Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Plasma Cell Neoplasms

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

For information about M protein–associated lymphoma, see the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in Indolent B-Cell Non-Hodgkin Lymphoma Treatment.

Incidence and Mortality

Estimated new cases and deaths from multiple myeloma in the United States in 2025:[1]

• New cases: 36,110.
• Deaths: 12,030.

Clinical Presentation and Evaluation

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

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

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

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

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

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

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

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

Monoclonal Gammopathy of Undetermined Significance (MGUS)

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

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

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

The following risk factors predict disease progression:

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

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

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

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

Isolated Plasmacytoma of Bone

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

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

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

Extramedullary Plasmacytoma

A patient has extramedullary plasmacytoma if the following are found:

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

Multiple Myeloma

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

Prognosis

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

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

Amyloidosis Associated With Plasma Cell Neoplasms

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

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

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

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

POEMS Syndrome

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

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