• Clinical science

Multiple myeloma (Plasmocytoma)

Abstract

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

  • Based on immunoglobulin type
    • IgG: 50% of multiple myelomas
    • IgA: 25% of multiple myelomas
    • Bence Jones myeloma (free light chains excreted in urine): 20% of multiple myelomas
    • IgD (rare: non-secretory myeloma): < 1% of multiple myelomas, type IgE

Abnormal production of monoclonal IgM suggests Waldenstrom's macroglobulinemia rather than multiple myeloma!
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

Durie-Salmon staging system

Stage I Stage II Stage III
Blood: hemoglobin > 10 g/dL Stage II is diagnosed if one of the parameters cannot be assigned to either stage I or stage III. < 8.5 g/dL
Blood: serum Ca2+ 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

Since renal function is also relevant for the prognosis, the classification also includes:

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

  • Confirmatory test: indicated for all patients with suspected MM
  • Fluorescence in situ hybridization (FISH): detect translocations/deletions for risk stratification
    • High risk: t(14;16), t(14;20); 17p13 deletion
    • Intermediate risk: t(4;14)
    • Standard risk: t(11;14), t(6;14)
  • Cytology: clusters of plasma cells
    • Mildly organized monoclonal cells
    • Perinuclear lucent zone
    • Clockface nuclei: Chromatin in the periphery of the nucleus resembles a cartwheel or clock face arrangement.

Imaging

  • First choice: X-ray skeletal survey
    • Osteolysis
    • Multiple lytic lesions ("punched-out" holes) in the skull
  • Alternatives
    • Low‑dose whole‑body CT: detection of osteolysis and osteopenia
    • FDG/PET scan or MRI: detects areas of active osteolysis
    • MRI: stain-like areas of decreased signal intensity on T1-weighted images in vertebrae, vertebral fractures, moderate contrast enhancement, evaluation of extramedullary manifestations

References:[6][2][1][7][8][9][10]

Differential diagnoses

Other plasma cell dyscrasias

Monoclonal gammopathy of undetermined significance (MGUS)

Waldenstrom's macroglobulinemia

References:[6][11][12][13][14]

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 (HCT).

  • Asymptomatic patients: watch and wait, unless patients have ≥ 60% clonal cells, excessive free light chains or ≥ 1 bone lesion
  • Symptomatic patients
    • Standard and intermediate risk
      • HCT eligible : induction therapy followed by autologous HCT
      • HCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomide)
    • High-risk patients should be enrolled in clinical trials
  • Supportive therapy

References:[2]

Complications

References:[15][16]

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:[17]

last updated 10/16/2018
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