Elranatamab +/- Lenalidomide Demonstrated Early Promise in Heavily Relapsed Myeloma

Bhagirathbhai Dholaria, MBBS

Phase 1 data from the MagnetisMM-1 trial (NCT03269136) of elranatamab (PF-06863135) in patients with relapsed/refractory multiple myeloma showed encouraging responses with tolerable safety, including in those who received prior BCMA-directed therapy or who were triple-class refractory.

Results, which were presented during the 18th Annual International Myeloma Workshop, showed that when the bispecific molecule was administered at doses that were 215 μg/kg or higher (n = 20), it induced an overall response rate (ORR) of 70.0%, with a stringent complete response (sCR)/CR rate of 30.0%. When elranatamab was given at the recommended phase 2 dose (RP2D) of 1000 μg/kg, the agent resulted in an even higher ORR at 83.3%.

Notably, 3 of 4 patients who previously received BCMA-directed therapy responded to treatment with elranatamab; 1 patient had a sCR, and the other 2 experienced very good partial responses (VGPRs). Moreover, all 4 patients who achieved a CR or sCR and were evaluated were found to have minimal residual disease negativity per International Myeloma Working Group (IMWG) criteria.

When given in combination with lenalidomide in 4 patients with triple-class refractory disease, elranatamab induced an ORR of 75.0%.

“Elranatamab, given either weekly or every other week, had a manageable safety profile in patients with relapsed or refractory multiple myeloma. Safety, pharmacokinetics [PK], and efficacy data support the RP2D of 1000 μg/kg,” Bhagirathbhai Dholaria, MBBS, lead study author and assistant professor of medicine in the Division of Hematology/Oncology at Vanderbilt-Ingram Cancer Center, said in a virtual presentation on the data. “These results support further development of elranatamab both as monotherapy as well as in combination with other myeloma drugs.”

It is known that BCMA is a member of the TNF receptor superfamily that is universally expressed in multiple myeloma, and elranatamab is a humanized heterodimeric bispecific molecule that was designed to target BCMA on myeloma cells, as well as CD3 on T cells.

In the multi-part, phase 1 MagnetisMM-1 trial, investigators set out to examine the safety, PK, and efficacy of elranatamab in patients with relapsed/refractory multiple myeloma. Data presented during the meeting focused on efficacy and safety observed with the subcutaneous dosing of the agent by itself, elranatamab monotherapy with priming, and the combination of elranatamab with lenalidomide.

In part 1 of the trial, the monotherapy portion, a total of 30 patients were included and they received single-agent elranatamab at the following doses, weekly: 80 μg/kg, 130 μg/kg, 215 μg/kg, 360 μg/kg, 600 μg/kg, or 1000 μg/kg.

Part 1.1 of the trial was comprised of 20 patients who received monotherapy with priming. Specifically, these patients received a single priming dose of 600 μg/kg or a fixed dose of 44 mg, which was followed 1 week later by a full dose of 1000 μg/kg or a fixed dose of 76 mg that was administered weekly or every 2 weeks.

Part 1C of the trial included 4 patients who were given a priming dose of elranatamab at 32 mg on cycle 0 day 1, followed 1 week later by a 44-mg dose of elranatamab given weekly starting on cycle 1 day 1 in combination with lenalidomide at a daily dose of 25 mg on days 1 through 21 of a 28-day treatment cycle, beginning with cycle 1.

Investigators performed safety assessments and treatment-emergent adverse effects (TEAEs) were graded via CTCAE version 4.03 criteria, cytokine release syndrome (CRS) was graded using ASTCT criteria, and dose-limiting toxicities were monitored to the end of cycle 1. Responses were evaluated using International Myeloma Working Group (IMWG) criteria.

By a data cutoff date of June 7, 2021, 30 patients had received subcutaneous single-agent elranatamab. Of these patients, 6 received the agent at 80 μg/kg, 4 at 130 μg/kg, 4 at 215 μg/kg, 4 at 360 μg/kg, 6 at 600 μg/kg, and 6 at 1000 μg/kg. The agent was administered on a weekly basis in these patients.

Among the 30 patients in part 1, the median age was 63.0 years (range, 46-80) with 40.0% of patients aged 65 years or older. Moreover, 56.7% of patients were female, 40.0% had Revised-International Staging System stage II disease at the time of their initial diagnosis, and 63.3% were determined to have standard cytogenetic risk. Notably, the median number of prior anti-myeloma therapies received was 8.0 (range 2-15), and 86.7% of patients had triple-refractory disease.

All patients had previously received proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Ninety percent of patients previously received bortezomib (Velcade), 86.7% had prior carfilzomib (Kyprolis), and 26.7% had ixazomib (Ninlaro). The IMiDs that were previously received included lenalidomide (96.7%), pomalidomide (Pomalyst; 90.0%), and thalidomide (Thalomid; 26.7%). Additionally, 96.7% of patients receive prior anti-CD38 therapies like daratumumab (Darzalex; 93.3%), isatuximab (Sarclisa; 13.3%) or another agent (6.7%).

Notably, 23.3% of patients previously received BCMA-targeted therapy in the form of an antibody-drug conjugate (20.0%) or a CAR T-cell therapy (10.0%).

For part 1 of the study, the median duration of follow-up for the 20 patients treated at doses of 215 μg/kg or higher was 10.9 months, and the median time to response in the 14 patients who responded to elranatamab monotherapy was 22 days (range, 21-50). In the 14 responders, the median duration of response has not yet been reached, but the probability of these patients being event free at 6 months was estimated to be 92.3% (95% CI, 56.6%-98.9%).

PK data revealed that exposure increased in an approximately dose-proportionate manner, and subcutaneous administration of the agent led to a prolonged absorption phase with a Tmax of 3 to 7 days following just 1 dose of elranatamab.

“The population PK analysis indicated that body weight was actually not a significant covariant for the total drug exposure, supporting a fixed-dose approach for the further development of this drug,” Dholaria noted. “Baseline soluble BCMA did not significantly interact with the PK of this drug.”

Investigators also noted that the serum cytokine increased predominantly after just the first dose of elranatamab and peaked 8 to 24 hours following administration. “However, the levels kind of stabilized and went down to baseline levels for the subsequent cycles,” Dholaria explained. “This was reflected by the way the CRS presented. Most patients developed CRS after the first dose and in subsequent cycles, they did not develop [this effect].”

No dose-limiting toxicities (DLTs) were reported in part 1 of the study. Common hematologic toxicities comprised lymphopenia (86.7%), anemia (76.7%), thrombocytopenia (56.7%), neutropenia (53.3%), and leukopenia (40.0%).

The overall incidence of CRS was 73.3%; these patients did not receive premedication or priming/step-up dosing to mitigate this effect. However, CRS cases were noted to only be grade 1 or 2 in severity. The median time to onset of CRS was 1 day (range, 1-3) and the median duration of the effect was 3 days (range, 1-10). Thirty percent of these patients were given tocilizumab (Actemra) and 10% were administered steroids.

“Notably, no treatment discontinuations, [dosing] interruptions, or dose modifications were required [because of] CRS in this study cohort,” Dholaria added.

Among the 20 patients who received elranatamab monotherapy with priming, 7 received the agent at a weekly dose of 1000 μg/kg and 13 were given the agent at the same dose but on a biweekly basis. These patients also did not receive premedication to mitigate CRS.

Safety data indicated that CRS was reported in all patients but was limited to grade 1 (50%) or grade 2 (50%). The median duration of CRS was 3 days (range, 2-7) in this cohort.

Other toxicities observed in these patients included neutropenia (80.0%), anemia (75.0%), thrombocytopenia (65.0%), injection site reaction (60.0%), fatigue (45.0%), hypomagnesemia (40.0%), hypophosphatemia (40.0%), decreased appetite, diarrhea, lymphopenia, and vomiting (35% each).

In the 4 patients included on part 1C, the combination therapy portion of the trial, no drug–drug interaction had been observed between elranatamab and lenalidomide. Notably, treatment-emergent peripheral neuropathy was not observed with the doublet, according to Dholaria.

“Hematologic effects were observed more frequently at a higher degree, as one would expect, but the CRS was relatively comparable,” Dholaria concluded. “Two of 4 patients developed CRS, all grade 2.”

_Reference

_{Dholaria B, Bahlis NJ, Raje NS, et al. MagnetisMM-1 study of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA) targeted CD3-engaging bispecific molecule, for patients with relapsed or refractory multiple myeloma (MM). Presented at: International Myeloma Workshop; September 8-11, 2021; Vienna, Austria.}