Multiple Myeloma (MM)

Definition & Pathophysiology

• Malignant proliferation of plasma cells in the bone marrow.
• Produces monoclonal immunoglobulin (M-protein) or light chains.
• Leads to bone destruction, renal impairment, anemia, and immunodeficiency.

Diagnostic criteria (IMWG 2014):

• ≥10% clonal plasma cells plus:
  • CRAB: hyperCalcemia, Renal dysfunction, Anemia, Bone lesions
  • OR SLiM biomarkers: ≥60% plasma cells, FLC ratio ≥100, >1 focal lesion on MRI.

Clinical Features

• Bone pain, fractures, lytic lesions
• Hypercalcemia (stones, groans, bones)
• Renal impairment (cast nephropathy, light-chain deposition)
• Anemia, infections (immunosuppression)

Risk Stratification

• Staging: Revised ISS (R-ISS) uses β2-microglobulin, albumin, LDH, cytogenetics.
• High-risk cytogenetics: del(17p), t(4;14), t(14;16).
• Standard-risk: t(11;14), hyperdiploidy.

Treatment Overview

Goal: disease control, prolong survival, improve QoL (not curative).

1. Initial Therapy (Transplant-Eligible)

• Induction:
  • VRd (bortezomib + lenalidomide + dexamethasone) = standard of care.
  • Alternatives: Dara-VRd (daratumumab + VRd), VCd (bortezomib + cyclophosphamide + dex).
• Stem cell collection → ASCT (autologous stem cell transplant).
• Maintenance: lenalidomide (preferred), bortezomib in high-risk.

2. Initial Therapy (Transplant-Ineligible)

• Dara-Rd (daratumumab + lenalidomide + dexamethasone).
• VRd-lite or Rd.

3. Relapsed/Refractory MM

• Choose regimen based on prior exposure, refractoriness, comorbidities.
• Options include:
  • Anti-CD38 mAbs: daratumumab, isatuximab
  • Proteasome inhibitors (PI): carfilzomib, ixazomib, bortezomib
  • IMiDs: lenalidomide, pomalidomide, thalidomide
  • Alkylators: cyclophosphamide, melphalan, bendamustine
  • Selinexor (XPO1 inhibitor)
  • Belantamab mafodotin (anti-BCMA ADC, currently withdrawn in some regions)
  • CAR-T therapies: idecabtagene vicleucel, ciltacabtagene autoleucel (anti-BCMA)
  • Bispecifics (BCMA/CD3): teclistamab, elranatamab (new approvals)

Supportive Care (High Yield for Pharmacists)

• Bone disease: bisphosphonates (zoledronic acid, pamidronate) or denosumab.
• Thromboprophylaxis: with IMiDs (aspirin vs anticoagulation based on risk).
• Antiviral prophylaxis: acyclovir with proteasome inhibitors (esp. bortezomib).
• Infection prevention: vaccination (pneumococcal, influenza), IVIG in recurrent infections.
• Renal impairment: avoid nephrotoxins, dose-adjust meds.
• Hypercalcemia: hydration, bisphosphonates, denosumab.

Key Adverse Effects to Monitor

• Bortezomib: peripheral neuropathy, herpes zoster reactivation.
• Carfilzomib: cardiac toxicity, hypertension.
• Lenalidomide/Pomalidomide/Thalidomide: VTE, cytopenias, teratogenicity.
• Daratumumab/Isatuximab: infusion reactions, interference with blood typing (Coombs test).
• Melphalan: myelosuppression, infertility.
• Bisphosphonates/denosumab: osteonecrosis of jaw, hypocalcemia.

High-Yield Pharmacist Pearls

• Always consider transplant eligibility before starting induction.
• VRd is standard first-line (add daratumumab if available).
• Lenalidomide maintenance post-ASCT improves PFS/OS.
• Monitor for VTE with IMiDs, viral reactivation with PIs, and bone health in all patients.
• New era: BCMA-targeted therapies (CAR-T, bispecifics) are changing relapsed/refractory MM management.

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