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Multiple Myeloma

(Myelomatosis; Plasma Cell Myeloma)

By James R. Berenson, MD, President and Chief Medical Officer, Institute for Myeloma and Bone Cancer Research

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Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Diagnosis typically requires demonstration of M-protein (sometimes present in urine and not serum, and rarely absent entirely) and either lytic bone lesions, light-chain proteinuria, or excessive plasma cells in bone marrow. A bone marrow biopsy is usually needed. Specific treatment most often includes some combination of conventional chemotherapy, corticosteroids, and one or more of the newer agents such as bortezomib, carfilzomib, lenalidomide, thalidomide, pomalidomide, daratumumab, or elotuzumab. High-dose melphalan followed by autologous peripheral blood stem cell transplantation may also be used.

The incidence of multiple myeloma is 2 to 4/100,000. Male:female ratio is 1.6:1, and the median age is about 65 yr. Prevalence in blacks is twice that in whites. Etiology is unknown, although chromosomal and genetic factors, radiation, and chemicals have been suggested.


The M-protein produced by the malignant plasma cells is IgG in about 55% of myeloma patients and IgA in about 20%; of patients producing either IgG or IgA, 40% also have Bence Jones proteinuria, which is free monoclonal kappa (κ) or lambda (λ) light chains in the urine. In 15 to 20% of patients, plasma cells secrete only Bence Jones protein. IgD myeloma accounts for about 1% of cases. Rarely, patients have no M-protein in blood and urine, although a new serum free light chain assay now demonstrates monoclonal light chains in many of these patients.

Diffuse osteoporosis or discrete osteolytic lesions develop, usually in the pelvis, spine, ribs, and skull. Lesions are caused by bone replacement by expanding plasmacytomas or by cytokines that are secreted by malignant plasma cells that activate osteoclasts and suppress osteoblasts. The osteolytic lesions are usually multiple; occasionally, they are solitary intramedullary masses. Increased bone loss may also lead to hypercalcemia. Extraosseous solitary plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract.

In many patients, renal failure (myeloma kidney) is present at diagnosis or develops during the course of the disorder. Renal failure has many causes, most commonly, it results from deposition of light chains in the distal tubules or hypercalcemia. Patients also often develop anemia usually due to kidney disease or suppression of erythropoiesis by cancer cells but sometimes also due to iron deficiency.

Susceptibility to bacterial infection may occur in some patients. Viral infections, especially herpes zoster infections, are increasingly occurring as a result of newer treatment modalities, especially use of the proteasome inhibitors bortezomib and carfilzomib. Amyloidosis occurs in 10% of myeloma patients, most often in patients with 2λ-type M-proteins.

Variant expressions of multiple myeloma occur (see Variant Expressions of Multiple Myeloma).

Variant Expressions of Multiple Myeloma



Extramedullary plasmacytoma

Plasmacytomas that occur outside of the medullary system

Solitary plasmacytoma of bone

Single bone plasmacytomas, which usually produce no M-protein

Osteosclerotic myeloma (POEMS syndrome)

Polyneuropathy (chronic inflammatory polyneuropathy)

Organomegaly (hepatomegaly, splenomegaly, or lymphadenopathy)

Endocrinopathy (eg, gynecomastia, testicular atrophy)


Skin changes (eg, hyperpigmentation, excess hair)

Nonsecretory myeloma

Absence of M-protein in serum and urine

Presence of M-protein in plasma cells

Symptoms and Signs

Persistent bone pain (especially in the back or thorax), renal failure, and recurring bacterial infections are the most common problems on presentation, but many patients are identified when routine laboratory tests show an elevated total protein level in the blood or show proteinuria. Pathologic fractures are common, and vertebral collapse may lead to spinal cord compression and paraplegia. Symptoms of anemia predominate or may be the sole reason for evaluation in some patients, and a few patients have manifestations of hyperviscosity syndrome (see Symptoms and Signs). Peripheral neuropathy, carpal tunnel syndrome, abnormal bleeding, and symptoms of hypercalcemia (eg, polydipsia, dehydration) are common. Patients may also present with renal failure. Lymphadenopathy and hepatosplenomegaly are unusual.


  • CBC with platelets, peripheral blood smear, ESR, and chemistry panel (BUN, creatinine, calcium, uric acid, LDH)

  • Serum and urine protein electrophoresis followed by immunofixation; quantitative immunoglobulins; serum free light chains

  • X-rays (skeletal survey)

  • Bone marrow examination

Multiple myeloma is suspected in patients > 40 yr with persistent unexplained bone pain, particularly at night or at rest, other typical symptoms, or unexplained laboratory abnormalities, such as elevated blood protein or urinary protein, hypercalcemia, renal insufficiency, or anemia. Laboratory evaluation includes routine blood tests, protein electrophoresis, x-rays, and bone marrow examination (1,2).

Routine blood tests include CBC, ESR, and chemistry panel. Anemia is present in 80% of patients, usually normocytic-normochromic anemia with formation of rouleau, which are clusters of 3 to 12 RBCs that occur in stacks. WBC and platelet counts are usually normal. ESR usually is > 100 mm/h; BUN, serum creatinine, LDH, and serum uric acid may be elevated. Anion gap is sometimes low. Hypercalcemia is present at diagnosis in about 10% of patients.

Protein electrophoresis is done on a serum sample and on a urine sample concentrated from a 24-h collection to quantify the amount of urinary M-protein. Serum electrophoresis identifies M-protein in about 80 to 90% of patients. The remaining 10 to 20% are usually patients with only free monoclonal light chains (Bence Jones protein) or IgD. They almost always have M-protein detected by urine protein electrophoresis. Immunofixation electrophoresis can identify the immunoglobulin class of the M-protein (IgG, IgA, or uncommonly IgD, IgM, or IgE) and can often detect light-chain protein if serum immunoelectrophoresis is falsely negative; immunofixation electrophoresis is done even when the serum test is negative if multiple myeloma is strongly suspected. Serum free light-chain analysis with delineation of kappa and lambda ratios helps confirm the diagnosis and can also be used to monitor efficacy of therapy and provide prognostic data. Serum level of beta-2 microglobulin is measured if diagnosis is confirmed or very likely and along with serum albumin is used to stage patients as part of the international staging system (see Table: International Staging System for Multiple Myeloma).

International Staging System for Multiple Myeloma



Median Survival (mos)


Beta-2microglobulin < 3.5 mcg/mL


Serum albumin ≥ 3.5 g/dL



Not stage I or III



Beta-2 microglobulin ≥ 5.5 mcg/mL


X-rays include a skeletal survey (ie, plain x-rays of skull, long bones, spine, pelvis, and ribs). Punched-out lytic lesions or diffuse osteoporosis is present in 80% of cases. Radionuclide bone scans usually are not helpful. MRI can provide more detail and is obtained if specific sites of pain or neurologic symptoms are present. PET-CT may provide prognostic information and can help determine whether patients have solitary plasmacytoma or multiple myeloma.

Bone marrow aspiration and biopsy are done and reveal sheets or clusters of plasma cells; myeloma is diagnosed when >10% of the cells are of this type. However, bone marrow involvement is patchy; therefore, some samples from patients with myeloma may show <10% plasma cells. Still, the number of plasma cells in bone marrow is rarely normal. Plasma cell morphology does not correlate with the class of immunoglobulin synthesized. Chromosomal studies on bone marrow (eg, using cytogenetic testing methods such as fluorescent in situ hybridization [FISH] and immunohistochemistry) may reveal specific karyotypic abnormalities in plasma cells associated with differences in survival.

Diagnosis and differentiation from other malignancies (eg, metastatic carcinoma, lymphoma, leukemia) and monoclonal gammopathy of undetermined significance typically requires multiple criteria

  • Clonal bone marrow plasma cells or plasmacytoma

  • M-protein in plasma and/or urine

  • Organ impairment (hypercalcemia, renal insufficiency, anemia, or bony lesions)

In patients without serum M protein, myeloma is indicated by Bence Jones proteinuria > 300 mg/24 h or abnormal serum free light chains, osteolytic lesions (without evidence of metastatic cancer or granulomatous disease), and sheets or clusters of plasma cells in the bone marrow.

Diagnosis reference

  • Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proc91(1):101-119, 2016.doi: 10.1016/j.mayocp.2015.11.007.

  • Rajkumar V. Myeloma today: disease definitions and treatment advances. Am J Hematol91(1):90-100, 2016. doi: 10.1002/ajh.24392.


The disease is progressive and incurable, but median survival has recently improved to > 5 yr as a result of advances in treatment. Unfavorable prognostic signs at diagnosis are lower serum albumin and higher beta-2 microglobulin levels. Patients initially presenting with renal failure also do poorly unless kidney function improves with therapy (which typically happens with current treatment options). Certain cytogenetic abnormalities increase risk of poor outcome.

Because multiple myeloma is ultimately fatal, patients are likely to benefit from discussions of end-of-life care that involve their doctors and appropriate family and friends. Points for discussion may include advance directives, the use of feeding tubes, and pain relief.


  • Chemotherapy for symptomatic patients

  • Thalidomide, lenalidomide, or pomalidomide, and/or bortezomib or carfilzomib, plus corticosteroids and/or conventional chemotherapy

  • Monoclonal antibodies, including elotuzumab and daratumumab

  • Possibly maintenance therapy with corticosteroids, thalidomide and/or lenalidomide

  • Possibly autologous stem cell transplantation

  • Possibly radiation therapy to specific symptomatic areas that do not respond to systemic therapy

  • Treatment of complications (anemia, hypercalcemia, renal insufficiency, infections, skeletal lesions)

Treatment of myeloma has improved in the past decade, and long-term survival is a reasonable therapeutic target (1-3). Therapy involves direct treatment of malignant cells in symptomatic patients or those with myeloma-related organ dysfunction (anemia, renal dysfunction, hypercalcemia, or bone disease). Asymptomatic patients probably do not benefit from treatment, which is usually withheld until symptoms or complications develop. Patients with evidence of lytic lesions or bone loss (osteopenia or osteoporosis) should be treated with monthly infusions of zoledronic acid or pamidronate to reduce the risk of skeletal complications.

Treatment references

  • Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proc91(1):101-119, 2016.doi: 10.1016/j.mayocp.2015.11.007.

  • Rajkumar V. Myeloma today: disease definitions and treatment advances. Am J Hematol91(1):90-100, 2016. doi: 10.1002/ajh.24392.

  • Berenson J, Spektor T, Wang J. Advances in the management of multiple myeloma. 2016.

Treatment of malignant cells

Until recently, conventional chemotherapy consisted only of oral melphalan and prednisone given in cycles of 4 to 6 wk with monthly evaluation of response. Recent studies show superior outcome with the addition of either bortezomib or thalidomide. Other chemotherapeutic drugs, including cyclophosphamide, bendamustine, doxorubicin and its newer analog liposomal pegylated doxorubicin also are more effective when combined with an immunomodulatory drug (thalidomide, lenalidomide, or its newer analog pomalidomide) or a proteasome inhibitor (bortezomib, or a newer drug, carfilzomib). Many other patients are effectively treated with bortezomib, corticosteroids, and either thalidomide (or lenalidomide), chemotherapy, or both.

Chemotherapy response (see Table: Defining Response to Cancer Treatment) is indicated by reduction in bone pain and fatigue, decreases in serum and urine M-protein, decreases in levels of the involved serum free light chain, increases in RBCs, and improvement in renal function among patients presenting with renal failure.

Autologous peripheral blood stem cell transplantation may be considered for patients who have adequate cardiac, hepatic, pulmonary, and renal function, particularly those whose disease is stable or responsive after several cycles of initial therapy. However, recent studies suggest that the newer treatment options are highly effective and may make transplantation less often necessary. Allogeneic stem cell transplantation after nonmyeloablative chemotherapy (eg, low-dose cyclophosphamide and fludarabine) or low-dose radiation therapy can produce myeloma-free survival of 5 to 10 yr in some patients. However, allogeneic stem cell transplantation with myeloablative or nonmyeloablative chemotherapy remains experimental because of the high morbidity and mortality resulting from graft vs host disease.

In relapsed or refractory myeloma, combinations of bortezomib or carfilzomib, and thalidomide, lenalidomide, or pomalidomide, with chemotherapy or corticosteroids may be used. These drugs are usually combined with other effective drugs that the patient has not yet been treated with, although patients with prolonged remissions may respond to retreatment with the same regimen that led to the remission. Patients who fail to respond to a given combination of drugs may respond when another drug in the same class (eg, proteasome inhibitors, immunomodulatory agents, chemotherapeutic drugs) is substituted. Following disease progression, monoclonal antibodies may be effective, including daratumumab and elotuzumab, the latter when combined with lenalidomide and dexamethasone, and the new oral proteasome inhibitor ixazomib.

Maintenance therapy has been tried with nonchemotherapeutic drugs, including interferon alfa, which prolongs remission but does not improve survival and is associated with significant adverse effects. Following a response to corticosteroid-based regimens, corticosteroids alone are effective as a maintenance treatment. Thalidomide may also be effective as a maintenance treatment, and recent studies show that lenalidomide alone or with corticosteroids is also effective maintenance treatment. However, there is some recent concern about secondary malignancy among patients receiving long-term lenalidomide therapy, especially after autologous stem cell transplantation.

Treatment of complications

In addition to direct treatment of malignant cells, therapy must also be directed at complications, which include anemia, hypercalcemia, renal insufficiency, infections, and skeletal lesions.

Anemia can be treated with recombinant erythropoietin (40,000 units sc once/wk) in patients whose anemia is inadequately relieved by chemotherapy. If anemia causes cardiovascular or significant systemic symptoms, packed RBCs are transfused. Plasma exchange is indicated if hyperviscosity develops (see Symptoms and Signs). Often patients are iron deficient and require intravenous iron. Patients with anemia should have periodic measurement of serum iron, transferrin, and ferritin levels to monitor iron stores.

Hypercalcemia is treated with vigorous saluresis, IV bisphosphonates after rehydration, and sometimes with calcitonin or prednisone.

Hyperuricemia may occur in some patients with high tumor burden and underlying metabolic problems. However, most patients do not require allopurinol. Allopurinol is indicated for patients with high levels of serum uric acid or high tumor burden and a high risk of tumor lysis syndrome with treatment.

Renal compromise can be ameliorated with adequate hydration. Even patients with prolonged, massive Bence Jones proteinuria ( 10 to 30 g/day) may have intact renal function if they maintain urine output > 2000 mL/day. Dehydration combined with high-osmolar IV contrast may precipitate acute oliguric renal failure in patients with Bence Jones proteinuria. Plasma exchange may be effective in some cases.

Infection is more likely during chemotherapy-induced neutropenia. In addition, infections with the herpes zoster virus are occurring more frequently in patients treated with newer antimyeloma drugs, especially bortezomib or carfilzomib. Documented bacterial infections should be treated with antibiotics; however, prophylactic use of antibiotics is not routinely recommended. Prophylactic use of antiviral drugs (eg, acyclovir, valganciclovir, famciclovir) is indicated for patients receiving either bortezomib or carfilzomib. Prophylactic IV immune globulin may reduce the risk of infection but is generally reserved for patients with recurrent infections. Pneumococcal and influenza vaccines are indicated to prevent infection. However, use of live vaccines is not recommended in these immunocompromised patients.

Skeletal lesions require multiple supportive measures. Maintenance of ambulation and supplemental calcium and vitamin D help preserve bone density. Vitamin D levels should be measured at diagnosis and periodically and dosing of vitamin D adjusted accordingly. Analgesics and palliative doses of radiation therapy (18 to 24 Gy) can relieve bone pain. However, radiation therapy may cause significant toxicity and, because it suppresses bone marrow function, may impair the patient’s ability to receive cytotoxic doses of systemic chemotherapy. Most patients, especially those with lytic lesions and generalized osteoporosis or osteopenia, should receive a monthly IV bisphosphonate (either pamidronate or zoledronic acid). Bisphosphonates reduce skeletal complications and lessen bone pain and may have an antitumor effect.

Key Points

  • Malignant plasma cells produce monoclonal immunoglobulin and invade and destroy bone.

  • Expanding plasmacytomas and cytokine secretion cause multiple, discrete, osteolytic lesions (usually in the pelvis, spine, ribs, and skull) and diffuse osteoporosis; pain, fractures, and hypercalcemia are common.

  • Anemia and renal failure are common.

  • Amyloidosis develops in about 10%, typically patients who produce excess lambda light chains.

  • Perform serum and urine protein electrophoresis followed by immunofixation, quantitative immunoglobulins, and measurement of serum free light chains.

  • Symptomatic patients and those with organ dysfunction should be treated with drug therapy and, for certain patients, autologous stem cell transplantation.

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