A 58-year-old man presents with bone pain, fatigue, and elevated creatinine (2.8 mg/dL). Serum protein electrophoresis shows an M-spike, and bone marrow biopsy reveals 65% clonal plasma cells. Interphase FISH panel on CD138-sorted cells shows the translocation marked **A** in the diagram. Which of the following is the most appropriate induction regimen for this patient?

Question

Accepted Answer

D. Bortezomib + lenalidomide + dexamethasone (VRd). ## Why Bortezomib + lenalidomide + dexamethasone (VRd) is right

The translocation marked **A** is t(4;14)(p16.3;q32), which places FGFR3 and MMSET under control of the IgH enhancer, driving overexpression of both genes. This translocation occurs in ~15% of multiple myeloma and is classified as HIGH-RISK per R-ISS and IMWG 2016 criteria, with median OS of 3–4 years. Per NCCN MM 2024 and mSMART 3.0 guidelines, **proteasome inhibitor (PI)-based induction is mandatory** for t(4;14) disease because bortezomib overcomes the adverse prognostic effect of this translocation. VRd (bortezomib + lenalidomide + dexamethasone) for 4–6 cycles followed by autologous stem cell transplant is the standard of care for transplant-eligible patients with this high-risk cytogenetic lesion.

## Why each distractor is wrong

- **Lenalidomide + dexamethasone (Rd)**: While Rd is acceptable for standard-risk myeloma, it lacks the proteasome inhibitor component that is mandatory for t(4;14) disease. PI-based regimens are required to overcome the adverse cytogenetics.
- **Thalidomide + dexamethasone (Td)**: Td is an older regimen rarely used in modern practice and does not include a proteasome inhibitor. It is inadequate for high-risk disease and does not address the FGFR3-MMSET biology.
- **Melphalan + prednisone (MP)**: MP is reserved for transplant-ineligible, frail, or elderly patients (typically >75 years). This 58-year-old is transplant-eligible and requires intensive PI-based therapy, not alkylator monotherapy.

**High-Yield:** t(4;14) = HIGH-RISK myeloma; **bortezomib is mandatory**; use VRd or D-VRd induction → ASCT in eligible patients.

[cite: IMWG 2016 R-ISS; mSMART 3.0; NCCN MM 2024]

Answer

A. Thalidomide + dexamethasone (Td)

Answer

B. Lenalidomide + dexamethasone (Rd)

Answer

C. Melphalan + prednisone (MP)

Explanation

Why Bortezomib + lenalidomide + dexamethasone (VRd) is right

Why each distractor is wrong

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