Multiple myeloma

Multiple myeloma (Kahler 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).

• 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

• Sex: : ♂ > ♀ (3:2) ^[1]
• Peak incidence: : 50–70 years ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• 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

• 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 → dysproteinemia (a state of pathologically increased synthesis of immunoglobulins and/or their subunits) → kidney damage (e.g., myeloma cast nephropathy) and/or paraprotein tissue deposition (may cause amyloidosis) ^[3][4]
  • Nonfunctioning antibodies → functional antibody deficiency
  • ↑ Serum viscosity → hyperviscosity syndrome

International Staging System (ISS) ^[5]

• 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.

Approach and diagnostic criteria ^[6]

• 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 ^[7]
  • Bone marrow biopsy (confirmatory test)
  • Laboratory tests (CBC and biochemistry) to assess for hypercalcemia, anemia and renal insufficiency
  • Imaging to assess for bone lesions

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 ^[8]
• 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 ^[9]

• First choice: low‑dose whole body CT (WBLD-CT) ^[10]
  • 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)

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.
• Supportive therapy
  • Osteolysis and bone pain
    • Bisphosphonates
    • Radiation therapy of osteolytic regions
  • Pancytopenia with anemia and increased risk of infection
    • Blood transfusions
    • Granulocyte-colony stimulating factor (G-CSF) and erythropoietin (EPO)

Other plasma cell dyscrasias

Monoclonal gammopathy of undetermined significance (MGUS) ^[11][12]

• Definition: : characterized by complete or incomplete monoclonal immunoglobulins (of any class) detectable in patient serum without accompanying clinical symptoms
• Epidemiology
  • Prevalence: ∼ 3% in general population ≥ 50 years of age ^[13]
  • The most common type of plasma cell dyscrasia (PCD)
• Classification
  • Non-IgM MGUS (IgG, IgA, IgD MGUS): most common form of MGUS (∼ 55% of cases)
  • IgM MGUS: ∼ 15% of cases
  • Light-chain MGUS (LC-MGUS)
• Diagnostics ^[14][15][16]
  • Usually, an incidental finding on workup (e.g., protein electrophoresis) for other conditions such as vasculitis, hypercalcemia, skin rashes, peripheral neuropathy, increased ESR, and hemolytic anemia
  • Screening may be considered in individuals ≥ 50 years of age with two or more affected first-degree relatives with multiple myeloma or related disorders (e.g., cryoglobulinemia, acquired von Willebrand syndrome, C3 glomerulonephritis, light-chain proximal tubulopathy)
  • Risk of progression to myeloma and presence of associated disorders is determined by the following predictors: presence of non-immunoglobulin G-type M protein, M-protein concentration ≥ 1.5 g/dL, and abnormal serum free light chain (SFLC) ratio
    • An M-protein concentration of 1.5–2.9 g/dL, presence of non-IgG M proteins, and abnormal SFLC studies is classified as moderate-to-high risk.
    • If the M-protein concentration exceeds 3 g/dL, it is likely that transformation to a severe PCD has already occurred.
  • Laboratory studies
    • CBC, serum creatinine, and calcium
    • SPEP and UPEP with immunofixation: UPEP is normal if there is no light chain proliferation; light chains (e.g., Bence Jones proteins) are filtered across the glomeruli while heavy chains are not.
    • Quantitative immunoglobulin assessment
    • SFLC studies
  • Bone marrow biopsy is indicated in moderate-to-high risk of progression to malignancy or if there is evidence of transformation to another PCD. ^[14]
  • Imaging
    • Skeletal imaging is indicated in moderate-to-high risk of progression to malignancy or if there is evidence of transformation to another PCD (i.e., M-protein concentration ≥ 3 g/dL, findings of a severe PCD).
    • Modality of choice: low-dose whole-body CT
    • Skeletal survey is indicated if CT is not available.
    • Whole-body MRI is indicated if CT results are inconclusive and multiple myeloma is suspected.
• Diagnostic criteria ^[6]
  • 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 “Approach and diagnostic criteria” above)
• Treatment: none required
• Complications
  • Multiple myeloma
    • Transformation of MGUS into multiple myeloma occurs in approx. 1% of cases
    • Typically arises from non-IgM MGUS
  • Light chain amyloidosis: can occur with all forms of MGUS
  • Waldenstrom macroglobulinemia: only arises from IgM MGUS
  • Increased risk of thrombosis (thromboprophylaxis is usually not required) and developing osteoporosis (bone densitometry should be performed at the time of diagnosis)
  • Lymphoma
• Follow-up: Long-term follow-up involving complete blood count, serum calcium and creatinine, SPEP, and SFLC studies is recommended at 6 months and then every 2–3 years to monitor the risk of progression to lymphoplasmacytic malignancy.

Waldenstrom macroglobulinemia ^[17]

• Definition: : a type of non-Hodgkin lymphoma associated with abnormal production of monoclonal IgM antibodies
• Epidemiology: mostly occurs in old age
• 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)
• 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
• Prognosis: good, as it is a type of indolent lymphoma

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.

Renal disease

• Dysproteinemia-associated kidney disease ^[3]
  • 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).
  • Monoclonal immunoglobulin deposition disease (MIDD)
    • Light chain deposition disease (LCDD)
    • Heavy chain deposition disease (HCDD)
    • Light and heavy chain deposition disease (LHCDD)
  • Type I cryoglobulinemia
    • An immune-mediated disorder characterized by the deposition of monoclonal immunoglobulins (IgG and IgM) within blood vessels.
    • Most commonly associated with protein-secreting monoclonal gammopathies, including monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, and multiple myeloma.
  • Type II cryoglobulinemia
  • Immunotactoid glomerulopathy
  • Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)
  • Monoclonal gammopathy-associated C3 glomerulopathy
  • Light-chain proximal tubulopathy
  • Monoclonal IgM-mediated kidney disease
  • Monotypic fibrillary glomerulonephritis
• Hypercalcemia-associated renal damage: leads to hypercalciuria and nephrocalcinosis
• Analgesic nephropathy: caused by long-term intake of NSAIDs for bone pain

Systemic manifestations

• 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
• Secondary plasma cell leukemia ^[18]
  • 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
• Hypercalcemic crisis: Osteolysis is associated with chronically elevated calcium levels, which can result in hypercalcemic crisis.

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

• 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