Teclistamab Shows Promise for Myeloma in Phase I Trial

Approximately three-quarters of patients with relapsed and/or refractory multiple myeloma (MM) responded to treatment with the bispecific antibody teclistamab, according to results from a phase I trial presented at the 2020 ASH Annual Meeting. Presenter Alfred Garfall, MD, from the Perelman School of Medicine at the University of Pennsylvania, noted that the off-the-shelf therapy was “quite well-tolerated” with no grade ≥3 cytokine release syndrome (CRS) and only mild neurotoxicity.

Teclistamab is a bispecific IgG-4 antibody that redirects CD3+ T cells to B-cell maturation antigen (BCMA)-expressing myeloma cells, Dr. Garfall explained, and preclinical studies have shown that it has potent antimyeloma activity. It can be administered either intravenously or subcutaneously.

In this phase I trial, investigators evaluated the safety and potential efficacy of teclistamab among 149 patients with MM that was either relapsed or intolerant to established therapies. Individuals who had received prior BCMA-targeted therapy were excluded from the trial. Participants were heavily pretreated, Dr. Garfall noted, with a median of six prior lines of therapy (range = 2-14). Eighty-one percent had triple class–refractory disease and 39% had penta-refractory disease.

A total of 84 patients received teclistamab intravenously and 65 received the drug subcutaneously.

In each group, teclistamab was administered in step-up doses for one week prior to the first full dose to reduce the risk of severe CRS, starting with 0.3 to 19.2 µg/kg in the intravenous (IV) cohort and 80 µg/kg in the subcutaneous cohort. The maximum doses were 720 µg/kg for IV dosing and 3,000 µg/kg for subcutaneous dosing.

During study follow-up, there were two dose-limiting toxicities across all doses – one grade 4 delirium and one grade 4 thrombocytopenia – and teclistamab 1,500 µg/kg administered subcutaneously was selected as the recommended phase II dose (RP2D).

Most of the toxicities observed with teclistamab were low-grade hematologic adverse events (AEs), Dr. Garfall reported. Neutropenia was the most common hematologic AE, but was generally transient and responsive to granulocyte colony-stimulating factor. The most common non-hematologic AE was CRS, which occurred in 55% of the entire patient population and 64% of patients who received the RP2D of teclistamab 1,500 µg/kg. However, the investigators added that all CRS events were grade 1 or 2, and no patient discontinued treatment due to CRS.

There were no new safety signals identified in this study. Infections were common (52% of all patients; 27% at RP2D) and were mostly low-grade. Neurotoxicity was rare (5% of all patients; 3% at RP2D). Only one of the patient deaths during follow-up was judged to be related to study treatment (pneumonia).

“In my experience, the most clinically significant toxicities were concentrated in the first couple cycles,” Dr. Garfall said. “[Patients] generally did not report cumulative toxicity and reported excellent quality of life, even after many months of therapy.”

Regarding efficacy, the investigators observed an overall response rate (ORR) of 73% among patients treated with the RP2D. Responses included:

  • 4 stringent complete responses
  • 1 complete response
  • 7 very good partial responses
  • 4 partial responses

Responses remained high among patients with triple class–refractory and penta-refractory disease, they added (70% and 75%, respectively). Responses also occurred rapidly, at a median of one month after treatment. The researchers found a similarly high ORR (69%) when looking at patients treated with the most active IV or subcutaneous doses.

Dr. Garfall also called the durations of response “remarkable” and, in the subcutaneous cohort, responses appeared to deepen over time. Of the 16 responders in the RP2D cohort, 15 (94%) were alive and progression-free after a median follow-up of 3.9 months, he reported.

Although the implications from this early-phase trial are limited by the short follow-up and lack of a control group, Dr. Garfall called these results encouraging.

“We are still learning about how people do over the long-term,” he told ASH Clinical News. “A phase II study of patients with a much larger number of patients who are all treated with the same dose and schedule will ultimately give us a better estimate of how likely patients are to respond.”

Study authors report relationships with Janssen, the manufacturer of teclistamab.

Reference

Garfall A, Usmani SZ, Mateos MV, et al. Updated phase I results of teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma (RRMM). Abstract #180. Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.