Multiple Myeloma

Plasma cell dyscrasia, CRAB criteria, risk stratification, and modern triplet/quadruplet induction plus transplant and maintenance strategies

Key Points

• Multiple myeloma is a malignancy of clonal plasma cells in the bone marrow; it accounts for ~10% of all hematologic malignancies and ~2% of cancer deaths in the US.
• CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions) define symptomatic myeloma requiring treatment.
• Cytogenetic risk stratification (FISH) is essential: high-risk features include del(17p), t(4;14), t(14;16), and gain(1q); standard-risk includes t(11;14) and hyperdiploidy.
• Triplet induction (bortezomib + lenalidomide + dexamethasone, VRd) is the US standard for transplant-eligible and many transplant-ineligible patients.
• Autologous stem cell transplantation (ASCT) remains a standard of care consolidation for transplant-eligible patients and deepens response.
• Lenalidomide maintenance post-ASCT significantly prolongs PFS and OS; continuous therapy is a recognized strategy in non-transplant patients.
• Daratumumab-based quadruplet regimens (Dara-VRd, Dara-VTd) are emerging as new standards, achieving MRD negativity in >50% of patients.

Epidemiology & Incidence

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States after non-Hodgkin lymphoma. In 2024, approximately 35,780 new cases and 12,540 deaths were projected. The median age at diagnosis is 69 years; fewer than 2% of cases occur before age 40. Black Americans are diagnosed at twice the rate of White Americans, and at a younger age — a disparity not fully explained by known risk factors. Myeloma exists on a spectrum: Monoclonal gammopathy of undetermined significance (MGUS) affects ~3% of adults over 50 and progresses to myeloma at ~1%/year. Smoldering…

Genetic Predispositions & Risk Factors

The etiology of multiple myeloma is multifactorial. Known risk factors include: • Race: Black Americans have 2–3× higher incidence; higher prevalence of MGUS in Black populations suggests a biologic predisposition. • Age: Incidence increases steeply after age 65. • Obesity: BMI >30 associated with ~20% increased risk. • Occupational exposures: Pesticides, Agent Orange, benzene, radiation exposure. • Family history: First-degree relatives of myeloma patients have ~2× increased risk; familial clustering is recognized. Cytogenetic and molecular subtypes (determined by FISH/SNP array at…

Clinical Presentation

Multiple myeloma presents through the consequences of malignant plasma cell infiltration of bone marrow and production of a monoclonal protein (M-protein). The classic mnemonic is CRAB: • Hypercalcemia (C): Occurs in ~15% at diagnosis; caused by osteoclast activation via RANKL pathway; presents with fatigue, confusion, constipation, polyuria, nausea. Calcium >11 mg/dL warrants urgent treatment. • Renal insufficiency (R): ~20–40% at diagnosis; etiologies include cast nephropathy (Bence Jones protein/free light chains tubular precipitation — the most common), hypercalcemia-induced…

Diagnosis & Staging

Diagnosis requires: ≥10% clonal plasma cells in bone marrow biopsy (or biopsy-proven plasmacytoma) PLUS one or more myeloma-defining events (MDE): CRAB criteria (any one): Hypercalcemia (Ca >11 mg/dL), Renal insufficiency (Cr >2 mg/dL or CrCl 1 focal lesion on MRI ≥5mm Workup: Serum protein electrophoresis (SPEP) + immunofixation, serum free light chains (kappa/lambda ratio), 24-hour urine protein electrophoresis + immunofixation, CBC, CMP, LDH, β2-microglobulin, BM biopsy with FISH/cytogenetics, whole-body low-dose CT or PET/CT (preferred over skeletal survey), MRI spine/pelvis if…

Treatment: Transplant-Eligible Patients

Induction therapy (3–4 cycles prior to stem cell collection): • VRd (bortezomib + lenalidomide + dexamethasone): The US standard induction; SWOG S0777 demonstrated VRd superior to Rd (PFS 43 vs. 30 months). • Daratumumab + VRd (Dara-VRd, PERSEUS trial): Quadruplet induction; significantly superior to VRd for PFS and MRD negativity (≥10⁻⁵); FDA approved 2024; emerging as new standard. • Dara-VTd (daratumumab + bortezomib + thalidomide + dexamethasone, CASSIOPEIA trial): European standard for transplant-eligible. • KRd (carfilzomib + lenalidomide + dexamethasone): Alternative triplet,…

Treatment: Relapsed/Refractory Myeloma

Myeloma remains incurable for most patients; relapse is inevitable. Multiple effective therapies are available across successive lines: First relapse (after PI + IMiD-based induction): • Daratumumab + carfilzomib + dexamethasone (Dara-Kd, CANDOR trial) • Daratumumab + bortezomib + dexamethasone (Dara-Vd, CASTOR trial) • Isatuximab + carfilzomib + dexamethasone (IKEMA trial) • Ixazomib + lenalidomide + dexamethasone (IRd, oral triplet — TOURMALINE-MM1) • Elotuzumab + lenalidomide + dexamethasone (ELd, ELOQUENT-2) Later lines (lenalidomide-refractory or triple-class refractory): • Pomalidomide…