Multiple Myeloma

Obligate precursor states (the mechanism examiners want)

• MGUS: essentially every case of myeloma is preceded by monoclonal gammopathy of undetermined significance — an M-protein present without CRAB features and with <10% clonal marrow plasma cells. Progression to overt malignancy occurs at roughly 1% per year and does not plateau, so surveillance is lifelong (IMWG criteria; NCCN Multiple Myeloma guideline).
• Smoldering myeloma: ≥10% clonal plasma cells or a substantial M-protein but no myeloma-defining event; risk of progression is highest in the first 5 years (on the order of 10% per year) and then falls.

Genetic/molecular drivers

• Primary IgH translocations at 14q32: the immunoglobulin heavy-chain enhancer is juxtaposed to an oncogene — t(11;14) (cyclin D1), t(4;14) (FGFR3/MMSET), t(14;16) (MAF). t(4;14), t(14;16) and del(17p) (TP53 loss) define high-risk disease.
• Hyperdiploidy: trisomies of odd-numbered chromosomes; generally standard-risk.
• Secondary events: MYC rearrangements and RAS/NRAS mutations drive transformation from MGUS to active myeloma; IL-6 from the marrow stroma supplies the proliferative signal.

Non-modifiable risk factors

• Advancing age: incidence rises steeply after 60; median diagnosis near 70.
• Black race: incidence roughly two- to three-fold that of White Americans, with MGUS also more prevalent — a favorite stem detail.
• Male sex: modestly increased risk.
• Family history of myeloma or MGUS in a first-degree relative.

Modifiable / exposure-related

• Obesity: the most consistently identified modifiable risk factor, linked to both MGUS and progression.
• Ionizing radiation (atomic-bomb and occupational cohorts) and occupational chemicals — benzene, pesticides/herbicides, and Agent Orange exposure (a VA-recognized presumptive condition).
• Chronic antigenic/immune stimulation is a proposed contributor but is not an established causal factor.

• Clonal proliferation of plasma cells: A single malignant plasma cell clone expands in the bone marrow, crowding out normal hematopoietic elements and causing anemia, thrombocytopenia, and leukopenia
• Monoclonal immunoglobulin (M-protein) overproduction: Malignant cells produce excessive amounts of complete immunoglobulin (IgG most common ~50%, IgA ~25%, IgD/E rare) or free light chains (kappa or lambda), visible as an M-spike on serum protein electrophoresis (SPEP)
• Cytokine-mediated bone destruction: Myeloma cells produce IL-6, TNF-α, and RANKL, which activate osteoclasts while inhibiting osteoblasts, leading to lytic bone lesions rather than sclerotic lesions
• Light chain nephropathy: Free light chains (especially lambda) are small enough to be filtered by the glomerulus, accumulating in renal tubules and causing "myeloma kidney" or light chain cast nephropathy
• Hypercalcemia mechanism: Results from increased osteoclast activity and production of PTHrP and IL-6 by myeloma cells
• Microenvironment support: Bone marrow stromal cells and endothelial cells support myeloma cell survival through adhesion molecules and autocrine/paracrine cytokine loops

• CRAB criteria (classic features): Calcium elevation (hypercalcemia), Renal insufficiency (creatinine >2 mg/dL or GFR <40), Anemia (Hgb <10 g/dL), Bone lesions (lytic lesions on skeletal survey)
• Bone pain (most common presenting symptom ~70% of patients): Typically affects the back, ribs, and pelvis; caused by lytic lesions and pathologic fractures; may be the sole presenting complaint
• Fatigue and weakness: Secondary to normocytic anemia from marrow crowding and reduced erythropoietin response
• Recurrent infections: Due to immune dysfunction from normal immunoglobulin suppression and neutropenia; respiratory tract and urinary tract infections most common
• Renal dysfunction: Presents with elevated creatinine, proteinuria (often light chains rather than albumin), and may progress to acute kidney injury from dehydration or contrast exposure
• Hypercalcemia symptoms: Polyuria, polydipsia, constipation, confusion, altered mental status
• Hepatosplenomegaly: Less common than in lymphomas but may occur
• Hyperviscosity syndrome (5-10% of patients): More common with IgM (Waldenström) but occurs in MM with high IgG levels; presents with visual changes (retinal hemorrhages), bleeding, neurologic symptoms

• Serum protein electrophoresis (SPEP): Detects M-spike (monoclonal protein); must have >30% of total serum proteins or >3 g/dL to be significant
• Serum free light chain ratio (SFLC): More sensitive than urine electrophoresis; elevated ratio (>100:1 or <0.01:1) indicates clonal predominance; essential for diagnosing "light chain myeloma"
• 24-hour urine protein electrophoresis: Detects Bence Jones proteins (free light chains); highly specific when present
• Bone marrow biopsy and aspiration: Shows ≥10% clonal plasma cells (or ≥30% for diagnosis in some contexts); must demonstrate clonality by flow cytometry or immunohistochemistry
• CRAB criteria or SLIM-CRAB criteria (updated): Diagnosis requires ≥10% clonal bone marrow plasma cells PLUS ≥1 CRAB criterion or ≥1 myeloma-defining event (≥60% plasma cells, involved/uninvolved SFLC ratio ≥100, or ≥2 focal lesions on MRI)
• Skeletal survey (X-rays): Detects lytic ("punched-out") bone lesions in skull, spine, pelvis, ribs; 70% of patients have lytic lesions; normal X-rays do NOT exclude myeloma
• MRI of spine: More sensitive than skeletal survey for detecting focal lesions and bone marrow involvement
• Laboratory assessment: CBC (anemia), comprehensive metabolic panel (renal function, calcium), LDH (prognostic marker—elevated = worse prognosis), β2-microglobulin (prognostic)
• Important diagnostic pearl: SPEP may be falsely negative in light chain only myeloma (~20% of cases)—must check urine electrophoresis and free light chains

• Induction therapy (for transplant candidates): Bortezomib/lenalidomide/dexamethasone (VRd) or bortezomib/thalidomide/dexamethasone (VTd); newer agents like daratumumab-based regimens now standard; 8-12 cycles given prior to transplant
• Autologous stem cell transplantation (ASCT): Standard of care for transplant-eligible patients (<75 years, adequate organ function); improves progression-free and overall survival; melphalan 200 mg/m² is typical conditioning regimen
• Maintenance therapy post-ASCT: Lenalidomide or bortezomib continued for 2-3 years to prolong remission
• For transplant-ineligible patients: Continuous bortezomib/lenalidomide/dexamethasone (VRd), lenalidomide/dexamethasone, or daratumumab-based therapy; avoid high-dose melphalan
• Treatment of specific complications:
• Hypercalcemia: IV hydration, bisphosphonates, corticosteroids, calcitonin for acute management
• Renal insufficiency: Aggressive hydration, avoid nephrotoxic agents (NSAIDs, aminoglycosides, high-dose bortezomib in early kidney disease), consider plasmapheresis in light chain cast nephropathy
• Bone disease: Zoledronic acid or pamidronate monthly for patients with lytic lesions to reduce skeletal events
• Infections: Prophylactic antibiotics for recurrent infections, pneumococcal/influenza vaccination
• Anemia: ESA (EPO) if Hgb <10 g/dL and not receiving bortezomib (proteasome inhibitors can worsen anemia)
• Novel agents and targeted therapy: Proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide), monoclonal antibodies (daratumumab, elotuzumab), and BCMA-targeted CAR-T cells (idecabtagene vicleucel) for relapsed/refractory disease
• Relapsed/refractory myeloma: Treat with different class of agent if possible; CAR-T cell therapy is emerging option for heavily pretreated patients

• Renal failure (25-50% at diagnosis): Caused by light chain cast nephropathy ("myeloma kidney"), hypercalcemia-induced acute tubular necrosis, and uric acid nephropathy from high tumor burden; may be irreversible if not managed quickly
• Spinal cord compression: Results from epidural extension of plasma cell infiltration or pathologic collapse of vertebral bodies; presents with back pain, radiculopathy, weakness, or incontinence; requires urgent MRI and may need radiation or surgical decompression
• Hypercalcemia: Severe

• ***Punched-out" lytic lesions* on skull film with a normal alkaline phosphatase: the classic paradox. Osteoblasts are suppressed by myeloma cytokines, so there is no reactive bone formation — which is also why the technetium bone scan is falsely negative. Do not order a bone scan; the IMWG and NCCN now favor whole-body low-dose CT (or PET-CT/MRI) over the traditional skeletal survey.
• Elevated total protein with a low or normal albumin (a wide gap between total protein and albumin), plus a narrow anion gap from cationic IgG, should trigger SPEP with immunofixation, UPEP, and serum free light chains — that trio is the single best next step in an older patient with back pain and anemia.
• Rouleaux formation on smear and a markedly elevated ESR reflect immunoglobulin coating of red cells; anemia is normocytic.
• Bence Jones proteins are missed by urine dipstick, which detects albumin only. A patient with heavy proteinuria on 24-hour collection but a bland dipstick has light-chain disease until proven otherwise.
• The association examiners test: myeloma patients die of infection, chiefly encapsulated organisms such as Streptococcus pneumoniae, because polyclonal immunoglobulin is suppressed despite a high total protein. Pneumococcal and influenza vaccination are standard.
• Drug-toxicity pairings: bortezomib → dose-limiting peripheral neuropathy and reactivation of varicella-zoster (proteasome inhibitors warrant antiviral prophylaxis, e.g., acyclovir); lenalidomide/thalidomide → venous thromboembolism (thromboprophylaxis required) and teratogenicity under a REMS program.
• Common distractors: Waldenström macroglobulinemia is IgM, causes hyperviscosity and lymphadenopathy but no lytic lesions; MGUS/smoldering myeloma lack CRAB or myeloma-defining events and are observed, not treated; a solitary plasmacytoma is treated with radiation; AL amyloidosis presents with nephrotic-range albuminuria, macroglossia, and periorbital purpura.
• Hypercalcemia in myeloma is PTH-independent — PTH is suppressed, distinguishing it from primary hyperparathyroidism.