T-Cell Redirection Therapy Shows Promise As Salvage Therapy in R/R Multiple Myeloma

In a retrospective analysis of 115 patients with relapsed/refractory multiple myeloma who progressed after therapy on a bispecific antibody, researchers found that the myeloma patients can be salvaged with sequential T-cell redirection therapy.

While the depth and duration of response to bispecific antibodies do not predict how patients with multiple myeloma will respond to CAR T-cell therapy as a second-line treatment, the T-cell therapy is effective for this patient population, according to data published in Blood Advances.1

In a retrospective analysis of 115 patients with relapsed/refractory multiple myeloma (RRMM) who progressed after therapy on a bispecific antibody, phase 1 dose escalation or phase 2 clinical trial researchers found that the myeloma patients can be salvaged with sequential T-cell redirection therapy.

This T-cell therapy led to an 84% (95% CI, 60%-97%) overall response rate (ORR), but median overall survival (OS) was not reached at a 30.5-month follow-up. Moreover, the clinical benefit rate favored patients on T-cell therapy at 84% (95% CI, 60%-97%) compared with 54% (95% CI, 37%-70%) in the non-T-cell redirection arm.

Eight patients given T-cell redirection as first salvage therapy (FST) had a complete response (CR), 4 had a stringent CR (sCR), 4 had a partial response, 1 patient had stable disease, and 2 patients had partial disease. In the non-T-cell redirection arm (n = 39), there were no sCRs, 1 CR, 4 very good partial responses, 14 partial responses, 2 had minimal responses (MR), 8 had stable disease, and 10 patients had partial disease.

Of the 115 patients that failed bispecific antibody treatment, 58 patients went on to receive their FST with either T-cell redirection or a non-T- cell redirection therapy, such as chemotherapy. Nineteen patients were given T-cell redirection as their FST with 32% of these patients needing to receive a second salvage therapy (SST) due to a relapse of non-response to therapy. In comparison, 79% of patients given a non-T-cell redirected therapy needed a SST with some of these patients moving on to T-cell redirected therapy for a total of 28 patient that ultimately received T-cell redirected therapy.

“Our data suggests that after treatment with a bispecific antibody, this high-risk patient population can still exhibit favorable outcomes when exposed again to T-cell redirection therapeutics such as other bispecific antibodies and CAR T-cell therapy,” the researchers wrote in their published results. “While conventional salvage therapy had a relatively good ORR of around 50%, it did not lead to durable responses, which translated to significantly lower [progression-free survival (PFS)] and OS.”

While the researchers noted the survival results were not durable, nor significant, they did favor the initial 19 patients given T-cell redirection therapy as FST. The median PFS1 of these patients was 28.9 months (95% CI, 18.7-NE), compared to 2.6 months (95% CI, 1.9-4.1) in the non-redirection arm. Within the 19 patients, those who received a bispecific antibody as FST had a median PFS of 18.7 months (95% CI, 2.3-18.7) vs the 9 patients who got CAR-T cell therapy who did not reach their median PFS1 (95% CI, 28.9-NE), however, this finding was not statistically significant.

PSF2 was also evaluated due to the additional patients that moved to T-cell redirection therapy with the researchers observing a median PFS2 of 30.9 months (95% CI, 21.3%-37.3%) in the 28 patients given T-cell redirection as either FST or SST, compared with 5.7 months (95% CI, 3.7-7.7) for the 30 patients the didn’t receive T-cell redirection therapy as either FST or SST.

OS was not reached among patients with T-cell redirection as FST nor patients on CAR T-cell therapy, but comparisons to patients in the other arm were not statistically significant. Sixty-two percent (95% CI, 44%-88%) of patients given T-cell redirection therapy had an OS at 2 years compared with to 24% (95% CI, 11%-49%) at 2 years for the remaining 30 patients.

“As the clinical use and advancement of T-cell redirection therapies continue to grow, effective strategies are needed to manage outcomes for patients who relapse or are unresponsive to this initial treatment,” said senior author of the study Samir Parekh, MD, director of Translational Research in Myeloma, co-leader of the Cancer Clinical Investigation program at The Tisch Cancer Institute, and a member of the Icahn Genomics Institute at the Icahn School of Medicine at Mount Sinai.2 “This study shows patients relapsing after initial bispecific antibodies therapy can benefit from a second bispecific antibody or CAR T-cell therapy.”

Patients in the analysis were treated on phase 1/2 trials and were a median of 60 years old at diagnosis and 67 years old at the time of their FST. Most patients in the analysis had IgG multiple myeloma with that subtype making up 50% of the T-cell redirection group. Moreover, 78% of patients overall were considered high-risk with 88% being triple-refractory and 84% progressed after being on pomalidomide (Pomalyst). Fifty-nine percent of patients had 1 prior autologous stem cell transplant.

All patients observed in the analysis were on bispecific antibody studies conducted at the Tisch Cancer Center at Mount Sinai hospital.

“Future clinical trials incorporating sequential combinations of T-cell redirection therapy will build upon these findings to further develop treatment guidelines and improve long-term outcomes for multiple myeloma patients,” Parekh said.

References
Mouhieddine T, Oekelen O, Melnekoff D, et al. Sequencing T-cell redirection therapies leads to deep and durable responses in relapsed/refractory myeloma patients. Blood Adv. 2022 Aug 26:bloodadvances.2022007923. doi:10.1182/bloodadvances.2022007923
Mount sinai researchers report encouraging immunotherapy option for relapsed myeloma patients. News release. Mount Sinai. Published September 1, 2022. Accessed September 14, 2022. https://bit.ly/3U4NnUJ