Paper Details

ABSTRACT

Background

ELRA, a BCMA-CD3 bispecific antibody, has shown deep, durable responses as monotherapy in patients (pts) with RRMM in the MagnetisMM-3 study. IBER is an oral cereblon E3 ligase modulator (CELMoD) with enhanced anti-myeloma tumoricidal and immune-modulatory activity compared with IMiD agents. ELRA in combination with IBER may deepen and prolong responses in RRMM based on complementary mechanisms of action. MagnetisMM-30 (NCT06215118) is a phase 1b, open-label, multicenter study with dose-escalation and dose-optimization parts, evaluating ELRA+IBER in pts with RRMM. Here, we report updated safety and efficacy results from the dose-escalation part.

Methods

Eligible pts were aged ≥18 y with RRMM; had received 2 to 4 prior lines of therapy (LOTs) including IMiD- and proteasome inhibitor-containing regimens; an ECOG performance status of 0 or 1; and no prior BCMA-directed, CD3-redirecting, or CELMoD therapy.

Dose finding was guided by a Bayesian Optimal Interval design. Pts received subcutaneous ELRA step-up dosing on days 1 and 4 (12 and 32 mg), and the first full dose of 76 mg on day 8. Pts then received ELRA+IBER at dose level (DL) 1, DL-1, or DL-2 in 28-day cycles. Pts received a starting dose of ELRA 76 mg (DL1: QW; DL-1 and DL-2: Q2W, followed by a protocol-specified transition to Q4W dosing) and IBER once daily (DL1 and DL-1: 1 mg; DL-2: 0.75 mg) on days 1-21 of each cycle. All pts were required to receive infection prophylaxis, including Ig replacement for IgG levels <400 mg/dL, anti-PJP, and anti-viral therapies.

The primary endpoint was dose-limiting toxicities (DLTs) through cycle 1. Secondary endpoints included adverse events and laboratory abnormalities, ORR, CR rate, time-to-event outcomes, pharmacokinetics, MRD negativity rate, and immunogenicity.

Results

At the data cutoff (May 21, 2026), 33 pts received study treatment during dose escalation (DL1: n=13; DL-1: n=9; DL-2: n=11). Median age was 68.0 y (range, 46-83); 19 pts (57.6%) were male, 6 (18.2%) had extramedullary disease, 4 (12.1%) had R-ISS stage III, and 12 (36.4%) had high-risk cytogenetics. Pts had a median of 3.0 prior LOTs; 26 (78.8%) had prior anti-CD38 therapy. 19 (57.6%) pts were refractory to prior anti-CD38 therapy and 16 (48.5%) were triple-class refractory.

Median (range) treatment duration was 8.6 mo (0.5-17.9) for ELRA and 9.0 mo (0.1-17.7) for IBER. At the data cutoff, 24 pts remained on ELRA (DL1: n=6; DL-1: n=9; DL-2: n=9) and 23 remained on IBER (DL1: n=5; DL-1: n=9; DL-2: n=9).

Among 25 DLT-evaluable pts (8 did not receive the minimum required ELRA or IBER dose during cycle 1), 4 experienced a DLT: 2 in DL1 (1 grade [G] 3 anorexia and 1 G4 neutropenia), and 2 in DL-1 (1 G3 febrile neutropenia and 1 G4 neutropenia). Treatment-emergent adverse events (TEAEs) were reported in 100% (G3/4 87.9%) of pts. The most common (any G ≥45% or G3/4 ≥10%) TEAEs included neutropenia (81.8%; all G3/4), cytokine release syndrome (69.7%; all G1/2), fatigue (54.5%; all G1/2), diarrhea (48.5%; all G1/2), thrombocytopenia (33.3%; G3/4 18.2%), anemia (27.3%; G3/4 15.2%), febrile neutropenia (15.2%; all G3/4), and lymphopenia (12.1%; all G3/4). Infections occurred in 22 pts (66.7%), with G3 infections in 15.2% and no G4/5 infections. Mandatory infection prophylaxis measures were associated with lower rates of infection. Immune effector cell–associated neurotoxicity syndrome occurred in 4 pts (12.1%; 2 G2 in DL1, 1 G1 and 1 G2 in DL-2).

At a median follow-up of 13.2 mo (95% CI, 9.6-16.6, by reverse Kaplan-Meier), the investigator-assessed ORR was 97.0% (95% CI, 84.2-99.9). A very good partial response or better was achieved by 84.8% (95% CI, 68.1-94.9) of pts, and 60.6% (95% CI, 42.1-77.1) achieved a CR or better. Among evaluable pts (those with ≥CR and evaluable for MRD, n=13), 100% achieved MRD negativity at 10^-5. ORRs (95% CI) were 92.3% (64.0-99.8), 100% (66.4-100.0), and 100% (71.5-100.0) for DL1, DL-1, and DL-2, respectively, with corresponding median follow-ups of 17.7, 13.2, and 8.6 mo. Median time to response was 1.4 mo (range, 0.5-5.4). Median duration of response was not reached, and the probability of maintaining a response at 6 mo was 90.4% (95% CI, 73.1-96.8).

Conclusions

ELRA+IBER demonstrated deep responses across DLs in BCMA-naive pts with RRMM, supporting further investigation of the potential for enhanced anti-myeloma activity with this combination. Dose optimization is currently ongoing.