Novel CAR-T effective for most patients with advanced multiple myeloma
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A chimeric antigen receptor T-cell therapy produced a response rate of 71% among patients with relapsed or refractory multiple myeloma, according to phase 1 study results published in The New England Journal of Medicine.
Most patients responded to a single dose of the therapy despite experiencing disease progression after prior B-cell maturation antigen (BCMA)-directed CAR-T, investigators noted.
Background
MCARH109 (Juno Therapeutics/Bristol Myers Squibb) is an investigational CAR T-cell therapy that targets G protein–coupled receptor, class C, group 5, member D (GPRC5D), a protein receptor known to be expressed by myeloma cells.
Lessons learned with CD19-directed CAR-T in other blood cancers suggested that — despite BCMA being an attractive target for treatment of multiple myeloma — the potential for loss of surface target antigen meant that researchers should be prepared to pursue other targets for those who have less durable responses to BCMA-directed therapy, according to Renier J. Brentjens, MD, PhD, deputy director and chair of medicine at Roswell Park Comprehensive Cancer Center.
“We have found that for BCMA, even though the treatment initially works, the tumor is still smart enough to stop expressing the target and escape the CAR T cells,” Brentjens told Healio.
Following BCMA, GPRC5D is the second of three targets Brentjens’ group plans to evaluate for cellular therapy-based treatment of multiple myeloma.
“The intent of this trial was to show that GPRC5D could be targeted safely and effectively for patients with multiple myeloma,” he said. “If this is possible, then it opens possibilities — including dual targeting — that can produce more durable responses.”
Methodology
Brentjens — along with co-investigators Sham Mailankody, MBBS, medical oncologist at Memorial Sloan Kettering Cancer Center and Eric L. Smith, MD, PhD, director of translational research for immune effector cell therapies at Dana-Farber Cancer Institute — conducted a dose-escalation study to determine the safety and preliminary efficacy of MCARH109 for 17 patients (median age, 60 years; range, 38-76; 76% male) with relapsed or refractory multiple myeloma treated at Memorial Sloan Kettering.
The study included heavily pretreated patients who received a median six (range, four to 14) prior therapies. Nearly half (47%) of study participants previously received a BCMA-targeted CAR T-cell therapy.
Patients underwent lymphodepleting chemotherapy followed by a single IV infusion of MCARH109 at one of four dose levels: 25 × 106, 50 × 106, 150 × 106 or 450 × 106 CAR T cells.
Safety served as the study’s primary endpoint. A secondary endpoint comprised clinical response according to International Myeloma Working Group assessment criteria and minimal residual disease in bone marrow.
Median follow-up was 10.1 months (95% CI, 8.5 to not reached).
Key findings
Investigators identified 150 × 106 CAR T cells as the maximum tolerated dose for MCARH109.
One patient who received a dose of 450 × 106 CAR T cells developed grade 4 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS). An additional two patients experienced grade 3 cerebellar dysfunction without an attributable cause.
No cases of cerebellar dysfunction or high-grade ICANS or CRS occurred among 12 patients who received doses between 25 × 106 to 150 × 106 CAR T cells.
Investigators reported an overall response rate of 71% (95% CI, 44-90) across all dose levels. Twelve patients (71%) achieved a partial response or better, and 10 (59%) achieved a very good partial response or better.
Six patients (35%) achieved a complete response or stringent complete response.
Researchers reported a 58% (95% CI, 28-85) ORR among patients who received doses of 25 × 106 to 150 × 106 cells.
Six (50%) of 12 patients who achieved a partial response or better remained progression free as of the study cutoff date, including two patients who had no disease progression more than a year after treatment.
Clinical implications
The study showed GPRC is a “suitable target” for CAR T-cell therapy as treatment for multiple myeloma, Brentjens said.
"The most significant result is that we can treat patients who failed previous BCMA-targeted CAR-T and get them back into remission with GPRC5D-directed cells,” he told Healio. “It is a proof of principle that there are multiple targets to pursue for this disease.”
There are numerous options moving forward with two validated targets for multiple myeloma, Brentjens added.
“The next step is to see if we can combine the two targets into a single therapy," he said. “Our results show there is still hope for a clinically beneficial CAR T-cell product for patients with multiple myeloma who have relapsed or did not respond after receiving BCMA-targeted CAR T cells.”
For more information :
Renier Brentjens, MD, PhD, can be reached at Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton streets, Buffalo, NY 14263; email: renier.brentjens@roswellpark.org.
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Mailankody S, et al. N Engl J Med 2022;doi:10.1056/NEJMoa2209900.
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