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Bispecific Antibody Active in Heavily Treated Multiple Myeloma

<ѻý class="mpt-content-deck">— Responses in 60% of patients who had received a median of five prior lines of therapy
MedpageToday
A computer rendering of an antibody.

Almost 60% of patients with heavily pretreated multiple myeloma responded to an investigational bispecific antibody, results from an ongoing phase I trial showed.

Overall, 57% of 124 patients had at least partial response to ABBV-383, a B-cell maturation antigen (BCMA)/CD3 T-cell-engaging fully human monoclonal antibody. In the subgroup of patients treated with the recommended phase II dose, the overall response rate increased to 60%, including very good partial response (VGPR) or better in 43%. The study population had received a median of five prior lines of therapy.

Treatment with the bispecific antibody was associated with a low rate of grade ≥3 adverse events and rapid resolution of cytokine release syndrome (CRS) with standard supportive measures, reported Peter Voorhees, MD, of the Levine Cancer Center in Charlotte, North Carolina, during the International Myeloma Society meeting in Los Angeles. The study was also published simultaneously in the .

"Promising efficacy was indicated by deep and durable responses," said Voorhees. "Median progression-free survival was not reached in the 60-mg [recommended phase II dose] cohort, 10.4 months for the overall population. Median duration of response was not achieved in the overall population or the 60-mg cohort, but the 12-month estimates were greater than 67% for the overall population and 77% in the 60-mg treated patients."

"We observed encouraging preliminary antitumor activity in heavily pretreated patients with relapsed/refractory multiple myeloma that supports further clinical evaluation," he added. "Enrollment in the 60-mg arm, given once every three weeks, has been completed. An additional dose level of 40-mg every three weeks is currently under exploration."

In his introductory comments, Voorhees said the design of ABBV-383 reflected the desire to maximize myeloma target-cell killing while minimizing off-target toxicity and cytokine release. The antibody induced tumor cell death in studies of cell lines and mouse xenograft models by means of recruitment of CD3+ cells to BCMA+ myeloma cells.

Investigators in the phase I trial recruited patients with relapsed/refractory multiple myeloma and a treatment history of at least three prior regimens, including a protease inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. The patients had essentially exhausted all treatment regimens known to provide clinical benefit in the setting.

The trial design comprised dosing cohorts of 0.025 mg to 120 mg. The 60-mg dose was chosen for dose expansion. The primary objectives were safety/tolerability, pharmacokinetics, and determination of recommended phase II dose. Clinical activity as defined by International Myeloma Working group criteria was a secondary objective.

The 124-patient study population included 60 patients treated with 60 mg of ABBV-383. The patients had a median age of 68, including the overall population and the phase II-dosing subgroup. More than 80% of the patients had triple-class refractory disease, and about 40% had disease refractory to five different myeloma therapies. More than 85% of the patients had disease refractory to the most recent therapy.

In the 60-mg cohort, grade ≥3 hematologic adverse events (AEs) consisted of neutropenia (37%), lymphopenia (17%), anemia, and thrombocytopenia (12% each). The most common nonhematologic grade ≥3 AEs were CRS, diarrhea, and hypogammaglobulinemia (2% each). Additionally, 43% of patients had AEs of infection, and three patients had immune effector cell-associated neurotoxicity syndrome. Five (8%) patients in the 60-mg cohort discontinued treatment because of AEs.

Overall, 43 (72%) patients in the 60-mg cohort developed CRS, which was considered serious in 16 (27%) cases. One patient had grade ≥3 CRS. The onset of CRS typically was the day of or day after the first dose, said Voorhees, and the median time to resolution was 1 day. One patient developed CRS after the first cycle of therapy.

The efficacy analysis of the overall patient population showed a complete response rate of 29%, VGPR in 14% of patients, and partial response in 14%. In the 60-mg cohort, the 60% overall response rate (ORR) comprised a complete response rate of 29%, VGPR in 14%, and partial response in 17%.

In the entire study population, the triple-refractory subgroup had a 51% ORR, including VGPR or better in 40%. The 60-mg cohort had an ORR of 54% and VGPR or better in 40%. Time to first response was less than a month, and time to first complete response was about 3 months.

ABBV-383 will join an already-crowded field of bispecific antibodies for myeloma, said invited discussant Thomas Martin, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

"It's best to be first," said Martin. "If you're not first, you need to be convenient and you need to be less toxic."

ABBV-383 appeared to meet at least some of the criteria with activity in heavily pretreated patients, dosing every 3 weeks, and low rates of severe CRS (which resolved quickly) and neurotoxicity.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ѻý in 2007.

Disclosures

The study was supported by TeneoOne and AbbVie.

Voorhees disclosed relationships with TeneoOne, AbbVie, Oncopeptides, Karyopharm Therapeutics, Bristol Myers Squibb, Secura Bio, Pfizer, Sanofi, Janssen, GlaxoSmithKline, and Janssen.

Primary Source

Journal of Clinical Oncology

D'Souza A, et al "A phase I first-in-human study of ABBV-383, a B-cell maturation antigen × CD3 bispecific T-cell redirecting antibody, in patients with relapsed/refractory multiple myeloma" J Clin Oncol 2022; DOI: 10.1200/JCO.22.01504.