery). In addition, erythropoietin is used to treat anemia, either alone or in conjunction with chemotherapy.

Cyclophosphamide (Cytoxan, Frindovxy)

Clinical Context:  Cyclophosphamide is chemically related to nitrogen mustards. It is an alkylating agent, and its mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Doxorubicin (Adriamycin, Caelyx, Rubex)

Clinical Context:  Doxorubicin is part of VAD (vincristine, Adriamycin, dexamethasone) therapy. It inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; these 2 events, in turn, can inhibit growth of neoplastic cells.

Doxorubicin liposomal (Doxil, Lipodox, Myocet)

Clinical Context:  Doxorubicin liposomal is a pegylated formulation that protects the liposomes and, thereby, increases blood circulation time. The drug inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; these 2 events can, in turn, inhibit growth of neoplastic cells.

Melphalan (Alkeran (DSC), Evomela, Hepzato)

Clinical Context:  Melphalan is an alkylating agent and a derivative of mechlorethamine that inhibits mitosis by cross-linking DNA strands. Historically, the melphalan/prednisone (MP) regimen was widely used in multiple myeloma. Indications for melphalan in multiple myeloma include conditioning prior to hematopoietic stem cell transplantation and palliative treatment.

Bortezomib (Boruzu, Velcade)

Clinical Context:  Bortezomib is the first drug approved in the group of anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells, which degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreasing cancer cell survival. Bortezomib is indicated for patients with multiple myeloma. Development of peripheral neuropathy is a limiting factor. A decreased incidence of peripheral neuropathy has been observed with SC administration compared with the IV route.

Carfilzomib (Kyprolis)

Clinical Context:  Proteasome inhibitor; elicits antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. It is indicated as monotherapy, in combination with dexamethasone, or in combination with lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma in patients who have received at least 1 prior line of therapy.  

Ixazomib (Ninlaro)

Clinical Context:  Reversible proteasome inhibitor. It preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome. It is indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy.

Panobinostat (Farydak)

Clinical Context:  Panobinostat is a histone deacetylase (HDAc) inhibitor. HDAc catalyzes the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Inhibition of HDAc activity results in increased acetylation of histone proteins and an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. It is indicated in combination with bortezomib and dexamethasone for treatment of multiple myeloma in patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

Class Summary

The choice of chemotherapy depends on several factors, including the patient’s performance status, age, kidney function, desire for inpatient or outpatient therapy, and likelihood of receiving future autologous stem cell transplantation.

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context:  Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. Melphalan with prednisone (MP) was once the most widely used regimen for multiple myeloma.

Dexamethasone (Baycadron, Decadron DSC, Dexamethasone Intensol)

Clinical Context:  Dexamethasone is part of many treatment regimens for multiple myeloma. Dexamethasone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli. 

Thalidomide (Thalomid)

Clinical Context:  Thalidomide, when used in combination with dexamethasone, is indicated for the treatment of patients with newly diagnosed multiple myeloma. Thalidomide is an immunomodulatory agent that may suppress excessive production of tumor necrosis factor (TNF)-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. Because of concerns regarding teratogenicity, thalidomide can only be prescribed by registered physicians and is dispensed by registered pharmacists. Patients must participate in ongoing surveys to receive therapy, and only a 28-d supply can be prescribed at a time.

Lenalidomide (Revlimid)

Clinical Context:  Lenalidomide is used in numerous combination regimens for treatment of newly diagnosed and relapsed/refractory multiple myeloma, and as monotherapy or in two-drug regimens for maintenance therapy. Lenalidomide is structurally similar to thalidomide. It has immunomodulatory and antiangiogenic properties, inhibits proinflammatory cytokine secretion, and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

Pomalidomide (Pomalyst)

Clinical Context:  Thalidomide analogue indicated in combination with dexamethasone for patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. Also used in combination with elotuzumab and dexamethasone.

Class Summary

Immunosuppressant agents inhibit key factors in the immune system that are responsible for immune reactions.

Teclistamab (Tecvayli)

Clinical Context:  Teclistamab is a bispecific T-cell engaging antibody that binds to CD3 receptors on T-cells and B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells. It is indicatedl for adults with relapsed or refractory MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Elranatamab (Elranatamab-bcmm, Elrexfio)

Clinical Context:  Elranatamab is a humanized BCMA-CD3 bispecific antibody. FDA granted accelerated approval for adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Class Summary

Agents in this drug class are antibody-drug conjugates. The antibody component is an afucosylated IgG1 directed against B-cell maturation agent (BCMA), a protein expressed on normal B lymphocytes and multiple myeloma cells. The small molecule component is MMAF, a microtubule inhibitor.

Idecabtagene vicleucel (Abecma)

Clinical Context:  Indicated for relapsed or refractory MM after ≥2 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Each idecabtagene vicleucel dose is customized using a patient’s own T-cells to help fight the myeloma. These T-cells are collected and genetically modified to include a new gene that facilitates targeting and killing myeloma cells. Once modified, the cells are infused back into the patient. 

Ciltacabtagene autoleucel (Carvykti)

Clinical Context:  CAR-T cell therapy featuring 2 BCMA-targeting single-domain antibodies; indicated for relapsed or refractory MM in adults who were previously treated with at least 1 prior therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

Class Summary

B-cell maturation antigen (BCMA)-directed, genetically modified autologous chimeric antigen receptor T-cell (CAR-T) therapies reprogram the patient’s own T-cells with a transgene encoding CAR that identifies and eliminates cells that express BCMA. Myeloma cells highly express the BCMA protein. 

Selinexor (Xpovio)

Clinical Context:  Selinexor blocks exportin 1 (XPO1), which leads to accumulation of tumor suppressor proteins in the nucleus, reductions in several oncoproteins, cell cycle arrest, and apoptosis of cancer cells. Indicated in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Class Summary

A selective inhibitor of nuclear export (SINE) acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell cycle arrest, and apoptosis of cancer cells.

Pamidronate (Aredia)

Clinical Context:  Pamidronate inhibits normal and abnormal bone resorption. It appears to inhibit bone resorption without inhibiting bone formation and mineralization. The optimal timing and duration of therapy are being studied. Pamidronate is administered intravenously (IV) over 2 hours.

Zoledronic acid (Reclast, Zometa)

Clinical Context:  Zoledronic acid inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors. It is effective in treating the hypercalcemia of malignancy.

Class Summary

Bisphosphonates inhibit bone resorption via action on osteoclasts or osteoclast precursors.

Epoetin alfa (Epoetin alfa-epbx, Epogen, Eprex)

Clinical Context:  Erythropoietin stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.

Erythropoietin is a naturally occurring hormone produced by the kidneys to stimulate bone marrow production of red blood cells. In patients with MM, administration of exogenous erythropoietin may correct anemia, leading to a significant improvement in performance status and quality of life.

Class Summary

Colony-stimulating factors induce erythropoiesis.

Motixafortide (Aphexda)

Clinical Context:  Indicated in combination with filgrastim to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. 

Plerixafor (Mozobil)

Clinical Context:  Indicated in combination with filgrastim to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma and non-Hodgkin lymphoma.

Class Summary

These drugs inhibit the C-X-C motif chemokine receptor 4 (CXCR4) and block binding of its cognate ligand, stromal-derived factor-1α (SDF-1α)/CXCL12. SDF-1α and CXCR4 play a role in trafficking and homing of hematopoietic stem cells to the marrow compartment.

Denosumab (Denosumab-bbdz, Denosumab-bmwo, Denosumab-dssb)

Clinical Context:  Monoclonal antibody that specifically targets RANKL. It binds to RANKL and inhibits its binding to RANK receptor, thereby preventing osteoclast formation. This results in decreased bone resorption and increases bone mass in osteoporosis. RANKL inhibition decreases tumor-induced bone destruction and SREs. Denosumab is indicated for prevention of SREs in patients with multiple myeloma.

Elotuzumab (Empliciti)

Clinical Context:  Humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocytic activation molecule family member 7) protein. SLAMF7 is expressed on myeloma cells and natural killer cells and plasma cells. Facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity. It is indicated in combination with lenalidomide and dexamethasone for multiple myeloma in patients who have received 1-3 prior therapies. Elotuzumab is also indicated in combination with pomalidomide and dexamethasone for patients with multiple myeloma who have received 2 or more prior therapies including lenalidomide and a proteasome inhibitor.

Daratumumab (Darzalex)

Clinical Context:  Monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is indicated for patients with multiple myeloma who have received at least 3 prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMiD. Other regimens for relapsed/refractory MM are approved for daratumumab in combination with dexamethasone plus bortezomib or lenalidomide or pomalidomide. It is also indicated for newly diagnosed MM in patients ineligible for ASCT as part of various combination regimens. Daratumumab in combination with bortezomib, thalidomide, and dexamethasone may also be considered in newly diagnosed MM in patients who are eligible for ASCT

Daratumumab/hyaluronidase (Daratumumab/hyaluronidase-fihj, Darzalex Faspro)

Clinical Context:  Daratumumab/hyaluronidase is a CD38-directed monoclonal antibody formulated with hyaluronidase, an endoglycosidase that increases permeability of subcutaneous tissue, allowing subcutaneous administration. It is approved for the same indications as daratumumab. Additionally, daratumumab/hyaluronidase is also indicated in newly diagnosed MM in patients who are eligible for ASCT in combination with bortezomib, lenalidomide, and dexamethasone.

Isatuximab (Isatuximab-irfc, Sarclisa)

Clinical Context:  Anti-CD38 monoclonal antibody indicated for relapsed or resistant multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor; in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy; and  in combination with bortezomib, lenalidomide, and dexamethasone for treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant.

Talquetamab (Talquetamab-tgvs, Talvey)

Clinical Context:  Talquetamab is a potential first-in-class, investigational T-cell redirecting bispecific antibody targeting both GPRC5D, a novel multiple myeloma target that does not shed over time, and CD3, a component of the T-cell receptor. It was granted accelerated approval to talquetamab (Talvey) for relapsed or refractory multiple myeloma in adults who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

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active multiple myeloma (MM) differentiated from smoldering multiple myeloma (MM)?What are the differential diagnoses for Multiple Myeloma?What are the guidelines for the standard workup for suspected multiple myeloma (MM)?Which blood studies are performed in the workup of multiple myeloma (MM)?What is the role of electrophoresis and immunofixation in the workup of multiple myeloma (MM)?What is the role of quantitative immunoglobulin (IgG, IgA, IgM) testing in the workup of multiple myeloma (MM)?What is the role of beta-2 microglobulin and C-reactive protein (CRP) testing in the workup of multiple myeloma (MM)?What is the role of serum viscosity testing in the workup of multiple myeloma (MM)?Which histologic findings are characteristic of multiple myeloma (MM)?What is the role of cytogenetic analysis of the bone marrow in the evaluation of multiple myeloma (MM)?Which systems are used to stage multiple myeloma (MM)?What is the Salmon-Durie classification of multiple myeloma (MM)?What is 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of multiple myeloma (MM)?What is the role of nonmyeloablative transplantation regimens in the treatment of multiple myeloma (MM)?What is the role of bortezomib-dexamethasone induction therapy in the treatment of multiple myeloma (MM)?What are the treatment options for multiple myeloma (MM) in patients with progressive or relapsing disease following autologous stem-cell transplantation?What is the role of idecabtagene vicleucel (Abecma) in the treatment of multiple myeloma (MM)?What is the role of radiation therapy in the treatment of multiple myeloma (MM)?What are possible complications of multiple myeloma (MM)?How is hypercalcemia treated in patients with multiple myeloma (MM)?What are the guidelines on the European Myeloma Network management of multiple myeloma (MM) complications?What is the role of surgery in the treatment of multiple myeloma (MM)?What dietary modifications are used in the treatment of multiple myeloma (MM)?What physical activity modifications are needed in the treatment of multiple myeloma (MM)?Which specialist consultations are needed for the treatment of multiple myeloma (MM)?What is included in the long-term monitoring of multiple myeloma (MM)?What is the role of interferon alfa in the treatment of multiple myeloma (MM)?What is the role of bisphosphonates in the treatment of multiple myeloma (MM)?What medication is FDA approved for prevention of skeletal-related events (SREs) in multiple myeloma (MM)?What is a possible severe adverse effect of bisphosphonate therapy for multiple myeloma (MM)?How is multiple myeloma (MM) prevented?Which organizations have issued guidelines for the workup of multiple myeloma (MM)?What are the International Myeloma Working Group (IMWG) guidelines for the workup of multiple myeloma (MM)?What are the National Comprehensive Cancer Network (NCCN) guidelines for the workup of multiple myeloma (MM)?What are the European Society for Medical Oncology (ESMO) guidelines for the diagnosis evaluation of multiple myeloma (MM)?What are the National Comprehensive Cancer Network (NCCN) criteria for a diagnosis of smoldering multiple myeloma (MM)?What are the National Comprehensive Cancer Network (NCCN) criteria for a diagnosis of active multiple myeloma (MM)?What are considered myeloma defining events in the diagnosis of multiple myeloma (MM)?What is the Revised International Staging System (R-ISS) and how is it used in the diagnosis of multiple myeloma (MM)?What are the guidelines for prevention of venous thromboembolism in patients with multiple myeloma (MM)?What are the American Society of Hematology (ASH) and ASCO recommendations for use of erythropoiesis-stimulating agents (ESAs) in multiple myeloma (MM)?What are the European Myeloma Network treatment guidelines for multiple myeloma (MM) complications?What are the National Comprehensive Cancer Network (NCCN) general treatment recommendations for multiple myeloma (MM)?What are the NCCN guidelines for primary induction therapy in patients with multiple myeloma (MM) who are candidates for transplantation?Which regimens does the National Comprehensive Cancer Network (NCCN) consider useful in elderly or frail patients with multiple myeloma (MM)?What are the NCCN guidelines for primary induction therapy in patients with multiple myeloma (MM) who are not candidates for transplantation?What does the NCCN recommend for maintenance therapy in patients with multiple myeloma (MM)?What does the NCCN recommend for salvage therapy in patients with multiple myeloma (MM)?What are the EHA-ESMO guidelines for first-line therapy to treat multiple myeloma (MM)?What are the EHA-ESMO guidelines for second-line therapy to treat multiple myeloma (MM)?What are the EHA-ESMO guidelines for third-line and subsequent therapy to treat multiple myeloma (MM)?What are the International Myeloma Working Group (IMWG) practice treatment guidelines for bone disease associated with multiple myeloma (MM)?What are the American Society of Clinical Oncology (ASCO) clinical practice guidelines governing bisphosphonate therapy for multiple myeloma (MM) patients?What type of medications are used in the treatment of multiple myeloma (MM)?Which medications in the drug class Selective Inhibitor of Nuclear Export are used in the treatment of Multiple Myeloma?Which medications in the drug class CAR T-Cell Therapies are used in the treatment of Multiple Myeloma?Which medications in the drug class Anti-BCMA Antibodies are used in the treatment of Multiple Myeloma?Which medications in the drug class Immunosuppressant Agents are used in the treatment of Multiple Myeloma?Which medications in the drug class Corticosteroids are used in the treatment of Multiple Myeloma?Which medications in the drug class Chemotherapeutic Agents are used in the treatment of Multiple Myeloma?Which medications in the drug class Bisphosphonates are used in the treatment of Multiple Myeloma?Which medications in the drug class Colony-stimulating Factors are used in the treatment of Multiple Myeloma?Which medications in the drug class CXCR4 Inhibitors are used in the treatment of Multiple Myeloma?

Author

Dhaval Shah, MD, Helen F Graham Cancer Center and Research Institute

Disclosure: Nothing to disclose.

Coauthor(s)

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Lesley Elizabeth Fox, MD, Pathologist, ReitPath Pathology, Austin, Texas

Disclosure: Nothing to disclose.

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Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Radiograph of the skull demonstrating a typical lytic lesion in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Radiograph of the skull demonstrating a typical lytic lesion in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.