First FDA-approved CAR T-cell therapy for multiple myeloma hailed as ‘game changer’
Although it took a bit longer than expected, the first FDA approval of a chimeric antigen receptor T-cell therapy for advanced multiple myeloma will have a major impact on clinical practice, according to experts.
“In the big picture, I think that this technology is a game changer,” Brian G.M. Durie, MD, chairman of the board of the International Myeloma Foundation, scientific director of the International Myeloma Working Group and specialist in multiple myeloma at Cedars-Sinai Medical Center, told Healio. “For the first time, we are seeing a powerful immune technology dramatically impact myeloma, even in [patients with] relapsed or refractory disease. This could lead at some point to a cure or give us clues to lead us in that direction.”
After an initial delay and review of an amended biologics license application, the FDA granted accelerated approval last month to idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) — a B-cell maturation antigen (BCMA)-directed, genetically modified, autologous CAR T-cell therapy — for treatment of adults with relapsed or refractory multiple myeloma.
The indication for the therapy, also known as ide-cel, applies to patients who received at least four previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody.
The agent is the first CAR T-cell therapy to receive FDA approval for treatment of multiple myeloma. It also is the first time the FDA has approved a CAR T-cell therapy that targets BCMA; all previously approved CAR T cells have targeted CD19, a protein commonly found on the surface of B-cell malignancies.
Efficacy and safety data
The FDA based its approval of ide-cel on data from the pivotal phase 2 KarMMa trial, which included 128 patients (median age, 61 years; range, 33-78) with relapsed or refractory multiple myeloma who received ide-cel at one of three dose levels: 150 × 106 CAR T cells, 300 × 106 CAR T cells or 450 × 106 CAR T cells.
Results, published earlier this year in The New England Journal of Medicine, showed 73% (95% CI, 66-81) of patients responded to treatment, with 33% (95% CI, 19-38) achieving a complete or stringent complete response. Twenty-six percent of patients achieved minimal residual disease-negative status, including 79% of those with a complete response or better.
Median PFS was 8.8 months (95% CI, 5.6-11.6) and median OS was 19.4 months (95% CI, 18.2 to not estimable), with a 12-month OS rate of 78%.
The significance of ide-cel’s approval cannot be overstated, according to Nikhil C. Munshi, MD, director of basic and correlative science within Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School.
“It’s very important because of the incredible effectiveness of this treatment, even in this late disease stage,” Munshi, one of the primary investigators for the KarMMa trial, told Healio. “Its ability to provide total responses and ones that are sustained is so incredible, and none of the current treatments in the field are able to achieve this level of activity.”
Durie agreed and said the response rates seen with ide-cel exceed those of other recently approved treatments for patients with relapsed or refractory multiple myeloma.
“These agents have a response rate in the 20% to 30% range and received FDA approval,” he said. “[For ide-cel], we have a response rate greater than 70% in this setting, so this is clearly a superior option compared with what we have experienced with more traditional therapy options.”
Most patients who received ide-cel tolerated the treatment well, according to Munshi, who pointed to the low frequency of serious (grade 3 or greater) treatment-related adverse events in the KarMMA study. Treatment-related toxicities associated with ide-cel are “quite manageable,” he said.
Safety results of the KarMMa trial showed 84% of patients treated with ide-cel experienced some form of cytokine release syndrome (CRS), with 5% having grade 3 or greater CRS. One patient in the study died of complications related to CRS.
Neurotoxicity was reported among 18% of patients who received ide-cel, with 3% experiencing grade 3 neurotoxicity-related adverse events.
Five patients in the trial (4%) experienced hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), a potential adverse effect of CAR T-cell therapy related to excessive immune activation.
The safety results showed BCMA-directed CAR T-cell therapy may have less high-grade toxicity than currently approved CD19-directed therapies, according to Lee Greenberger, PhD, chief scientific officer of The Leukemia & Lymphoma Society. This opens the door to further study for potential outpatient administration of ide-cel, which could benefit patients and the health care system.
“Once a patient has to be hospitalized, it usually means there will be higher management costs associated with the disease,” he said. “If they don’t have to be hospitalized, or hospitalized for an extended period, then it reduces the cost.”
CAR T-cell therapies associated with a low incidence of CRS or neurotoxicity could be candidates for outpatient administration, Greenberger said.
“Nevertheless, if they’re treated as outpatients and wind up going home, then they have to be very carefully observed and be near a facility to treat them should they develop symptoms that could lead to serious safety issues,” he added.
Greenberger said the approval of ide-cel will have “a major impact, as most of the CAR T-cell therapies have.”
He believes ide-cel will be integrated with other therapies for myeloma with the goal of providing long-term disease control and, ultimately, long-term survival.
With an OS rate of more than 19 months, ide-cel — in combination with additional therapy — can benefit patients even if they experienced disease relapse after BCMA-targeted CAR T-cell therapies, Greenberger said.
Such potential has generated excitement among clinicians and patients alike, Durie said.
“I think that there is huge interest in the patient community,” Durie said. “Patients want access to this therapy.”
Durie said he anticipates cell therapies like ide-cel will move into earlier lines of treatment for certain patients. He highlighted the ongoing KarMMa-4 study of patients with newly diagnosed, high-risk multiple myeloma as an example.
“I do believe that more extended remissions will occur if ide-cel is given earlier in the disease course, possibly long-term remissions,” Durie said. “We have a hard time defining when someone is cured, but much longer remissions could occur with earlier treatment.”
With more BCMA-directed CAR T-cell therapies in development, the approval of ide-cel marks the beginning of a period in which clinicians can offer patients a therapy with superior disease control that reduces secondary symptoms of myeloma, including bone and renal impairment, Greenberger said.
“If we can treat these patients earlier with these therapies, then we are going to see better outcomes,” he told Healio. “It’s a very optimistic time for patients with multiple myeloma.”
Ide-cel’s approval was “a first step in the right direction” and will hopefully be only one of many for patients with multiple myeloma, Munshi said.
“I am extremely excited that this option will be available,” Munshi said, adding that despite a growing number of agents being approved to treat multiple myeloma, therapies for patients with advanced disease remain limited in number and durability.
“This provides physicians with a choice after second and third relapse that is effective and that lasts long enough to be meaningful,” he said. “This therapy provides great hope for these patients.”
For more information:
Brian G.M. Durie, MD, can be reached at firstname.lastname@example.org.
Lee Greenberger, PhD, can be reached at email@example.com.
Nikhil C. Munshi, MD, can be reached at firstname.lastname@example.org.