Cellular therapy is quickly becoming an attractive option for heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). According to data presented at the ASCO20 Virtual Scientific Program, a pair of chimeric antigen receptor (CAR) T-cell products have generated impressive rates of response that appear to be sustainable as well.
In the pivotal KarMMa study, idecabtagene vicleucel (ide-cel) demonstrated frequent, deep, and durable responses in a population of patients with heavily pretreated RRMM, with an overall response and complete response rate of 73% and 33%, respectively.
In a phase 1/2 trial, orvacabtagene autoleucel (orva- cel) also proved to be highly active in a similarly highly refractory population of MM, with an overall response rate of 92%, including 68% of patients with very good partial response or better.
Authors of the studies called the results “highly encouraging” and said that both approaches represent potential new treatment options for patients with RRMM, for which there is no clear standard of care.
Ide-Cel
As reported by Nikhil C. Munshi, MD, medical oncologist at Dana-Farber Cancer Institute, outcomes of triple- class exposed RRMM patients are especially poor, with a median progression-free survival of only 3 to 4 months.
Ide-cel is a B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy that has shown promising tolerability and efficacy in RRMM patients. An early phase 1 study demonstrated an overall response rate of 85%, with a 10.9-month duration of response and a tolerable toxicity profile, said Dr Munshi.
For this pivotal phase 2 study, patients with RRMM who had received 3 or more lines of therapy, including immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, were eligible for enrollment. Patients also had to be refractory to the last line of therapy. Of 140 patients enrolled, 128 received ide-cel.
“Both primary and secondary end points were met, with an overall response of 73% and complete response of 33%,” said Dr Munshi. “At the target dose of 450 million cells, overall response was 82%, and 39% of patients had a complete response.”
Median time to first response was 1 month, and median time to complete response was 2.8 months. Median follow-up was 13.3 months across all dose levels.
Responses were deep too, said Dr Munshi, who noted that 26% of patients tested negative for minimal residual disease (MRD), and at the target dose, nearly half of patients were MRD negative.
“Clinical meaningful efficacy was observed across various subgroups,” said Dr Munshi. “Responses occurred irrespective of age, high-risk cytogenetics, tumor burden, BCMA expression, and extramedullary disease.”
At the target dose level, median duration of response was 11.3 months, and among patients achieving a complete response, duration of response improved to 19 months.
Similarly, median progression-free survival increased with depth of response, from 12 months in the overall patient population to 20 months in patients achieving complete response.
Finally, safety data showed manageable toxicities. At the target dose level, 96% of patients experienced cytokine release syndrome (CRS). However, most of these events were grade 1/2, and less than 6% of patients had grade 3 or higher CRS at the target dose levels, said Dr Munshi, who noted that neurotoxicity was also of lower grade and limited extent.
Other significant adverse events involved cytopenia, with 91% and 63% of patients experiencing neutropenia and thrombocytopenia, respectively. Infections were also observed in 69% of patients and were not dose related. Importantly, said Dr Munshi, there were 5 deaths overall within 8 weeks of ide-cel infusion. Two patients died following myeloma progression and 3 died of adverse events.
“Overall, ide-cel provides an attractive and excellent option for treatment of triple-class exposed multiple myeloma,” Dr Munshi concluded.
Orva-Cel
Sham Mailankody, MBBS, medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, reported data from a phase 1/2 trial of orva-cel, a BCMA-directed CAR T-cell therapy for patients with heavily pretreated RRMM.
“Orva-cel was highly active, with an overall response rate of 92% and a very good partial response or better in 68% of patients across the 3 highest dose levels tested,” said Dr Mailankody.
Robust expansion of CAR T-cells was observed at the 3 highest dose levels, and 84% of the responding evaluable patients were also MRD negative. Responses were observed even in patients with the highest baseline levels of soluble BCMA, Dr Mailankody reported.
Finally, the safety profile of orva-cel was encouraging at all dose levels, said Dr Mailankody, with low incidence of grade 3 or higher CRS and neurologic events.
The study is continuing to enroll patients with RRMM at the recommended phase 2 dose (600 × 106 CAR T-cells) and includes a separate cohort for patients who have progressed after prior BCMA-directed therapies.