- Clinical science
Multiple myeloma (Kahler's disease, plasma cell myeloma, myelomatosis) is a malignant 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).
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
- Sex: ♂ > ♀ (3:2)
- Peak incidence: 50–70 years
Epidemiological data refers to the US, unless otherwise specified.
- Based on immunoglobulin type
- Neoplastic proliferation of plasma cells
Overproduction of monoclonal immunoglobulin and/or light chains
- Non-functioning antibodies → functional antibody deficiency
- ↑ Serum viscosity → hyperviscosity syndrome
- Often asymptomatic
- Bone pain- especially back pain (most common symptom), spontaneous fractures
- Symptoms of
- Mild fever, night sweats, weight loss
- Weakness and anemia
- Increased risk of infection
- Increased risk of petechial bleeding
- Foamy urine, caused by Bence Jones proteinuria
Enlarged lymph nodes are not a typical finding!
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|| || || |
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:
Approach and diagnostic criteria
- The following tests are required for patients with suspected MM
|Main criterion||Plus at least one of the following “myeloma-defining events”|
|Multiple myeloma|| |
CRAB indicates organ damage: Calcium increased, Renal insufficiency, Anemia, and Bone lesions!
- Peripheral blood smear: Rouleaux formation
- Electrophoresis and immunofixation
- Urinalysis: 24-hour urine collection (protein, creatinine clearance)
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.
First choice: low‑dose whole‑body CT (WBLD-CT)
- Detection of osteolysis and osteopenia
- More sensitive than x-rays in detecting active myeloma lesions.
- 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), stain-like areas of decreased signal intensity on T1-weighted images in vertebrae, vertebral fractures, moderate contrast enhancement, evaluation of extramedullary manifestations
- Characterized by complete or incomplete monoclonal immunoglobulins detectable in patient serum without accompanying clinical symptoms
- Diagnostic criteria
- Evaluation: MGUS usually precedes multiple myeloma.
- Treatment: none required (watch and wait)
- 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.
- Impaired platelet function → hemorrhagic diathesis with petechial bleeding
- Normochromic anemia
- Raynaud's phenomenon
Formation of cold agglutinins (IgM) with hyperviscosity syndrome
- Impaired acral blood flow
- Impaired vision, hearing, and renal function
- Lymph node enlargement possible
- Constitutional symptoms (e.g., fatigue, headache)
The differential diagnoses listed here are not exhaustive.
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
- Supportive therapy
- ; : light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia, and malabsorption syndromes.
- Most common cause of renal injury and renal failure in patients with MM
- Pathophysiology: Light chains are directly toxic to renal tissue and protein complex (cast) formation in the distal nephron leads to tubular obstruction
- Clinical findings: fatigue, peripheral edema and dyspnea, oliguria
- Light chain deposition disease
- Renal involvement with AL amyloidosis
- Renal damage caused by hypercalcemia → hypercalciuria (nephrocalcinosis)
- Analgesic nephropathy due to long-term intake of NSAIDs for bone pain
- (myeloma kidney)
Secondary plasma cell leukemia
- 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.
- The course of disease and prognosis are highly variable.