Multiple Myeloma — Viva

Q1: Definition, classification and the CRAB features (2 min)

• Define multiple myeloma: a clonal malignancy of terminally differentiated B-cells (plasma cells) in the bone marrow producing a monoclonal protein.
• Reproduce CRAB verbatim: C hypercalcaemia, R renal impairment, A anaemia, B bone lesions (lytic or pathological fracture). ^[2]
• Distinguish the plasma-cell spectrum: MGUS (M-protein under 30 g/L, marrow under 10 percent, no CRAB) versus smouldering myeloma (M-protein at least 30 g/L or marrow at least 10 percent, no CRAB) versus symptomatic myeloma (CRAB or a myeloma-defining biomarker such as free light chain ratio at least 100, more than one focal MRI lesion).

Q2: Pathophysiology and mechanism (3 min)

• Bone: plasma cells secrete RANKL (and DKK1), activating osteoclasts and suppressing osteoblasts — uncoupled resorption, lytic lesions, hypercalcaemia.
• Renal: excess free light chains precipitate as tubular casts (cast nephropathy); plus amyloidosis, hypercalcaemia, dehydration and nephrotoxins.
• Anaemia: marrow infiltration plus renal anaemia (low erythropoietin) — normocytic.
• Immune paresis: suppression of normal polyclonal immunoglobulin — recurrent infection. ^[2]
• Cytogenetics: hyperdiploidy vs non-hyperdiploidy; high-risk del(17p)/TP53, t(4;14), t(14;16), gain(1q) detected by FISH.

Q3: Investigations and staging (3 min)

• SPEP + UPEP + immunofixation + serum free light chains; bone-marrow biopsy with FISH cytogenetics; whole-body low-dose CT (or MRI/PET-CT). ^[1]
• IMWG 2014 criteria: clonal marrow plasma cells at least 10 percent plus a myeloma-defining event (CRAB or biomarker).
• Revised International Staging System (R-ISS): albumin, beta-2 microglobulin, LDH, high-risk cytogenetics — stages I to III.
• Pitfall: a normal SPEP does not exclude light-chain/non-secretory myeloma; urine dipstick misses Bence Jones protein.

Q4: Management — definitive and supportive (3 min)

• Induction: VRd (bortezomib + lenalidomide + dexamethasone) for 4 to 6 cycles. ^[1]
• Fit patient: autologous stem-cell transplant after high-dose melphalan, then lenalidomide maintenance.
• Transplant-ineligible: DRd (daratumumab + lenalidomide + dexamethasone) or VRd-lite, continuous therapy.
• Relapsed/refractory: daratumumab (anti-CD38), carfilzomib/ixazomib, pomalidomide, bispecific antibodies (teclistamab), anti-BCMA CAR-T (ide-cel, cilta-cel).
• Supportive: zoledronic acid or denosumab (bone, hypercalcaemia); aciclovir (herpes zoster on bortezomib); VTE prophylaxis (lenalidomide); avoid NSAIDs/contrast in renal failure.

Q5: Complications, prognosis and an emergency (2 min)

• Emergencies: hypercalcaemic crisis (IV saline + bisphosphonate), spinal cord compression (IV dexamethasone + urgent MRI + radiotherapy/decompression), cast-nephropathy AKI (hydrate, bortezomib, avoid nephrotoxins), hyperviscosity (plasmapheresis). ^[1]
• Median survival now 7 to 10 years with modern therapy; worse with high-risk cytogenetics, high LDH, renal failure (R-ISS 5-year overall survival: stage I 82 per cent, stage III 40 per cent).
• Myeloma remains incurable but treatable as a chronic disease; depth of response and MRD negativity correlate with survival.

References3ShowHide

1. [1]Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma Nat Rev Dis Primers, 2017.PMID 28726797
2. [2]Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol, 2014.PMID 25439696
3. [3]Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group J Clin Oncol, 2015.PMID 26240224