Elranatamab After Prior BCMA-Directed Therapy Induces Early Responses in RRMM

Ajay K. Nooka, MD, MPH, FACP

In patients with relapsed/refractory multiple myeloma who received prior treatment with a BCMA-directed therapy, erlanatamab (PF-06863135) monotherapy produced early, deep, and durable responses, according to a pooled analysis of patients enrolled in multiple studies from the MagnetisMM program.¹

The findings were from the phase 1 MagnetisMM-1 (NCT03269136), phase 1 MagnetisMM-2 (NCT04798586), phase 2 MagnetisMM-3 (NCT04649359), and phase 2 MagnetisMM-9 (NCT05014412) trials, and were presented at the 2023 ASCO Annual Meeting showed that at a median follow-up of 11.3 months (range, 0.3-32.3), patients treated with elranatamab after any prior BCMA-directed therapy (n = 87) achieved an overall response rate (ORR) of 46% (95% CI, 35.2%-57.0%), including a stringent complete response (sCR) rate of 4.6%, a complete response (CR) rate of 13.8%, a very good partial response (VGPR) rate of 24.1%, and a partial response (PR) rate of 3.4%). Among patients who experienced a response (n = 40), the median time to response was 1.7 months (range, 0.3-9.3).

Among patients who received a prior BCMA-directed antibody-drug conjugate (ADC; n = 59), the ORR was 42.4% with sCR, CR, VGPR, and PR rates of 5.1%, 13.6%, 20.3%, and 3.4%, respectively. Those who had prior treatment with a BCMA-directed CAR T-cell therapy (n = 36) achieved an ORR of 52.8%, including sCR, CR, VGPR, and PR rates of 2.8%, 16.7%, 27.8%, and 5.6%, respectively. Notably, 8 patients received prior treatment with both a BCMA-directed ADC and CAR T-cell therapy.

“These results support elranatamab monotherapy as a treatment option for patients with relapsed/refractory myeloma post–BCMA-directed therapy,” Ajay K. Nooka, MD, MPH, FACP, said in a presentation of the data. Nooka is a professor and director of the Myeloma Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine. He is also scientific director of Winship Data and Technology Applications Shared Resource at Winship Cancer Institute of Emory University in Atlanta, Georgia.

Elranatamab is a bispecific antibody targeting BCMA and CD3. Data from the MagnetisMM-3 study demonstrated that patients who have not been exposed to a prior BCMA-directed therapy achieved an ORR of 61.0% (95% CI, 51.8%-69.6%). At a median follow-up of 14.7 months (range, 0.2-25.1), the median progression-free survival (PFS) has not yet been reached (NR; 95% CI, 9.9-not evaluable [NE]), and the median duration of response (DOR) was also NR (95% CI, NE-NE).2

For the pooled analysis, investigators evaluated the efficacy and safety of the bispecific antibody in patients enrolled in 1 of the 4 MagnetisMM trials who received at least 1 proteasome inhibitor, 1 immunomodulatory drug, 1 anti-CD38 monoclonal antibody, and 1 BCMA-directed ADC and/or CAR T-cell therapy.1

Patients drawn from MagnetisMM-1 (n = 13) received 215 µg/kg to 1000 µg/kg of subcutaneous elranatamab once every week or once every 2 weeks. One patient selected from MagnetisMM-2 was given elranatamab at 1000 µg/kg subcutaneously once per week with a step-up dose of 600 µg/kg. Patients in MagnetisMM-3 (n = 64) were administered 76 mg of subcutaneous elranatamab once per week with 2 step-up doses of 12 mg and 32 mg. Those from MagnetisMM-9 (n = 9) were treated with 76 mg of subcutaneous elranatamab once per week with 2 step-up doses of 4 mg and 20 mg.

Efficacy end points were assessed by investigators using International Myeloma Working Group criteria. Safety end points included treatment-emergent adverse effects (TEAEs) graded by Common Terminology Criteria for Adverse Events, as well as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).

Among all patients, the median age was 66.0 years (range, 40-84). Thirteen patients were at least 75 years old, including 12 who received prior treatment with a prior BCMA-directed ADC and 1 who received a prior BCMA-directed CAR T-cell therapy. Additionally, 47.1% of patients were male, and 64.4% of patients were White; however, race was not reported for 21.8% of patients.

Patients had an ECOG performance status of 0 (29.9%), 1 (65.5%), or 2 (4.6%). Per the Revised Multiple Myeloma International Staging System, 20.7% of patients had stage 1 disease, 50.6% had stage 2 disease, and 23.0% of patients had stage 3 disease. Disease stage data were missing or unknown for 5.7% of patients.

Furthermore, 65.5% and 24.1% of patients had standard and high cytogenetic risk, respectively. Cytogenetic risk data were missing for 10.3% of patients. Fifty-four percent of patients had extramedullary disease, and extramedullary disease status was missing for 3.4% of patients. Bone marrow plasma cells were less than 50% in 70.1% of patients, and this information was missing for 11.5% of patients.

Patients received a median of 7.0 (range, 3-19) prior lines of therapy, and 81.6% of patients underwent prior stem cell transplant. “This was a heavily pretreated patient population,” Nooka noted.

All patients were triple-class exposed, and 85.1% of patients were penta-drug exposed. Furthermore, 96.6% of patients were triple-class refractory, 55.2% were penta-drug refractory, and 85.1% were refractory to their last line of therapy. Additionally, 62.1% were refractory to prior BCMA-directed therapy, including 54.0% and 11.5% who were refractory to a prior BCMA-directed ADC or CAR T-cell therapy, respectively.

At data cutoff, the median duration of treatment was 3.5 months (range, 0.03-30.9), and 39.1% of patients received more than 6 months of treatment. Twenty-three percent of patients who previously received any BCMA-targeted agent were still receiving elranatamab at data cutoff. Reasons for treatment discontinuation included progressive disease (46.0%), AEs (11.5%), death (10.3%), lack of efficacy (2.3%), and patient withdrawal/refusal of further treatment (6.9%).

Additional data showed that 50% of responders (n = 20/40) were still in response at data cutoff. Notably, DOR data were not yet mature after censoring data for 57.5% of responders. The median DOR was 17.1 months (95% CI, 9.8-NE). The median DOR was 13.6 months (95% CI, 6.8-NE) and NE (95% CI, 9.8-NE) for patients who received a prior BCMA-directed ADC or CAR T-cell therapy, respectively.

The median PFS was 5.5 months (95% CI, 2.2-10.0) for all patients, 3.9 months (95% CI, 1.9-6.6) for those given a prior BCMA-directed ADC, and 10.0 months (95% CI, 1.9-NE) for those given a prior BCMA-directed CAR T-cell therapy. The median overall survival was 12.1 months (95% CI, 7.5-NE) in the overall population, 12.1 months (95% CI, 6.4-NE) in patients who treated with a prior BCMA-directed ADC, and 12.1 months (95% CI, 6.5-NE) in patients administered a prior BMCA-directed CAR T-cell therapy.

Safety findings showed that the toxicity profile of elranatamab was similar to findings reported in patients naïve to BCMA-directed therapy who were treated in MagnetisMM-3.

The most common hematologic TEAEs reported in at least 20% of patients consisted of anemia (any grade, 58.6%; grade 3/4, 46.0%), neutropenia (44.8%; 41.4%), thrombocytopenia (40.2%; 28.7%), lymphopenia (32.2%; 29.9%), and leukopenia (21.8%; 12.6%). Non-hematologic TEAEs included CRS (any-grade, 65.5%; grade 3/4, 2.3%), diarrhea (35.6%; 0%), COVID-19 related (25.3%; 9.2%), decreased appetite (23.0%; 1.1%), cough (21.8%; 1.1%), injection site reaction (20.7%; 0%), and pyrexia (20.7%; 1.1%).

Notably, TEAEs led to death in 23 patients, including 11 due to disease progression, 8 due to infections, including COVID-19 (n = 5) and septic shock/sepsis (n = 3), and 4 due to other causes, including pulmonary embolism, fall, cardiac arrest, and cardiogenic shock.

Infections were reported in 73.6% of patients, including 26.4% of patients who had grade 3/4 infections and 9.2% who experienced grade 5 infections. Additionally, 25.3% of patients experienced COVID-19–related TEAEs, and 6.9% of patients permanently discontinued treatment due to infections.

Regarding CRS, 48.3% of patients had maximum event of grade 1, 14.9% of patients had a maximum event of grade 2, and 2.3% of patients had a maximum event of grade 3. No instances of grade 4/5 CRS were reported. Notably, 9.2% of patients experienced more than 1 CRS event. In patients who received step-up dosing at 12 mg and 32 mg (n = 64), any-grade CRS was reported in 60.9% of patients, and 1.6% of patients had grade 3 CRS.

The median time to CRS onset was 2.0 days (range, 1.0-4.0), and the median time to resolution was 2.0 days (range, 1.0-10.0). Tocilizumab (Actemra) was given to 21.8% of patients who had CRS, and 11.5% received steroids. One patient permanently discontinued treatment due to CRS.

Additionally, any-grade ICANS occurred in 5.7% of patients, including 3.4% of patients who had a maximum grade 2 event and 2.3% of patients who had a maximum grade 3 event. ICANS was reported more than once in 1 patient. The median time to onset of ICANS was 2.0 days (range, 1.0-3.0), and the median time to resolution was 2.0 days (range, 1.0-18.0). Furthermore, 2.3% of patients received tocilizumab for ICANS, and 3.5% were given steroids. ICANS led to permanent treatment discontinuation in 2 patients.

Editor’s note: Dr Nooka reported receiving honoraria from Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol Myers Squibb/Celgene, Cellectar, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Secura Bio, and Takeda; serving in a consulting or advisory role for Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol Myers Squibb, Cellectar, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Secura Bio, and Takeda; receiving institutional research funding from Amgen, Arch Oncology Bristol Myers Squibb/Celgene, Cellectar, GlaxoSmithKline, Janssen Oncology, Pfizer, and Takeda; and receiving travel expenses from GlaxoSmithKline.

_References

_{1. Nooka AK, Lesokhin AM, Mohty M, et al. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) and prior B-cell maturation antigen (BCMA)-directed therapies: A pooled analysis from MagnetisMM studies. J Clin Oncol. 2023;41(suppl 16):8008. doi:10.1200/JCO.2023.41.16_suppl.8008}

_{2. Mohty M, Tomasson MH, Arnulf B, et al. Elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, for patients (pts) with relapsed/refractory multiple myeloma (RRMM): Extended follow up and biweekly administration from the MagnetisMM-3 study. J Clin Oncol. 2023;41(suppl 16):8039. doi:10.1200/JCO.2023.41.16_suppl.8039}