Elranatamab Induces Promising Responses in Patients With Penta/Triple-Refractory Myeloma

Nizar Jacques Bahlis, MD

Patients with penta- or triple-class refractory multiple myeloma in cohort A the open-label phase 2 MagnetisMM-3 study (NCT04649359) elicited an objective response rate (ORR) by blinded independent central review (BICR) of 61.0% (95% CI, 51.8%-69.6%) on treatment with the CD3/BCMA bispecific antibody elranatamab, according to findings presented at the 2022 ASH Annual Meeting.¹

A very good partial response or better was achieved for 55.3% of patients treated with elranatamab, with 27.6% of patients achieving a complete remission or better. Of those achieving a complete remission (n = 22), 90.9% achieved minimal residual disease (MRD)-negativity at a threshold of 10-5. The median time to response was 1.2 months.

Although medians were not achieved, the 6- and 12-month progression-free survival rates with elranatamab were 65.2% and 58.8%, respectively. At 6 months, the overall survival rate with elranatamab was 76.1% and 63.6% at 12 months.¹

“Elranatamab is very efficacious and well tolerated in patients with relapsed/refractory multiple myeloma. Overall response rate is high at 61%, and it was early, deep, and durable,” lead investigator Nizar Jacques Bahlis, MD, from the Arnie Charbonneau Cancer Institute at the University of Calgary, in Canada, said during a presentation of the results at ASH. “The most common grade 3/4 treatment-emergent adverse events [TEAEs] were hematologic events and nonhematologic events were predominantly grade 1/2.”

In November 2022, the FDA granted elranatamab a breakthrough therapy designation.²

Cohort A of the MagnetisMM-3 study enrolled 123 patients with multiple myeloma that was refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Patients had received a median of 5.0 prior therapies (range, 2-22), and most were triple-class refractory (96.7%), with nearly half being penta-class refractory (42.3%).¹

In the first week of treatment, patients received elranatamab step-up subcutaneous dosing to mitigate adverse events. The step-up dosing consisted of elranatamab at 12 mg on day 1 followed by 32 mg on day 4. After the first week, elranatamab was administered subcutaneously once per week at 76 mg. The step-up dosing was started later in the study, with 119 of the 123 patients receiving treatment in this fashion. Premedication of acetaminophen, diphenhydramine, and dexamethasone were also administered prior to the first 3 doses of elranatamab.¹

The median age of patients was 68 years (range, 36-89) and ECOG performance scores were 0 (36.6%), 1 (57.7%), and 2 (5.7%). A majority were male (55.3%) and most were White (58.5%). High-risk cytogenetics were present in a quarter of patients (25.2%) and nearly one-third had extramedullary disease (31.7%). There were 15.4% of patients with stage III disease per the revised Multiple Myeloma International Staging System, with the remaining patients having stage I (22.8%), II (55.3%), or unknown (6.5%).

At the data cutoff for the ASH presentation, which was October 14, 2022, the median follow-up was 10.4 months, and the median duration of treatment was 5.6 months. The median duration of response was not yet reached at the time of the analysis, with 77.3% of responses still ongoing at the data cutoff (n = 58/75). The 9-month duration of response rate was 84.4% and the 9-month progression-free survival rate was 63.0%.¹

The primary cause of elranatamab discontinuation was progressive disease (35.0%), with 10.6% discontinuing elranatamab due to adverse events (AEs) and 6.5% from death. TEAEs led to permanent elranatamab discontinuation in 15.4% of patients. The most commonly reported TEAEs of grade 3/4 in severity were neutropenia (48.0%), anemia (36.6%), lymphopenia (24.4%), thrombocytopenia (22.0%), COVID-19 (11.4%), and hypokalemia (9.8%). There were 21 grade 5 TEAEs in the study, with 2 considered treatment-related by the investigators (pseudomonal pneumonia and failure to thrive).

An infection of any grade was reported in 66.7% of patients, with 35.0% of patients experiencing a grade 3/4 infection. COVID-19–related TEAEs of any grade were experienced by 25.2% of patients. Infections led to permanent discontinuation of elranatamab in 6.5% of patients. Over the course of the study, 40.7% patients received intravenous immunoglobulin to counter infections. Injection site reactions were seen in 26% of patients, all of which were grade 1/2 in severity.¹

Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were assessed using American Society for Transplant and Cellular Therapy criteria, with all events deemed to be grade 1 or 2 in severity. In those who received the step-up dosing, CRS was experienced by 56.3% of patients and ICANS was observed in 3.4%. Of those with CRS or ICANS, 22.7% and 1.7% received tocilizumab (Actemra), respectively, and 8.4% and 1.7% received steroids, respectively. The median time to resolution of CRS/ICANS was 2.0 days and there were no discontinuations due to these AEs. CRS occurred early, with 90.6% of cases occurring during the step-up phase and 98.8% of events within the first 3 doses.¹

“The step-up priming regimen successfully mitigated the rate and severity of CRS, and the CRS profile was predictable,” Bahlis said. “CRS events occurred early, with the majority limited to the step-up doses.”

There are several ongoing phase 3 studies exploring elranatamab alone or in combinations for patients with multiple myeloma. The phase 3 MagnetisMM-5 study (NCT05020236) is evaluating the BCMA/CD3 bispecific as a single agent and in combination with daratumumab (Darzalex) for patients with relapsed/refractory multiple myeloma. The phase 3 MagnetisMM-7 study (NCT05317416) is examining elranatamab for patients with newly diagnosed multiple myeloma as maintenance therapy compared with lenalidomide.

_References

_{1. Bahlis NJ, Tomasson MH, Mohty M, et al. Efficacy and Safety of Elranatamab in Patients with Relapsed/Refractory Multiple Myeloma Naïve to B-Cell Maturation Antigen (BCMA)-Directed Therapies: Results from Cohort A of the Magnetismm-3 Study. Blood. 2022;140(suppl 1):391-393. doi:10.1182/blood-2022-162440}

_{2. Pfizer’s elranatamab granted FDA breakthrough therapy designation for relapsed or refractory multiple myeloma. News release. Pfizer Inc. November 3, 2022. Accessed December 10, 2022. bit.ly/3T20rbE}