Multiple myeloma

Last updated: July 21, 2023

Summarytoggle arrow icon

Multiple myeloma (MM) is a malignant plasma cell dyscrasia characterized by uncontrolled proliferation and diffuse infiltration of monoclonal plasma cells in the bone marrow. Malignant plasma cells produce monoclonal proteins (also known as M proteins or paraproteins) such as abnormal immunoglobulins (e.g., IgG, IgA) and free light chains (e.g., Bence Jones proteins). MM is more common in older adults and manifests with nonspecific symptoms (fever, night sweats, weight loss), symptoms of hypercalcemia, bone pain, and/or back pain. This condition is sometimes discovered incidentally in asymptomatic individuals. The proliferation of plasma cells suppresses normal bone marrow function, which may lead to anemia, bleeding, and/or infection. Plasma cell proliferation can also result in osteolysis and hypercalcemia. Renal complications are common, including myeloma cast nephropathy, light chain deposition disease, amyloid light-chain (AL) amyloidosis with renal involvement, and nephrocalcinosis. Most patients are treated with a combination of high-dose chemotherapy and autologous stem cell transplantation; patients with impaired functional status are treated with chemotherapy alone. While advancements in treatment regimens have resulted in improved patient outcomes, most patients with MM eventually relapse.

Definitiontoggle arrow icon

Epidemiologytoggle arrow icon

Epidemiological data refers to the US, unless otherwise specified.

Classificationtoggle arrow icon

  • Based on immunoglobulin type [2]
    • IgG and IgA: typical multiple myeloma; majority of patients
    • Bence Jones myeloma (free light chains excreted in urine): 15–20% of multiple myelomas
    • IgD, IgE, and IgM: very rare subtypes of multiple myelomas

Pathophysiologytoggle arrow icon

Clinical featurestoggle arrow icon

Enlarged lymph nodes are not a typical finding.

Diagnosticstoggle arrow icon

Approach [5][6][7]

Evaluation of a patient with suspected multiple myeloma (e.g., a patient with CRAB criteria) should include CBC, CMP, immunoglobulin studies, LDH, β2 microglobulin, bone imaging, and a bone marrow biopsy.

Diagnostic criteria

International Myeloma Working Group diagnostic criteria for multiple myeloma [8]
Criteria Description

Myeloma defining events

End-organ damage (CRAB criteria)
  • Calcium > 11 mg/dL or > 1 mg/dL above the ULN
  • Renal insufficiency: GFR < 40 mL/min or serum creatinine > 2 mg/dL
  • Anemia: Hb < 10 g/dL or more than 2 g/dL below the LLN
  • Bone lesions: ≥ 1 osteolytic lesions on imaging
Biomarkers of malignancy

CRAB criteria for organ damage due to a plasma cell disorder: Calcium increased, Renal insufficiency, Anemia, Bone lesions

Evaluation for biomarkers of malignancy may allow for diagnosis and treatment of multiple myeloma before end-organ damage has occurred.

Laboratory tests [7][8]

Routine studies

Myeloma biomarkers

Additional testing

Further evaluation for differential diagnoses (guided by clinical features) may include:

Imaging studies [5][6][10]

Whole-body low-dose CT (WBLDCT)

Skeletal survey

Low sensitivity; no longer considered the best initial test

  • Indications
    • Obtain if other more sensitive techniques are not available.
    • May be used to evaluate for skull and rib lesions, which are not well detected by WBLDCT or MRI.
  • Findings

Ancillary tests

Bone marrow biopsy

Stagingtoggle arrow icon

Revised International Staging System (R-ISS) [12]

The R-ISS is currently the most commonly used staging system.

Revised International Staging System for multiple myeloma [12]
Stage Laboratory features 5-year overall survival rate
  • 82%
  • Not R-ISS stage I or stage III
  • 62%
  • 40%

The R-ISS for multiple myeloma incorporates LDH levels and FISH in addition to the variables used in the International Staging System (i.e., β2 microglobulin and albumin), which improves its ability to stratify risk and determine the prognosis of patients with newly diagnosed multiple myeloma. [12]

International Staging System (ISS) [13]

International Staging System for multiple myeloma [12]
Stage Laboratory features Median survival from diagnosis

β2 microglobulin < 3.5 mg/L AND albumin ≥ 3.5 g/dL

> 5 years


Not stage I or stage III

3–4 years


β2 microglobulin ≥ 5.5 mg/L

2–3 years

Durie-Salmon staging system

Durie-Salmon staging system for multiple myeloma [14]
Stage I: All of the following must be present. Stage II Stage III: ≥ 1 of the following must be present.
Blood: hemoglobin > 10 g/dL Not stage I or stage III < 8.5 g/dL
Blood: serum calcium Normal (< 2.8 mmol/L) > 3.0 mmol/L
Urine: monoclonal Ig Low concentration High concentration
X-ray: bones One (maximum) solitary osteolytic lesion Several advanced osteolytic lesions


Managementtoggle arrow icon

General principles [5][6][7][15]

Refer all patients to a transplant center to determine eligibility for stem cell transplantation.

Stem cell transplantation [5][6][11]

Neither advanced age nor poor renal function are absolute contraindications for autologous stem cell transplantation.

Autologous stem cell transplantation improves median overall survival by ∼12 months but is not curative. [11]

Chemotherapy [5]

There is no expert consensus regarding the optimal chemotherapeutic regimen or number of cycles.

Overview of chemotherapeutic agents commonly used for multiple myeloma [5]
Medication class Common agents
Proteasome inhibitors
Cancer immunotherapy
For the mechanism of action and common adverse effects, see “Chemotherapeutic agents.”

Choice of regimen depends on transplant eligibility, disease risk factors (e.g., R-ISS stage, cytogenetics), patient factors (e.g., frailty, comorbidities, functional status), and patient preferences (e.g., length and quality of life).

Monitoring [5][11][16]

  • Response to treatment
    • Defined based on International Myeloma Working Group (IMWG) criteria [16]
    • Categories range from stringent complete response to progressive disease
  • Clinical relapse
    • Defined as recurrence or worsening of myeloma-defining events (e.g., CRAB) after clinical improvement [11]
    • Management (i.e., salvage/delayed autologous HSCT and/or chemotherapy) should be individualized.
    • After a relapse, therapy may be continued until the disease progresses.

Nearly all patients will relapse; the average time to first relapse is ∼ 3–4 years after initial diagnosis.

Prevention of complications [11][17]

Management of complications [11]

Management should be provided under specialist guidance.

Overview of the management of complications of multiple myeloma
Complication Management options
Bone disease [18][22]
Renal disease [23]
Peripheral neuropathy [17]
Hematological complications [11][17][18] Anemia
  • Granulocyte-colony stimulating factor (G-CSF): if neutrophil count < 1,000 cells/mL

Treatment of pain (e.g., due to compressive myelopathy or pathological fractures) includes low-dose radiotherapy, high-dose corticosteroids, and invasive therapy (e.g., vertebroplasty, balloon kyphoplasty).

All patients with active multiple myeloma should be treated with bisphosphonates (unless contraindicated), regardless of the presence or absence of imaging findings of bone disease related to multiple myeloma.

Bisphosphonate therapy and denosumab both increase the risk of osteonecrosis of the jaw. Ensure patients undergo a comprehensive dental evaluation and any necessary dental procedures before starting therapy for bone disease. [22]

Differential diagnosestoggle arrow icon

Overview of plasma cell dyscrasias (PCDs)

Multiple myeloma should be differentiated from other plasma cell dyscrasias.

Diagnostic criteria for plasma cell dyscrasias associated with multiple myeloma [8][18][24]
Plasma cell dyscrasia Diagnostic criteria

Smoldering multiple myeloma

Solitary plasmacytoma
Plasma cell leukemia
POEMS syndrome
Monoclonal gammopathy of undetermined significance (MGUS)
Waldenstrom macroglobulinemia [25][26]

POEMS syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell proliferative disorders, Skin changes

Monoclonal gammopathy of undetermined significance (MGUS) [27][28]


Characterized by complete or incomplete monoclonal immunoglobulins (of any class) detectable in patient serum without accompanying clinical symptoms



Risk stratification [30]

Patients can be stratified into the following categories according to their risk of progression to multiple myeloma or related malignancy.

  • Low-risk MGUS includes all of the following:
  • Moderate to high-risk MGUS: any feature not considered low-risk

Diagnostics [30][31][32]


  • Management is usually expectant.
  • Long-term follow up: Monitor for progression to lymphoplasmacytic malignancy.

Monitor patients with MGUS for progression to lymphoplasmacytic malignancy.


Waldenstrom macroglobulinemia [26]


A type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies


Mostly occurs in older adults

Clinical features

Diagnostics [26]

Diagnostic criteria may help establish a diagnosis; see “Diagnostic criteria for plasma cell dyscrasias.”

Overproduction of monoclonal IgM suggests Waldenstrom macroglobulinemia rather than multiple myeloma.


Usually reserved for symptomatic patients


Good, as it is a type of indolent lymphoma

POEMS syndrome

See “Diagnostic criteria for plasma cell dyscrasias” for details.

The differential diagnoses listed here are not exhaustive.

Complicationstoggle arrow icon

Renal disease

Systemic manifestations

We list the most important complications. The selection is not exhaustive.

Prognosistoggle arrow icon

  • The course of disease and prognosis are highly variable.
  • Therapeutic options have improved significantly. However, complete remission is rare.
  • Poor prognostic factors include

Referencestoggle arrow icon

  1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 Patients With Newly Diagnosed Multiple Myeloma. Mayo Clinic Proceedings. 2003; 78 (1): p.21-33.doi: 10.4065/78.1.21 . | Open in Read by QxMD
  2. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23 (12): p.2210-2221.doi: 10.1038/leu.2009.174 . | Open in Read by QxMD
  3. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019; 37 (14): p.1228-1263.doi: 10.1200/jco.18.02096 . | Open in Read by QxMD
  4. Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 2021; 32 (3): p.309-322.doi: 10.1016/j.annonc.2020.11.014 . | Open in Read by QxMD
  5. Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and Management of Multiple Myeloma. JAMA. 2022; 327 (5): p.464.doi: 10.1001/jama.2022.0003 . | Open in Read by QxMD
  6. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15 (12): p.e538-e548.doi: 10.1016/s1470-2045(14)70442-5 . | Open in Read by QxMD
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  10. Mateos MV, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020; 10 (10).doi: 10.1038/s41408-020-00366-3 . | Open in Read by QxMD
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  14. Therneau TM, Kyle RA, Melton LJ, et al. Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition. Mayo Clin Proc. 2012; 87 (11): p.1071-1079.doi: 10.1016/j.mayocp.2012.06.014 . | Open in Read by QxMD
  15. Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood. 2011; 117 (21): p.5573-5581.doi: 10.1182/blood-2011-01-270140 . | Open in Read by QxMD
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