Elranatamab Plus Daratumumab and Lenalidomide Yields Durable Responses, Manageable Safety

Elranatamab (Elrexfio; Pfizer) plus daratumumab (Darzalex; Janssen Biotech, Inc) and lenalidomide (Revlimid; Celgene Corporation) yielded a durable response and manageable safety profile in patients with transplant-ineligible newly diagnosed multiple myeloma (TI NDMM). The data were presented at the 2025 International Myeloma Society Annual Meeting in Toronto, Canada.

Elranatamab is a humanized bispecific antibody targeting BCMA and CD3, designed to activate and redirect T-cells to kill myeloma cells. It has demonstrated encouraging clinical activity across multiple MagnetisMM trials, including MagnetisMM-1 (NCT03269136) and MagnetisMM-3 (NCT04649359). Results from MagnetisMM-3 formed the basis for the FDA’s accelerated approval of elranatamab for adults with relapsed or refractory multiple myeloma who have undergone at least 4 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.^1-3

"In this phase 2 trial, the intent was to utilize consolidative therapy post-standard care ide-cel," Matthew Lei, PharmD, BCOP, clinical pharmacy specialist from Massachusetts General Hospital, explained in an interview with Pharmacy Times. "From the KarMMa [NCT03361748] and KarMMa-3 [NCT03651128] trials, we know that although the majority of patients respond, these responses are not durable. The median [progression-free survival] is approximately 12 months or a little over 12 months. The goal is to deepen response, with the aim of improving progression-free survival."^4-6

In the MagnetisMM-6 (NCT05623020),⁷ a phase 3, open-label, randomized study, elranatamab, in combination with daratumumab and lenalidomide (EDR), continues to show its benefit for patients with TI NDMM. The study has 2 parts: part 1 is evaluating the optimal dose for EDR, which will be used for part 2. These data presented are interim results from part 1 dose level G (DLG).⁸

Inclusionary criteria for patients (age ≥ 65 or age < 65 years; median age 75.0 years; range, 67–83) included diagnosis of TI NDMM, measurable disease, ECOG of 2 or more, and adequate liver, renal and bone marrow function. Of the patients, 37.8% were male, 86.5% were white, and 13.5% were Asian. Five patients (13.5%) had R-ISS stage 3 disease, 24.3% had 50% or higher baseline bone marrow plasma cells, 2.7% had an ECOG performance status of 2, none had extramedullary disease, and 24.3% were classified as frail per the simplified international Myeloma Working Group IMWG frailty score.⁸

The patients were treated with subcutaneous (SC) elranatamab as a priming regimen followed by elranatamab 76 mg SC every 4 weeks (Q4W) on cycle (C) 1 day (D) 1; daratumumab at a dose of 1800 mg SC weekly (D1, D8, D15, D22 in C1–C2), every 2 weeks (D1, D15 in C3–C6), and Q4W (D1 in C7+); and oral lenalidomide 25 mg daily on D1 and D21 in 28-day cycles. The primary outcomes assessed in DLG include safety and preliminary efficacy.⁸

Of the enrolled patients (n = 37), 34 received EDR and 32 had ongoing treatment at the data cutoff of 7.9 months. The confirmed overall response rate (ORR) by investigator assessment was 97.3% (95% CI, 85.8–99.9), with 94.6% achieving very good partial response (VGPR) or better. Median time to response was 1.5 months (range, 0.3–4.2), and median time to VGPR or better was 2.4 months (range, 1.2–4.3).⁸

The safety data presented at IMS show that 100% of patients treated with EDR experienced a treatment-emergent adverse event (grade [G] 3/4 TEAE, 94.6%). Hematologic TEAEs were reported in 83.8% of patients (G3/4 78.4%), and infections in 70.3% (G3/4 18.9%). Frequent infections included (any grade ≥10%) upper respiratory tract infection (21.6%, G3/4 0%) and Escherichia urinary tract infection (10.8%, G3/4 2.7%). There was one grade 5 case of Candida pneumonia.⁸

Cytokine release syndrome (CRS) occurred in 62.2% of patients, all less than grade 2; one patient experienced grade 2 immune effector cell-associated neurotoxicity syndrome. Prophylactic therapy was administered as follows: antivirals to 81.1% of patients, anti-Pneumocystis jirovecii agents to 83.8%, antibacterials to 10.8%, and antifungals to 16.2%; 91.9% received immunoglobulin replacement.⁸

"We know that there are specific mechanisms of resistance with CAR-T cells and T-cell engagers," Lei said. "Some are overlapping, and some are not. The goal is to combine these strategies sequentially, with the aim of reinvigorating CAR-T activity. This way, we gain activity from both the T-cell engager and the CAR-T cell, hopefully improving response and durability."⁴

He continued, "The approach is based both on mechanism and sequencing. Data show that sequential T-cell engager therapy, or T-cell engager therapy prior to CAR-T, is inferior compared to CAR-T followed by sequential T-cell engagers. This strategy leverages those insights to improve response and PFS."⁴

These findings reinforce the potential of T-cell–redirecting therapies to achieve rapid and durable responses while highlighting the importance of monitoring and managing TEAEs. Pharmacists play a key role in optimizing treatment administration, monitoring for toxicity, and supporting patient adherence to these complex regimens.

REFERENCES

1. Gerlach A. ASCO 2025: Adding elranatamab to daratumumab, lenalidomide induces durable responses in newly diagnosed multiple myeloma. Pharmacy Times. May 29, 2025. Accessed September 17, 2025. https://www.pharmacytimes.com/view/adding-elranatamab-to-daratumumab-and-lenalidomide-induces-durable-responses-in-newly-diagnosed-multiple-myeloma

2. PF-06863135 as single agent and in combination with immunomodulatory agents in relapse/​refractory multiple myeloma. Updated March 18, 2025. Accessed May 28, 2025. https://clinicaltrials.gov/study/NCT03269136

3. MagnetisMM-3: Study of elranatamab (PF-06863135) monotherapy in participants with multiple myeloma who are refractory to at least one PI, one IMiD and one anti-CD38 mAb. Updated January 27, 2025. Accessed May 28, 2025. https://clinicaltrials.gov/study/NCT04649359

4. Ferruggia K, Lei M. IMS 2025: Elranatamab Consolidation After Ide-Cel Shows Promise in Relapsed or Refractory Multiple Myeloma. Pharmacy Times. September 17, 2025. Accessed September 18, 2025. https://www.pharmacytimes.com/view/ims-2025-elranatamab-consolidation-after-ide-cel-shows-promise-in-relapsed-or-refractory-multiple-myeloma

5. Efficacy and safety study of bb2121 in subjects with relapsed and refractory multiple myeloma (KarMMa). Updated May 23, 2025. Accessed September 18, 2025. https://clinicaltrials.gov/study/NCT03361748

6. Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3). Updated December 15, 2022. Accessed September 18, 2025. https://www.clinicaltrials.gov/study/NCT03651128

7. 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). Updated May 13, 2025. Accessed May 28, 2025. https://clinicaltrials.gov/study/NCT05623020

8. 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. 2025 International Myeloma Society Annual Meeting. September 17, 2025, to September 20, 2025. Toronto, Canada. Abstract OA-07