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Key Clinical Summary: Optimizing Treatment Sequencing and use of BCMA BsAb combinations in RRMM

This is a micro-learning module summary of a presentation by Dr Saad Usmani which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This activity is supported by an independent medical educational grant from Johnson & Johnson. This online education program has been designed for US Healthcare Professionals.

The treatment landscape for relapsed/refractory multiple myeloma (RRMM) is shifting rapidly as immunotherapies enter earlier lines of treatment. Because a high percentage of patients become refractory to lenalidomide and anti-CD38 monoclonal antibodies (e.g., daratumumab) during or immediately following frontline therapy, optimizing the combination and sequencing of novel agents is essential to maximize progression-free survival (PFS).

Clinical Trial Evidence for Novel Combinations

The MajesTEC-3 Trial: Teclistamab + Daratumumab

  • Design and Population: This phase 3 study evaluated the combination of the BCMA-directed bispecific antibody (BsAb) teclistamab plus the anti-CD38 antibody daratumumab (Tec-Dara) versus investigator's choice of standard triplet care (daratumab, pomalidomide, and dexamethasone [DPd] or daratumumab, bortezomib, and dexamethasone [DVd]). Critically, more than 95% of patients enrolled in this trial were anti-CD38 naive.
  • Efficacy Outcomes: At 36 months, the Tec-Dara combination demonstrated a monumental efficacy benefit over standard triplets:
    • PFS Rate: 83.4% for Tec-Dara versus 29.7% for the standard triplet arm.
    • Median PFS: Not reached for Tec-Dara compared to 18.1 months for standard triplets (Hazard Ratio: 0.17).
    • Depth of Response: Tec-Dara delivered significantly higher minimal residual disease (MRD) negativity rates at the 10 to the minus 5 threshold (58.4% vs 17.1%).
    • Overall Survival (OS): The 36-month OS rate was 83.3% for Tec-Dara versus 65.0% for the standard triplets, showing a statistically significant survival benefit.

The MonumenTAL-3 Trial: Talquetamab + Daratumumab

  • Design and Population: This randomized phase 3 study examined the GPRC5D-directed BsAb talquetamab combined with daratumumab, with or without pomalidomide (Tal-DP or Tal-D), versus standard DPd. The trial enrolled a heavily lenalidomide-refractory population, with roughly 11% having prior anti-CD38 exposure.
  • Efficacy Outcomes: Both talquetamab-containing combination regimens significantly improved outcomes over standard therapy:
    • PFS Rate (24 months): 81.3% for Tal-DP and 77.6% for Tal-D, compared to 51.2% for the DPd control arm (which achieved a median PFS of 24.4 months).
    • Depth of Response: The MRD-negative complete response (CR) rate reached 52.3% with Tal-DP and 46.3% with Tal-D, compared to just 15.9% with DPd.
    • Survival: Both combination arms demonstrated clinically meaningful OS benefits, with over 87% of patients alive at 2 years.

Comparative Analysis: Combination vs Monotherapy and Standard Triplets
To correctly utilize these regimens, clinicians must evaluate the patient's exact prior anti-CD38 exposure and refractoriness:

  • Anti-CD38 Naive or Sensitive Patients: For patients in early relapse with short prior exposure to anti-CD38 therapy and a long initial PFS (greater than 4 years), traditional anti-CD38 triplets or novel combinations like Tec-Dara represent highly effective choices.
  • Anti-CD38 Refractory Patients (The Monotherapy Role): When a patient is explicitly anti-CD38 refractory, adding daratumumab to a BsAb does not provide optimal benefit. In this setting, MajesTEC-9 evaluated teclistamab monotherapy against pomalidomide-bortezomib-dexamethasone (PVd) or carfilzomib-dexamethasone (Kd). In a population where 85.5% were anti-CD38 refractory, teclistamab monotherapy doubled the median PFS (17.3 months vs 8.2 months; Hazard Ratio: 0.29), demonstrating that monotherapy is the superior approach over standard second-line triplets when anti-CD38 resistance is established.

Longitudinal Safety and Tolerability Profiles
While combining anti-CD38 antibodies with BsAbs deepens remissions, clinicians must remain vigilant regarding overlapping toxicities:

  • Infection Risk: BCMA-directed BsAbs carry a pronounced and persistent risk of severe (Grade 3/4) infections, particularly respiratory and COVID-19 related, which peak during the first 6 months of therapy. This risk declines as patients switch to less frequent dosing intervals (every 2 or 4 weeks).
  • GPRC5D Side Effects: In anti-CD38 combinations utilizing talquetamab, the primary adverse events of interest are non-hematologic, including taste changes (exceeding 70%), non-rash skin changes, nail-related events, and weight loss. Real-world evidence reveals that proactive treatment modifications, dose delays, and scheduling adjustments can successfully mitigate these oral and dermatologic toxicities without sacrificing overall efficacy.

Content is accurate as of the date of release.