• Clinical science

Multiple myeloma

Summary

Multiple myeloma (Kahler's disease, plasma cell myeloma, myelomatosis) is a malignant plasma cell dyscrasia characterized by uncontrolled proliferation and the diffuse infiltration of monoclonal (=same type) plasma cells in the bone marrow. Plasmacytoma, a subtype of multiple myeloma, originates from the same type of malignant plasma cells but is characterized by solitary cell proliferation that forms a mass. Malignant plasma cells generally produce monoclonal proteins (also known as M proteins or paraproteins), such as abnormal antibodies (e.g., IgG or IgA) or immunoglobulin light chains (e.g., Bence Jones protein). The condition is most common in elderly patients, who present with unspecific symptoms (fever, night sweats, weight loss), bone pain, or back pain, although multiple myeloma may also be asymptomatic; in this case, it is often a coincidental finding of serum protein electrophoresis. Proliferating plasma cells suppress normal bone marrow function, which leads to clinical findings of anemia, bleeding and/or infection. Additionally, plasma cell proliferation may result in extensive skeletal destruction with hypercalcemia. Complications arising from multiple myeloma often affect the kidneys, leading to conditions such as myeloma cast nephropathy, light chain deposition disease, amyloid light-chain (AL) amyloidosis with renal involvement, and nephrocalcinosis. Younger patients in good general condition are treated with a combination of high-dose chemotherapy and autologous stem cell transplantation, whereas older or frail patients are treated with immunomodulatory drugs (bortezomib, thalidomide, lenalidomide) combined with conventional chemotherapy (melphalan).

Definition

Multiple myeloma is a malignant plasma cell dyscrasia, a group of conditions characterized by the abnormal proliferation of the same type (=monoclonal) of a plasma cell that may also secrete a monoclonal immunoglobulin and/or immunoglobulin fragment (e.g., light chain)

  • Multiple myeloma: diffuse infiltration of the bone marrow
  • Plasmacytoma: extramedullary solitary mass that may affect bones or soft tissue

References:[1]

Epidemiology

  • Sex: > (3:2)
  • Peak incidence: 50–70 years

References:[2][1][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Classification

References:[1]

Pathophysiology

References:[2]

Clinical features

Enlarged lymph nodes are not a typical finding!

References:[1]

Stages

There are two staging systems. The international staging system is preferred because it is less subjective than the Durie-Salmon staging system (can be accessed under extra information).

International Staging System (ISS)

Stage I Stage II Stage III
Serum concentration
Median survival
  • > 5 years
  • 3–4 years
  • 2–3 years

References:[5]

Diagnostics

Approach and diagnostic criteria

Diagnostic criteria
Main criterion Plus at least one of the following “myeloma-defining events”
Multiple myeloma
Plasmacytoma

CRAB indicates organ damage: Calcium increased, Renal insufficiency, Anemia, and Bone lesions!

Laboratory tests

Bone marrow biopsy

Imaging [6]

  • First choice: low‑dose whole‑body CT (WBLD-CT)
  • Alternatives
    • X-ray skeletal survey: multiple lytic lesions ("punched-out" holes), e.g. in the skull
    • FDG/PET scan: detects areas of active osteolysis
    • MRI: visualizes infiltration and replacement of bone marrow (e.g., in the spine and pelvis)

References:[7][2][1][8][9][10][11]

Differential diagnoses

Other plasma cell dyscrasias

Monoclonal gammopathy of undetermined significance (MGUS)

  • Characterized by complete or incomplete monoclonal immunoglobulins (of any class) detectable in patient serum without accompanying clinical symptoms
  • Epidemiology
  • Diagnostic criteria
  • Complications: multiple myeloma (approx. 1% of MGUS cases per year transform into multiple myeloma)
  • Treatment: none required (monitor M-protein levels)

Waldenstrom macroglobulinemia

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

References:[7][12][13][14][15]

The differential diagnoses listed here are not exhaustive.

Treatment

The choice of therapy depends on the outcome of the patient's category, general condition, and eligibility for hematopoietic stem cell transplantation (HSCT).

References:[2]

Complications

References:[16][17]

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

Prognosis

  • The course of disease and prognosis are highly variable.
    • Therapeutic options have improved significantly. However, complete remission is rare.
    • Negative prognostic factors include advanced stage according to the ISS staging system, advanced age, β2 microglobulin, ↓ serum albumin, CRP, and LDH.

References:[18]

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  • 2. Shah D. Multiple Myeloma. In: Besa EC. Multiple Myeloma. New York, NY: WebMD. http://emedicine.medscape.com/article/204369. Updated December 8, 2016. Accessed April 12, 2017.
  • 3. Fanning SR. Extramedullary Plasmacytoma. In: Besa EC. Extramedullary Plasmacytoma. New York, NY: WebMD. http://emedicine.medscape.com/article/207233. Updated December 1, 2015. Accessed April 12, 2017.
  • 4. Di Muzio B. Plasmacytoma. https://radiopaedia.org/articles/plasmacytoma. Updated January 1, 2017. Accessed April 12, 2017.
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  • 6. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology. 2017; 28(suppl_4): pp. iv52–iv61. doi: 10.1093/annonc/mdx096.
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  • 9. Clarke K, Dobro S, Brande L. Always Work Up a Significant Globulin Gap. http://www.shmabstracts.com/abstract/always-work-up-a-significant-globulin-gap/. Updated January 1, 2015. Accessed April 12, 2017.
  • 10. Lambert L, Ourednicek P, Meckova Z, Gavelli G, Straub J, Spicka I. Whole-body low-dose computed tomography in multiple myeloma staging: Superior diagnostic performance in the detection of bone lesions, vertebral compression fractures, rib fractures and extraskeletal findings compared to radiography with similar radiation exposure. Oncol Lett. 2017; 13(4): pp. 2490–2494. doi: 10.3892/ol.2017.5723.
  • 11. Cooper EH, Plesner T. Beta-2-microglobulin review: Its relevance in clinical oncology. Med Pediatr Oncol. 1980; 8(4): pp. 323–334. doi: 10.1002/mpo.2950080403.
  • 12. Gertz MA. Waldenström macroglobulinemia: 2017 update on diagnosis, risk stratification, and management. Am J Hematol. 2017; 92(2): pp. 209–217. doi: 10.1002/ajh.24557.
  • 13. 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): pp. 1071–1079. doi: 10.1016/j.mayocp.2012.06.014.
  • 14. 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): pp. 5573–5581. doi: 10.1182/blood-2011-01-270140.
  • 15. Rajkumar SV, Ansell SM, Kyle RA, Connor RF. Epidemiology, Pathogenesis, Clinical Manifestations, and Diagnosis of Waldenström Macroglobulinemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/epidemiology-pathogenesis-clinical-manifestations-and-diagnosis-of-waldenstrom-macroglobulinemia. Last updated May 29, 2018. Accessed June 21, 2018.
  • 16. Rotaru I, Găman G, Dumitrescu D, Foarfă C. Secondary plasma cell leukemia. Rom J Morphol Embryol. 2012; 53(4): pp. 1073–1076. pmid: 23303035.
  • 17. Parmar MS. Light Chain-Associated Renal Disorders. In: Batuman V. Light Chain-Associated Renal Disorders. New York, NY: WebMD. https://emedicine.medscape.com/article/244082. Updated November 21, 2015. Accessed April 5, 2018.
  • 18. Rajkumar SV. Overview of the Management of Multiple Myeloma. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/overview-of-the-management-of-multiple-myeloma. Last updated December 23, 2016. Accessed April 12, 2017.
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  • Schieferdecker A, Hörber S, Ums M, et al. Comparison of three different serum-free light-chain assays—implications on diagnostic and therapeutic monitoring of multiple myeloma. Blood Cancer Journal. 2020; 10(1). doi: 10.1038/s41408-019-0267-8.
last updated 06/14/2020
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