A 58-year-old woman with relapsed multiple myeloma (after 18 months of remission on VTD induction and ASCT) presents with rising M-spike and bone pain. She has normal renal function and no neuropathy. Which drug is the preferred first-line option for relapsed/refractory multiple myeloma (RRMM) in this patient?

Explanation

## First-Line Treatment of Relapsed/Refractory Multiple Myeloma (RRMM) **Key Point:** Lenalidomide + dexamethasone is the preferred first-line regimen for relapsed multiple myeloma (MM) in patients who have not previously received lenalidomide and have adequate renal function. ### Standard Approach to RRMM The choice of salvage therapy depends on: 1. **Prior therapy exposure:** What drugs were used in induction and maintenance? 2. **Time to relapse:** Early relapse (<12 months) suggests aggressive biology 3. **Organ function:** Renal function, neuropathy status 4. **Patient fitness:** Ability to tolerate combination therapy ### First-Line RRMM Regimens | Scenario | Preferred Regimen | Rationale | |----------|-------------------|----------| | **Prior PI, no prior IMiD** | **Lenalidomide + Dex** | IMiD-naïve; excellent response rates (60–70% ≥PR) | | **Prior IMiD, no prior PI** | **Bortezomib + Dex** or **Carfilzomib + Dex** | PI-naïve; rapid response | | **Prior both PI and IMiD** | **Pomalidomide + Dex** | Pomalidomide active in lenalidomide-refractory disease | | **Early relapse (<12 mo)** | **Carfilzomib + Dex** | Faster kinetics; higher response rates | **High-Yield:** In this patient: - Prior therapy: **VTD + ASCT** (bortezomib-based, so PI-exposed) - **No prior lenalidomide exposure** - **Normal renal function** (no contraindication to IMiDs) - **No neuropathy** (can safely re-challenge bortezomib if needed) - **Time to relapse: 18 months** (intermediate; not ultra-early) **Therefore: Lenalidomide + dexamethasone is optimal** — IMiD-naïve status, good renal function, and proven efficacy in PI-pretreated patients. ### Mechanism of Lenalidomide Lenalidomide (immunomodulatory drug, IMiD): - Cereblon (CRBN) binding → selective degradation of IKZF1 and IKZF3 - Enhanced T-cell proliferation and IL-2/TNF-α production - Direct anti-angiogenic effects - Synergistic with dexamethasone ### Why Not Other Options? **Pomalidomide + Dex:** - Reserved for **lenalidomide-refractory** disease (progression on lenalidomide) - This patient is lenalidomide-naïve; pomalidomide is more toxic and should not be used first-line - Higher rates of infection and cytopenias **Bortezomib + Dex:** - Patient already received bortezomib in induction (VTD) - While re-challenge is possible, lenalidomide is preferred as a switch strategy in PI-pretreated patients - Risk of cumulative neuropathy if bortezomib is re-used **Carfilzomib + Dex:** - Second-generation PI; excellent for early relapse (<12 months) - This patient has intermediate time to relapse (18 months), not ultra-early - Carfilzomib is more expensive and reserved for PI-refractory or very aggressive disease - Not first-line in PI-pretreated, IMiD-naïve patients **Clinical Pearl:** The principle of RRMM management is **"switch class" when possible** — if the patient received a PI in induction, use an IMiD in relapse; if they received an IMiD, use a PI. This maximizes response rates and delays resistance. **Mnemonic:** **RRMM Strategy = Switch Class** - Prior **PI** (bortezomib) → Use **IMiD** (lenalidomide) - Prior **IMiD** → Use **PI** (bortezomib or carfilzomib) - Prior **both** → Use **pomalidomide** (most potent IMiD) ### Evidence Base - **MM-009 / MM-010 trials:** Lenalidomide + dexamethasone vs. dexamethasone alone in relapsed MM → superior PFS and OS with lenalidomide - **ASPIRE trial:** Lenalidomide + bortezomib + dexamethasone (RVD) superior to bortezomib + dexamethasone in relapsed MM - **ENDEAVOR trial:** Carfilzomib superior to bortezomib in relapsed MM, but lenalidomide is still preferred first-line in IMiD-naïve patients [cite:Harrison 21e Ch 191]