Summary
Multiple myeloma (Kahler's disease) is a malignant plasma cell dyscrasia characterized by uncontrolled proliferation and the diffuse infiltration of monoclonal plasma cells in the bone marrow. Plasmacytoma, an early-stage plasma cell dyscrasia, 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
- 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)
- Plasmacytoma: an early-stage plasma cell dyscrasia characterized by a single lesion that affect bones (solitary plasmacytoma of bone) or soft tissue (solitary extramedullary plasmacytoma), or in rare cases multiple solitary lesions in soft tissue, bone or both (multiple solitary plasmacytoma)
- Multiple myeloma: a malignant plasma cell dyscrasia characterized by uncontrolled proliferation and the diffuse infiltration of monoclonal plasma cells in the bone marrow
Epidemiology
Epidemiological data refers to the US, unless otherwise specified.
Classification
- Based on immunoglobulin type [2]
Pathophysiology
-
Neoplastic proliferation of plasma cells
- Bone marrow infiltration by malignant plasma cells → suppression of hematopoiesis → leukopenia, thrombocytopenia, anemia
- Cell proliferation → osteolysis → hypercalcemia
-
Overproduction of monoclonal immunoglobulin and/or light chains
- Nonfunctioning antibodies → functional antibody deficiency
- ↑ Serum viscosity → hyperviscosity syndrome
Clinical features
- Often asymptomatic
- Mild fever, night sweats, weakness, and weight loss
- Bone pain, especially back pain (most common symptom)
- Symptoms of hypercalcemia
- Spontaneous fractures
- Increased risk of infection
- Increased risk of petechial bleeding
- Foamy urine (caused by Bence Jones proteinuria)
Enlarged lymph nodes are not a typical finding.
Stages
International Staging System (ISS) [3]
| International Staging System for multiple myeloma | |||
|---|---|---|---|
| Features | Stage I | Stage II | Stage III |
| Serum concentration |
|
|
|
| Median survival |
|
|
|
Diagnostics
Approach and diagnostic criteria [4]
- The following tests are required for patients with suspected MM
- Serum protein electrophoresis or free light chain assay (best initial test)
- 24-hour urine protein electrophoresis [5]
- Bone marrow biopsy (confirmatory test)
- Laboratory tests (CBC and biochemistry; ) to assess for hypercalcemia, anemia and renal insufficiency
- Imaging to assess for bone lesions
| Diagnostic criteria [4] | ||
|---|---|---|
| Types | 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
-
CBC
- Anemia, thrombocytopenia, leukopenia, eventually pancytopenia
- ↓ Reticulocyte count
- Peripheral blood smear: rouleaux formation
-
Biochemistry
- Elevated total protein levels (often one of the first signs)
- Hypercalcemia
- ↑ Creatinine
- Massively increased ESR
- Paraprotein (gamma) gap: Paraproteins produced by malignant plasma cells increase the difference between total serum protein and a normal albumin concentration.
- ↑ β2 microglobulin [6]
-
Electrophoresis and immunofixation
- Serum protein electrophoresis (best initial test): monoclonal gammopathy with M protein (M spike)
-
Urine protein electrophoresis: Bence Jones proteins
- Bence Jones proteins are monoclonal immunoglobulin light chains produced by neoplastic cells.
- Presence in urine is suggestive of plasma cell disorders such as multiple myeloma or Waldenstrom macroglobulinemia.
-
Urinalysis
- 24-hour urine collection (protein, creatinine clearance)
- Urine dipstick negative for protein
Bone marrow biopsy
- Indication: confirmatory test indicated for all patients with suspected MM
- Fluorescence in situ hybridization (FISH): detect translocations/deletions for risk stratification
-
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.
- Intracytoplasmic crystalline inclusion bodies containing IgG
Imaging [7]
-
First choice: low‑dose whole body CT (WBLD-CT) [8]
- Detection of osteolysis and osteopenia
- More sensitive than x-rays in detecting active myeloma lesions
-
Alternatives
- 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)
Treatment
The choice of therapy depends on the outcome of the patient's category, general condition, and eligibility for hematopoietic stem cell transplantation (HSCT).
- 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
- HSCT eligible: induction therapy followed by autologous HSCT
- HSCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomide)
- High-risk patients should be enrolled in clinical trials.
- Standard and intermediate risk
-
Supportive therapy
-
Osteolysis and bone pain
- Bisphosphonates
- Radiation therapy of osteolytic regions
- Pancytopenia with anemia and increased risk of infection
-
Osteolysis and bone pain
Differential diagnoses
Other plasma cell dyscrasias
Monoclonal gammopathy of undetermined significance (MGUS) [9][10]
- Definition: : characterized by complete or incomplete monoclonal immunoglobulins (of any class) detectable in patient serum without accompanying clinical symptoms
-
Epidemiology
- Prevalence: ∼ 3% in individuals 45–75 years of age
- The most common type of plasma cell dyscrasia
-
Diagnostic criteria
- Paraproteins: monoclonal immunoglobulins detectable in serum < 3 g/dL (30 g/L)
- Bone marrow: < 10% of monoclonal plasma cells in bone marrow
- No evidence of organ damage or multiple myeloma-associated disease (See “CRAB” mnemonic above.)
- Complications: multiple myeloma (approx. 1% of MGUS cases per year transform into multiple myeloma)
- Treatment: none required (monitor M-protein levels)
Waldenstrom macroglobulinemia [11]
- Definition: : a type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies. It mostly occurs in old age and has a good prognosis, as it is a type of indolent lymphoma.
-
Clinical features
-
Peripheral neuropathy
- Extremities are involved first with progressive, proximal, symmetrical spread
- Presents with paresthesias and weakness (sensory and motor nerve involvement)
- Impaired platelet function → hemorrhagic diathesis with petechial bleeding
- Normochromic anemia
-
Formation of cold agglutinins (IgM) with hyperviscosity syndrome
- Raynaud phenomenon
- Impaired acral blood flow
- Cerebral venous thrombosis
- Impaired vision (e.g., blurry vision)
- Retinal hemorrhages, engorged retinal veins on fundoscopic exam
- Impaired hearing
- Headaches
- Impaired renal function
- Lymph node enlargement possible
- Constitutional symptoms (e.g., fatigue)
-
Peripheral neuropathy
-
Diagnosis
- ↑ ESR, ↑ uric acid, ↑ LDH, and ↑ alkaline phosphatase
- Bone marrow biopsy and aspirate: > 10% abnormal plasma cells with Dutcher bodies (periodic acid-Schiff positive, intranuclear inclusions of IgM deposits)
-
Treatment
- Only indicated in symptomatic patients
- Causative: anti-CD20 antibodies (e.g., rituximab), Bruton tyrosine kinase inhibitors (e.g., ibrutinib), purine nucleoside analogs (fludarabine and cladribine), alkylating agents (e.g., cyclophosphamide)
- Hyperviscosity syndrome: plasmapheresis
Overproduction of monoclonal IgM suggests Waldenstrom macroglobulinemia rather than multiple myeloma!
POEMS syndrome
- Definition: a rare plasma cell disorder that causes chronic overproduction of proinflammatory cytokines
-
Diagnostic criteria
- Polyneuropathy
- Organomegaly
- Endocrinopathy
- Increased production of monoclonal plasma proteins
- Skin changes
The differential diagnoses listed here are not exhaustive.
Complications
- AL amyloidosis: Light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia, and malabsorption syndromes.
-
Infections
- Increased risk due to immunodeficiency (nonfunctional immunoglobulins) and side effects of medications
- Major cause of death in patients with multiple myeloma
- Hypercalcemic crisis: Osteolysis is associated with chronically elevated calcium levels, which can result in hypercalcemic crisis.
-
Renal disease
-
Myeloma cast nephropathy (myeloma kidney)
- Most common cause of renal injury and renal failure in patients with MM
- Diagnosed by markedly positive urine sulfosalicylic acid test and/or urine protein electrophoresis
- It may progress to end-stage renal disease (ESRD).
- Light chain deposition disease
- Renal involvement with AL amyloidosis
- Renal damage caused by hypercalcemia → hypercalciuria and nephrocalcinosis
- Analgesic nephropathy due to long-term intake of NSAIDs for bone pain
-
Myeloma cast nephropathy (myeloma kidney)
-
Secondary plasma cell leukemia [12]
- Leukemic course secondary to multiple myeloma
- Diffuse spreading of abnormal cells and distribution of large amounts of plasma cells into the circulatory system
- Rare; occurs in 2–3% of cases
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.
- Poor prognostic factors include
- Advanced stage according to the ISS staging system
- Advanced age
- ↑ β2 microglobulin
- ↓ Serum albumin
- ↑ CRP
- ↑ LDH