*Multiple Myeloma

Chapter: Multiple Myeloma
McMaster Section Editor(s): Mark Crowther
Section Editor(s) in Interna Szczeklika: Andrzej Hellmann, Bogdan Ochrem
McMaster Author(s): Kylie Lepic, Mark Crowther
Author(s) in Interna Szczeklika: Anna Dmoszyńska
Additional Information

Definition, Etiology, PathogenesisTop

Multiple myeloma (MM) or plasma cell myeloma (PCM) is a hematologic malignancy that involves the proliferation and accumulation of monoclonal plasma cells, which produce monoclonal immunoglobulin or its fragments (M protein). Neoplastic cells most probably originate from memory B cells. The etiology is unknown.

Clinical Features and Natural HistoryTop

Clinical manifestations are caused by the proliferation of neoplastic plasma cells, which secrete monoclonal (abnormal) proteins as well as cytokines. The manifestations include:

1) Bone pain (the most common symptom, present at some stage in a majority of patients) in the lumbar spine, pelvis, ribs, or less commonly in the skull and long bones. This is caused by osteolytic lesions and pathologic fractures (eg, vertebral compression fractures).

2) Features of hypercalcemia and its complications: Symptoms may occur in up to 20% of patients.

3) Features of renal failure: These are present at the time of diagnosis of MM in ~30% of patients.

4) Symptoms of anemia (seen in a majority of patients).

5) Neurologic signs and symptoms: These may include limb paresis or paralysis (due to spinal cord or nerve compression caused by vertebral body fracture or extramedullary plasma cell tumor [plasmacytoma]) and rarely features of peripheral neuropathy. The manifestations are seen in ~10% of patients.

6) Recurrent respiratory and urinary tract infections.

7) Features of hyperviscosity syndrome (in <10% of patients): Somnolence, headache, hearing impairment, altered mental status, heart failure, and bleeding (usually epistaxis or gingival bleeding).

8) Rarely, extramedullary plasmacytoma and enlargement of the liver, peripheral lymph nodes, and spleen.

In ~10% to 15% of patients the disease is indolent and requires no treatment (so-called smoldering MM). However, in the majority of patients the disease is progressive or relapses after subsequent lines of treatment.


Diagnostic Tests

1. Complete blood count in the majority of patients reveals normocytic (less commonly macrocytic) normochromic anemia, with the formation of red blood cells in the form of rouleaux in 50% of patients. Less commonly, leukopenia or thrombocytopenia are observed.

2. Bone marrow examination: More than 10% of clonal plasma cells.

3. Cytogenetic studies may be performed for risk stratification.

4. Other laboratory tests: Hypergammaglobulinemia; decreased levels of normal immunoglobulins; monoclonal protein identified in blood and urine electrophoresis and immunofixation; presence of abnormal light chains in blood and/or urine (monoclonal urinary light chains are referred to as Bence Jones proteinuria); hypercalcemia; increased serum uric acid, creatinine, beta2-microglobulin, C-reactive protein, and lactate dehydrogenase levels; rarely cryoglobulinemia. Hyperproteinemia and the erythrocyte sedimentation rate (this may be markedly elevated) are nonspecific tests and we do not perform them routinely in our setting (at McMaster University).

5. Skeletal imaging studies (radiography, computed tomography [CT] and/or magnetic resonance imaging [MRI], or positron emission tomography [PET]-CT) reveal focal osteolytic lesions—most commonly in the flat and long bones—as well as osteoporosis and pathologic fractures. Radiographs should include the skull, brachial and femoral bones, pelvis, spine, and all painful locations.

Diagnostic Criteria

1. According to the 2014 International Myeloma Working Group criteria, MM is diagnosed in patients with clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and at least one of the following myeloma-defining events:

1) Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

a) Hypercalcemia: Serum calcium >0.25 mmol/L above the upper limit of normal or >2.75 mmol/L.

b) Renal insufficiency: Creatinine clearance <40 mL/minute or serum creatinine >177 micromol/L.

c) Anemia: Hemoglobin level >2 g/dL below the lower limit of normal or <10 g/dL.

d) Bone lesions: One or more osteolytic lesions on skeletal radiography, CT, or PET-CT.

2) Any one or more of the following biomarkers of malignancy:

a) Clonal bone marrow plasma cells ≥60%.

b) An involved to uninvolved serum free light chain (FLC) ratio ≥100 if the involved FLC concentration is ≥100 mg/L.

c) More than 1 focal lesion ≥5 mm in diameter on MRI studies.

2. Smoldering MM:

1) Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg/24 hours and/or clonal bone marrow plasma cells 10% to 60%.

2) Absence of myeloma-defining events or amyloidosis.

3. Solitary plasmacytoma: A solitary tumor of the bone or (in 1%-2% of patients) other organs, with normal results of bone marrow aspiration and trephine biopsy, normal skeletal radiographs and MRI (or CT) of the spine and pelvis (except for the primary lesion), negative CRAB (hypercalcemia, renal failure, anemia, bone lesions) criteria, and absence or low levels of serum and urine monoclonal immunoglobulin.

4. Plasma cell leukemia: A peripheral blood malignant plasma cell count >2000/microL or >20% of the circulating white blood cells. This is an aggressive disease with a poor prognosis and short survival.

5. POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) is a very rare manifestation of MM.

Differential Diagnosis

1. Other types of monoclonal gammopathy (diseases characterized by the proliferation of a single clone of plasma cells producing the M protein):

1) Monoclonal gammopathy of undetermined significance: The presence of a monoclonal protein alone is an observation that requires no treatment but may transform to MM at a rate of ~1% per year. It can be associated with other conditions (malignancy, connective tissue diseases [rheumatoid arthritis, systemic lupus erythematosus, polymyositis], nervous system diseases [multiple sclerosis, myasthenia, Gaucher disease], bacterial [eg, bacterial endocarditis] or viral [cytomegalovirus, hepatitis C and B viruses] infections) as well as develop in patients after solid organ or hematopoietic stem cell transplantation.

2) Other plasma cell dyscrasias: Amyloidosis, immunoglobulin light chain deposition disease, heavy chain deposition diseases, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.

2. Reactive polyclonal plasmacytosis in patients with infection (eg, rubella, infectious mononucleosis), chronic inflammation, and liver disease (usually <10% plasma cells in bone marrow, absence of M protein, polyclonal plasma cells).

3. Bone metastases of cancer (eg, renal cancer, breast cancer, non–small cell lung cancer, prostate cancer).


Antineoplastic Treatment

1. Patients with asymptomatic (smoldering) myeloma require follow-up only.

2. Patients aged <70 years and patients ≥70 years with no comorbidities are candidates for high-dose chemotherapy (myeloablative dose of melphalan) followed by autologous peripheral blood stem cell transplantation (PBSCT) after achieving a response to induction chemotherapy (usually 4 cycles of multiagent therapy such as VTd [bortezomib, thalidomide, dexamethasone], CyBorD [cyclophosphamide, bortezomib, dexamethasone], or VRd [bortezomib, lenalidomide, dexamethasone]).

3. Patients not qualified for autologous PBSCT: Chemotherapy, usually using VMP (bortezomib, melphalan, prednisone), Rd (lenalidomide, dexamethasone), or MPT (melphalan, prednisone, thalidomide).

4. Patients with treatment resistance or relapse: Immunomodulators (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), bendamustine, monoclonal antibodies. In selected patients a second autologous transplant or an allogeneic PBSCT may be performed.

5. Solitary plasmacytoma: Surgery or radiation and close monitoring for progression to systemic myeloma.

Supportive Treatment

1. Treatment of kidney failure:

1) Appropriate hydration (fluid intake >3 L/d).

2) Prompt initiation of antimyeloma therapy.

3) Avoidance of nephrotoxic drugs (eg, nonsteroidal anti-inflammatory drugs, aminoglycosides) and contrast media.

4) Treatment of hyperuricemia with allopurinol (see Gout).

5) Plasmapheresis is an expensive and invasive treatment that has been shown to not modify outcomes,Evidence 1Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to marked imprecision. Clark WF, Stewart AK, Rock GA, et al; Canadian Apheresis Group. Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med. 2005 Dec 6;143(11):777-84. Erratum in: Ann Intern Med. 2007 Mar 20;146(6):471. PubMed PMID: 16330788.except rarely in patients with hyperviscosity.

2. Prevention of bony complications and treatment of osteolysis is based on bisphosphonates administered for 2 years or longer in patients with lytic lesions (to be resumed in case of disease progression or relapse). The agents include:

1) Pamidronate disodium (INN pamidronic acid) 60 to 90 mg as a 3- to 4-hour IV infusion in 500 mL 0.9% saline every 4 weeks with consideration given to lower doses for patients with renal insufficiency.

2) Zoledronate (INN zoledronic acid) 2 to 8 mg as a 5- to 15-minute IV infusion in 500 mL 0.9% saline every 4 weeks.

In patients with vertebral compression fractures, consider vertebroplasty or kyphoplasty. Calcium and vitamin D supplementation is used in the case of deficiencies.

3. Treatment of hypercalcemia and hypercalcemic crisis.

4. Treatment of hyperproteinemia and coagulopathy: Plasmapheresis with substitution of albumin or clotting factors.

5. Treatment of symptomatic anemia: Erythropoiesis-stimulating agents or transfusions if required (see Anemia of Chronic DiseaseSarcoidosis).

6. Analgesic treatment: Acetaminophen (INN paracetamol), opioids (avoid nonsteroidal anti-inflammatory drugs), radiotherapy, surgery (vertebroplasty).

7. Prevention of infections: Influenza and pneumococcal vaccinations, and acyclovir (INN aciclovir) in patients treated with bortezomib. Consider intravenous immunoglobulin or subcutaneous immunoglobulin in patients with severe recurrent infections.

8. Antithrombotic prophylaxis: Acetylsalicylic acid 75 to 100 mg/d or low-molecular-weight heparin (see Table 4 in Primary Prevention of Venous Thromboembolism) in patients treated with thalidomide or lenalidomide in combination with dexamethasone.


Outcomes in MM vary depending on staging and risk stratification. Five-year overall survival rates are >45%.

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