FDA Approves Elranatamab for Relapsed or Refractory Multiple Myeloma

FDA

The FDA has granted accelerated approval to elranatamab-bcmm (Elrexfio) for the treatment of adult patients with relapsed or refractory multiple myeloma who have previously received at least 4 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.^1,2

The regulatory decision is supported by data from the phase 2 MagnetisMM-3 trial (NCT04649359), which showed that elranatamab elicited an overall response rate (ORR) of 57.7% (95% CI, 47.3%-67.7%) in the 97 patients who were naïve to BCMA-directed therapy; this included a complete response (CR) rate of 25.8%, a very good partial response (VGPR) rate of 25.8, and a partial response (PR) rate of 6.2%. Notably, 82% of responders were estimated to continue to respond to treatment for 9 months or longer. The median time to response was 1.22 months (range, 0.9-6.5), and the median duration of response (DOR) was not yet reached (NR; 95% CI, 12.0-not evaluable [NE]). At a median follow-up of 11.1 months (95% CI, 10.6-12.0), the 6-month and 9-month DOR rates were 90.4% (95% CI, 78.4%-95.9%) and 82.3% (95% CI, 67.1%-90.9%), respectively.^1,2

The label also includes findings from cohort B (n = 64), which was comprised of patients who previously received a PI, IMiD, anti-CD38 monoclonal antibody, and a BCMA-targeted therapy; 63 of these patients had received at least 4 prior lines of therapy. In these patients, elranatamab elicited an ORR of 33.3% (95% CI, 22.0%-46.3%). After a median follow-up of 10.2 months (95% CI, 9.9-11.0), the median DOR was NR (95% CI, NE-NE) and the 9-month DOR rate was 84.3% (95% CI, 58.7%-94.7%).^1,2

Longer-term findings from cohort A (n = 123) indicated that elranatamab induced an ORR of 61%. The DOR, progression-free survival, and overall survival were NR at the time of the presentation delivered during the 2023 EHA Congress.¹ The probability of maintaining a response at 15 months was 72% in these patients. Notably, 80% of responders who switched to every-other-week dosing at least 6 months before the data cutoff date maintained their response, or experienced improved response after switching; 38% attained a CR or better post switch.

Continued approval for this indication is contingent upon verification of clinical benefit in the confirmatory MagnetisMM-5 trial (NCT05020236), according to Pfizer. This phase 3 trial, which was initiated in 2022, is being done in patients with double class–exposed, relapsed/refractory disease. Data will be shared with the public when available.¹

“Elrexfio reflects our ongoing commitment to developing scientific breakthroughs that meaningfully improve outcomes for people with cancer. Discovered at Pfizer, we advanced this therapy from a first-in-patient trial to approval in less than five years, because we know that time is life for people living with multiple myeloma,” Angela Hwang, chief commercial officer and president of Global Biopharmaceuticals Business at Pfizer, stated in a press release. “With significant responses in a patient population with highly refractory disease, we believe Elrexfio is poised to potentially become the new standard of care for multiple myeloma, as we plan to build upon this indication with continued development across the expansive MagnetisMM program.”

The open-label, single-arm, multicenter MangetisMM-3 trial enrolled patients with multiple myeloma who were refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38 monoclonal antibody.² To be eligible for enrollment, patients needed to have measurable disease per International Myeloma Working Group (IMWG) criteria, an ECOG performance status of 0 to 2, and acceptable bone marrow, renal, and hepatic function. They also needed to have a left ventricular ejection fraction of 40% or higher. Those who underwent stem cell transplantation (SCT) within 12 weeks before enrollment, and those who had active infections, were excluded.

A total of 123 patients who were naïve to prior BCMA-directed therapy comprised the pivotal cohort A, and 64 patients who were previously exposed to BCMA-targeted antibody-drug conjugates or CAR T-cell therapies comprised cohort B.

Study participants were administered subcutaneous elranatamab via step-up doses of 12 mg on day 1 and 32 mg on day 4 of treatment, followed by the first treatment dose of the agent at 76 mg on day 8. Thereafter, patients were given elranatamab at once-weekly doses of 76 mg. After 24 weeks, those who achieved PR or better by IMWG criteria, who had their response continue for at least 2 months, had their dose interval changed from once weekly to every 2 weeks.

In cohort A, the median number of prior lines of treatment received was 5, with range of 2 to 22 lines; of the 123 patients, 97 did not have prior exposure to BCMA-directed treatment and had received 4 or more prior lines of therapy. As such, the 97 patients comprised the efficacy population for the trial.

The median age in that population was 69 years (range, 46-89), and 18.6% of patients were 75 years or older. Moreover, 40% of patients were female and 59.8% were White. Regarding disease stage at the time of study entry, 20.6% had stage I disease, 53.6% had stage II disease, and 17.5% had stage III disease. The majority of these patients (96.9%) were triple-class refractory and 94.8% were refractory to the last line of therapy received. Additionally, 69.1% of patients previously underwent autologous SCT and 7.2% underwent allogeneic SCT. Moreover, 22.7% of patients had high-risk cytogenetics and 34.0% of patients had baseline extramedullary disease.

Key efficacy objectives were ORR and DOR by blinded independent central review and in accordance with IMWG criteria.

Safety of elranatamab was examined in 183 patients who received the recommended dose regimen of the agent, given at 12 mg on day 1, 32 mg on day 4, and 76 mg once weekly beginning on day 8. Forty-two percent of patients were exposed to the agent for at least 6 months, and 9% were exposed for at least 1 year.

Adverse effects (AEs) that required dose interruptions were observed in 73% of patients, and 17% of patients experienced toxicities that led to permanent treatment discontinuation of the drug.

Sixty-eight percent of patients experienced serious toxicities, and these included pneumonia (25%), sepsis (13%), cytokine release syndrome (CRS; 13%), upper respiratory tract infection (4.4%), acute kidney injury (3.8%), urinary tract infection (3.3%), COVID-19 (3.3%), encephalopathy (3.3%), pyrexia (2.2%), and febrile neutropenia (2.2%).

Ten percent of patients experienced AEs that proved to be fatal, and these included pneumonia (3.3%), sepsis (2.7%), acute respiratory distress syndrome (0.5%), cardio-respiratory arrest (0.5%), cardiogenic shock (0.5%), cardiopulmonary failure (0.5%), COVID-19 (0.5%), failure to thrive (0.5%), and pulmonary embolism (0.5%).

The most common AEs experienced by at least 10% of patients who received elranatamab on the study included CRS (any grade, 58%; grade 3 or 4, 0.5%), hypogammaglobulinemia (13%; 2.2%), fatigue (43%; 6%), injection site reactions (37%; 0%), pyrexia (21%; 2.7%), edema (18%; 1.1%), diarrhea (36%: 1.1%), nausea (22%; 0%), constipation (15%; 0%), vomiting (14%; 0%), upper respiratory tract infection (34%; 4.9%), pneumonia (32%; 19%), sepsis (15%; 11%), urinary tract infection (12%; 4.4%), musculoskeletal pain (34%; 2.7%), reduced appetite (26%; 1.1%), rash (25%; 0%), dry skin (13%; 0%), skin exfoliation (10%; 0%), cough (24%; 0%), dyspnea (15%; 3.3%), headache (18%; 0.5%), encephalopathy (15%; 2.7%), sensory neuropathy (13%; 0.5%), motor dysfunction (y13%; 2.2%), cardiac arrhythmia (16%; 2.2%), hemorrhage (13%; 1.6%), insomnia (13%: 0%), and fall (10%; 0.5%).

Laboratory abnormalities reported in at least 30% of patients included decreased lymphocyte count (91%; 84%), white blood cell count (69%; 40%), hemoglobin (68%; 43%), neutrophil count (62%; 51%), platelet count (61%; 32%), albumin (55%; 6%), potassium (36%; 8%), and creatinine clearance (32%; 10%). Other abnormalities included increased aspartate aminotransferase (40%; 6%), creatinine (38%; 3.3%), alanine aminotransferase (36%; 3.8%), and alkaline phosphatase (34%; 1.1%).

“Most patients [with] multiple myeloma will experience relapse or resistance of their disease to treatment, often facing increased symptom burden and lowering their chance of surviving longer with each attempted line of therapy,” Ajay Nooka, MD, MPH, MagnetisMM clinical trial investigator and director of the Multiple Myeloma Program at Winship Cancer Institute of Emory University, added in the press release.¹ “By offering durable clinical response with an established safety profile and the convenience of subcutaneous administration, Elrexfio provides a much-needed new option for heavily pretreated...patients who are struggling with relapsed myeloma.”

References

1. Pfizer's Elrexfio receives US FDA accelerated approval for relapsed or refractory multiple myeloma. News release. Pfizer. August 14, 2023. Accessed August 14, 2023. https://investors.pfizer.com/Investors/News/news-details/2023/Pfizers-ELREXFIO-Receives-U.S.-FDA-Accelerated-Approval-for-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
2. Elranatamab-bcmm (Elrexfio) Prescribing Information. Pfizer; August 2023. Accessed August 14, 2023. https://labeling.pfizer.com/ShowLabeling.aspx?id=19669