Paper Details

ABSTRACT

Background

Despite advances, relapses remain inevitable for most patients (pts) with multiple myeloma, highlighting the need for more effective therapies in earlier lines of treatment. ELRA, a BCMA-CD3 bispecific antibody, demonstrated deep and durable responses with a manageable safety profile in MagnetisMM-3. MagnetisMM-5 (NCT05020236) is a phase 3 randomized clinical trial evaluating the efficacy and safety of ELRA, or ELRA plus daratumumab (ELRA-DARA), versus DPd in pts with RRMM who received ≥1 prior line of therapy. Here, we report the primary analysis, comparing ELRA monotherapy vs DPd, and a descriptive analysis of the ELRA-DARA arm.

Methods

Eligible pts had received 1-4 prior lines of therapy, including lenalidomide (LEN) and a proteasome inhibitor. Pts were randomized 1:1:1 to ELRA, ELRA-DARA, or DPd. Pts in the ELRA arm received SC ELRA step-up priming doses (12 mg on D1, 32 mg on D4) followed by 76 mg QW beginning on C1D8. Pts who achieved PR or better for ≥2 mo transitioned to Q2W dosing from C7, then to Q4W dosing from C13. Pts in the DPd arm received standard regimen as evaluated in the APOLLO trial. The primary endpoint was PFS by blinded independent central review per IMWG 2016 criteria. Secondary endpoints included OS (key), CRR, ORR, MRD-negative (by NGS) CR rate, and safety. Pts in the ELRA-DARA arm received ELRA as in the monotherapy arm plus SC daratumumab 1800 mg QW from C1D15, Q2W from C3D15, and Q4W from C8. Mandatory infection prophylaxis, including Ig replacement, was implemented in Jun 2023 and its impact was analyzed in a subgroup of pts enrolled after the protocol amendment. Data cutoff date was Feb 26, 2026.

Results

In total, 727 pts were randomized, including 497 in the primary analysis (ITT: ELRA, 245; DPd, 252). Median age was 65 y (range, 30-90). Pts had a median of 2 prior lines of therapy (range, 1-4); 71.8% were refractory to LEN; 5.9% had prior anti-CD38 therapy. Fifteen pts (6 in ELRA, 5 in ELRA-DARA, 4 in DPd) did not receive study treatment and were excluded from the safety analysis.

At 31.6 mo of median follow-up, ELRA significantly prolonged PFS vs DPd (HR, 0.56; 95% CI, 0.42-0.74; p<0.0001). Median PFS was not reached (95% CI, 41.7-NE) for ELRA vs 27.1 (95% CI, 17.6-32.5) mo for DPd; 36-mo PFS rate was 63.5% (95% CI, 56.3-69.8) vs 41.1% (95% CI, 34.3-47.8) for ELRA and DPd, respectively. PFS benefit with ELRA was consistent across prespecified and clinically relevant subgroups, including age ≥75 y, LEN-refractory, high-risk cytogenetics, and extramedullary disease. ITT pts in the ELRA arm had higher CR or better rate (63.7% vs 32.9%; OR, 3.56; 95% CI, 2.46-5.16) and MRD-negative (10^-5) CR rate (47.3% vs 15.9%; OR, 4.89; 95% CI, 3.19-7.51) than pts in the DPd arm. OS data were immature at data cutoff although the preliminary estimate favored ELRA. Among the 134 pts enrolled after implementation of mandatory infection prophylaxis, PFS was improved with ELRA vs DPd (HR, 0.41; 95% CI, 0.23-0.74) at a median follow-up of 28.1 mo.

At data cutoff, 40.6% and 31.9% of pts remained on study treatment with ELRA and DPd, respectively. Median (range) treatment duration was 22.3 (0.03-43.2) mo for ELRA, 18.9 (0.1-43.1) mo for DPd. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) were comparable between arms (ELRA, 81.6%; DPd, 88.7%). Infections of any grade occurred in 85.8% (43.9% grade ≥3) and 86.3% (41.1% grade ≥3) of pts on ELRA and DPd, respectively. CRS was reported in 72.0% (1.3% grade 3; no grade 4) and ICANS in 2.1% (no grade 3/4) of pts who received ELRA. Mandatory infection prophylaxis was associated with lower rates of grade ≥3 infections among pts who received ELRA.

In the ELRA-DARA arm, median PFS was not reached (95% CI, NE-NE) with 32.5 mo of median follow-up; 36-mo PFS rate was 74.7% (95% CI, 68.0-80.1). CR or better response was reported in 68.3% of pts and MRD-negative CR in 58.3%. Grade 3/4 TEAEs were reported in 82.7% of pts; infections of any grade occurred in 91.6% (53.8% grade ≥3). CRS was reported in 72.9% (0.4% grade 3; no grade 4) and ICANS in 3.6% (0.4% grade 3; no grade 4) of pts who received ELRA-DARA.

Conclusions

In MagnetisMM-5, ELRA monotherapy significantly prolonged PFS, substantially increased MRD-negative responses, compared with DPd, and demonstrated a manageable safety profile. These results support ELRA monotherapy as a highly effective, off-the-shelf treatment option beginning as early as second line of therapy for pts with RRMM.