Elranatamab Combo Yields Early Efficacy in Transplant-Ineligible NDMM

"Initial data from MagnetisMM-6 part 1 dose level G demonstrate that the combination of elranatamab plus daratumumab [and] lenalidomide is effective and manageable in transplant-ineligible patients with NDMM," according to the study authors.

Combining elranatamab-bcmm (Elrexfio) with daratumumab (Darzalex) and lenalidomide (Revlimid) demonstrated early and promising efficacy in a small cohort of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), according to a presentation on findings from part 1 of the phase 3 MagnetisMM-6 trial (NCT05623020) at the 22^nd Annual International Myeloma Society Meeting and Exposition.¹

With a data cutoff of December 23, 2024, and a median follow-up of 4.6 months (range, 1.2-6.2), the combination yielded an overall response rate (ORR) of 91.9%, which included very good partial responses (VGPRs) or better in 81.1% of patients. After an extended median follow-up of 7.9 months (range, 1.2-9.5) and a data cutoff of April 1, 2025, the ORR was 97.3%, the VGPR or better rate was 94.6%, and 27.0% of patients experienced a complete response (CR) or better. Investigators noted that although the median follow-up was short, the CR rate is expected to increase over time.

“Initial data from MagnetisMM-6 part 1 dose level G demonstrate that the combination of elranatamab plus daratumumab [and] lenalidomide is effective and manageable in transplant-ineligible patients with NDMM…Responses are expected to deepen further with longer follow-up,” lead author Suzanne Trudel, MSc, MD, a clinician scientist at Princess Margaret Cancer Centre, and coauthors wrote in the presentation.¹ “The safety profile was consistent with known toxicities of the components.”

Investigators hypothesized that sequencing the BCMA-CD3 bispecific antibody elranatamab with lenalidomide and daratumumab could enhance immune cell-mediated myeloma cell death. This potential synergistic effect was based on lenalidomide’s ability to stimulate the activation of CD4-positive and CD8-positive T cells and natural killer cells as well as daratumumab’s immunomodulatory effects against myeloma cells that express CD38.

Investigators of the MagnetisMM-6 trial aimed to assess the safety and efficacy of elranatamab plus lenalidomide with or without daratumumab vs daratumumab plus lenalidomide and dexamethasone among those with NDMM who are ineligible for transplant. In part 1 of the study, investigators explored the optimal dosing of the elranatamab-based combinations among patients with relapsed/refractory disease or NDMM to determine the recommended phase 3 dose for part 2.

This analysis focused on dose level G of the trial, in which patients received elranatamab at 76 mg subcutaneously every 4 weeks, daratumumab at 1800 mg subcutaneously, and lenalidomide at 25 mg orally.

The trial’s primary end point was dose-limiting toxicities (DLTs) during the DLT observation period. Secondary end points included adverse effects (AEs) and laboratory abnormalities, ORR, CR rate, time to response, duration of response (DOR), progression-free survival (PFS), overall survival, minimal residual disease (MRD) negativity, pharmacokinetics, and immunogenicity.

Patients 18 years and older with relapsed/refractory multiple myeloma or transplant-ineligible NDMM and measurable disease per International Myeloma Working Group guidelines were eligible for enrollment on the trial. Other eligibility criteria included having adequate liver, renal, and bone marrow function as well as an ECOG performance status of 0 to 2. Those with smoldering multiple myeloma, monoclonal gammopathy of undetermined significance, or plasma cell leukemia were ineligible for study entry.²

Among 37 evaluable patients, the median age was 75.0 years (range, 67-83), and most were female (62.2%) and White (86.5%). Most patients had an ECOG performance status of 0 (59.5%), revised International Staging System stage II disease (54.1%), lower than 50% baseline bone marrow plasma cells, and no frailty (75.7%).

Of the 37 patients who received at least 1 dose of elranatamab, 34 received the triplet combination, and 3 received elranatamab alone and discontinued therapy during the step-up dosing procedures. As of the cutoff of April 1, 2025, 86.5% (n = 32) patients were still receiving treatment.

Treatment-emergent AEs (TEAEs) of any grade and grades 3 or 4, respectively, affected 100% and 94.6% of the study population. The most common grade 3/4 toxicities were hematologic in nature and consisted of neutropenia (73.0%), anemia (18.9%), and thrombocytopenia (10.8%). Cytokine release syndrome (CRS) occurred at grades 1 (45.9%) and 2 (16.2%); no grade 3 or higher events were highlighted. Additionally, 1 patient experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS).

Infections of any grade and grades 3 or 4 occurred in 70.3% and 18.9% of patients, respectively. The most common any-grade infections included upper respiratory tract infection (21.6%), Escherichia urinary tract infection (10.8%), and cytomegalovirus reactivation (10.8%). Regarding the use of anti-infective prophylaxis, investigators administered immunoglobulin replacement therapy, anti-viral prophylaxis, and anti-Pneumocystis jirovecii agents to 91.9%, 81.1%, and 83.8% of patients, respectively.

Investigators are currently enrolling patients for part 2 of the phase 3 MagnetisMM-6 trial, which will assess elranatamab plus daratumumab and lenalidomide vs daratumumab plus lenalidomide and dexamethasone among patients with transplant-ineligible or transplant-deferred NDMM. The phase 3 portion will include treatment de-escalation. The primary end points will be the MRD negativity rate at 12 months and PFS; secondary end points include overall and sustained MRD negativity rate, duration of MRD negativity, ORR, CR rate, time to response, DOR, and duration of CR.

References

1. Trudel S, Quach H, Pour L, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. Presented at the 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-07.
2. A study to learn about the effects of the combination of elranatamab (PF-06863135), daratumumab, lenalidomide or elranatamab and lenalidomide compared with daratumumab, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma who are not candidates for transplant (MagnetisMM-6). ClinicalTrials.gov. Updated September 8, 2025. Accessed September 17, 2025. https://tinyurl.com/344t6836