Multiple Myeloma

A clonal malignancy of a differentiated B-lymphocyte — the plasma cell — producing monoclonal immunoglobulin that invades and destroys adjacent bone tissue. Suspect in patients > 40 with persistent unexplained bone pain (especially at night/rest), elevated blood/urinary protein, hypercalcaemia, renal failure, or anaemia.

Demographics: relatively rare (~1.8% of new US cancer diagnoses); a disease of the elderly (median age at diagnosis ~70). Slight male predominance; incidence roughly doubled in Black/African American populations. Asymptomatic in 20% of patients.

Pattern: weakness + unexplained back pain + susceptibility to infection — summarised as CRAB: hyperCalcaemia, Renal dysfunction, Anaemia, Bone pain/lytic lesions.

History

Bone pain (> 80% of patients, from lytic lesions or pathological fractures — particularly back or thorax); bone tenderness; weakness, tiredness, increased thirst; anorexia/weight loss; symptoms of anaemia; bleeding tendency; recurrent infections.

Investigations

• Suggestive abnormalities: hypercalcaemia at diagnosis in ~10% (bone destruction); impaired renal function (light chain deposition in distal tubules); anaemia (present in 80%, typically normocytic/normochromic with rouleaux formation); elevated total protein; ESR usually > 100.
• Diagnosis is based on: serum protein electrophoresis showing a paraprotein; serum free light chains; urine protein electrophoresis (24-hour collection); Bence-Jones protein in urine; bony lytic lesions on skeletal survey; ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) plus ≥1 CRAB or SLiM criterion.

Management

Treatment has improved substantially in the last 20 years and is risk/eligibility stratified:

• Transplant-eligible, high-risk — induction (e.g. daratumumab + bortezomib + lenalidomide + dexamethasone, quadruplet therapy) followed by early autologous stem cell transplant, then proteasome-inhibitor maintenance until progression.
• Transplant-ineligible — extended induction (e.g. VRd for 8–12 cycles, or daratumumab + lenalidomide + dexamethasone) continued until progression.
• Relapsed/refractory disease — CAR-T cell therapy (ciltacabtagene autoleucel, idecabtagene vicleucel) and bispecific antibodies (teclistamab) are approved options.

Prognosis: progressive and incurable; the two main drivers are disease stage and biology. By the Revised International Staging System, 5-year overall survival is ~82% for stage I, ~62% for stage II, and ~40% for stage III; high-risk cytogenetics (t(4;14), t(14;16), t(14;20), 17p deletion) worsen outcomes independent of stage. Median survival now exceeds 8–10 years for many patients on modern regimens.

Precursor: MGUS

Monoclonal gammopathy of uncertain significance (MGUS) — production of paraprotein by non-cancerous plasma cells, without other clinical features of multiple myeloma. Incidence rises with age (from ~1% at 25 years to >5% over 70). Usually asymptomatic; sometimes associated with peripheral neuropathy or increased fracture risk. Up to 25% progress to myeloma or a related B-cell disorder (~1%/year). No antineoplastic treatment is recommended; monitor with clinical exam and serum/urine protein electrophoresis every 6–12 months.