NEW YORK – Heavily pretreated, refractory multiple myeloma patients have a new treatment option following the US Food and Drug Administration's approval last week of Bristol Myers Squibb and Bluebird Bio's idecabtagene vicleucel (Abecma), the first CAR T-cell therapy approved in this setting.
To be eligible for idecabtagene vicleucl, or ide-cel, relapsed or refractory multiple myeloma patients must have undergone four previous lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Ide-cel involves harvesting a patient's immune cells, engineering them in BMS's manufacturing facility so they target the B-cell maturation antigen (BCMA) protein found on the surface of multiple myeloma cells, then infusing them back into the patient after a lymphodepleting chemotherapy regimen.
The FDA has approved several autologous CAR T-cell therapies for hematologic malignancies. Ide-cel is BMS's second CAR T-cell therapy approval this year; the company received FDA approval for lisocabtagene maraleucel (Breyanzi) for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma in February. Still, ide-cel's approval is notable in that it is for multiple myeloma, a new disease indication for CAR T-cell therapy, and targets a new cell-surface protein, BCMA, whereas other approved CAR T-cell therapies target CD19.
Ide-cel has been under development for years, and made headlines last spring when the FDA declined to accept BMS and Bluebird's application for the therapy on the grounds that the application lacked key details. Now, based on data from the pivotal Phase II KarMMa trial, the agency has determined that the drug's risk/benefit profile in refractory multiple myeloma patients is sufficient for market approval.
Kristen Hege, BMS's senior VP of early clinical development in hematology oncology and cell therapy, has been leading the ide-cel program from inception and said the approval provides a much-needed option in this heavily treated population. "My colleagues are telling me just how many patients they have who have just been waiting for Abecma to be approved because they've run out of options," said Hege, who treats patients at the University of California San Francisco part-time.
Among other FDA-approved options for patients in this setting is the BCMA-targeted antibody-drug conjugate belantamab mafodotin-blmf (GlaxoSmithKline's Blenrep). Belantamab received accelerated approval as a fifth-line multiple myeloma treatment last summer based on a 31 percent overall response rate. While Hege was hesitant to offer direct comparisons between ide-cel and other BCMA-targeted treatments, she highlighted that the clinical response rate seen with ide-cel was "exceedingly uncommon" in late-line myeloma patients and that the minimal residual disease responses were "pretty much unprecedented" in this setting.
Questions of Duration
While ide-cel may be the first CAR T-cell therapy to market for multiple myeloma, it may not end up being the best, according to experts closely watching the space. Many in the field are waiting to see the regulatory fate of Janssen and Legend Biotech's BCMA-targeted CAR T-cell therapy ciltacabtagene autoleucel, or cilta-cel, which is also under development for relapsed or refractory multiple myeloma. Toward the end of 2020, Janssen had initiated a rolling submission for cilta-cel with the FDA.
While BMS touted the strength of the data underlying ide-cel's approval, other experts in the field may be more reserved in their evaluation of the evidence. In the pivotal Phase II KarMMa trial, among 100 relapsed or refractory multiple myeloma patients, 72 percent experienced either partial or complete responses, and 28 percent experienced complete responses. The median duration of response was 11 months among all responding patients and 19 months among those with a complete response.
The minimal residual disease data that Hege emphasized included a 21 percent minimal residual disease negativity rate among the 100 patients treated and 75 percent among the patients with a complete response. Cytokine release syndrome and neurotoxicity were common adverse events, but the more severe versions of these toxicities — defined as grade 3 or higher — occurred in just nine and four percent respectively of 127 patients in the trial's safety cohort.
Although overall response rate was the trial's primary endpoint that facilitated FDA approval, the progression-free survival and overall survival data from the KarMMa trial were published in February in the New England Journal of Medicine. Among 128 patients treated with ide-cel, the median progression-free survival was 8.8 months, and while the overall survival data were not mature, the estimate was a median of 19.4 months.
Relative to other FDA-approved autologous CAR T-cell therapies, an 8.8-month median progression-free survival is not all that long, acknowledged Lee Greenberger, CSO of the Leukemia and Lymphoma Society. Greenberger recognized this difference with several caveats, including that the ide-cel approval was "obviously good news" for refractory multiple myeloma patients and that these types of comparisons are imperfect, given differences in indications and targets.
With those caveats in mind, "what we see [with ide-cel] does not match the previous approved CAR T-cell products," Greenberger acknowledged. "Progression-free survival with ide-cel is relatively short," he said, whereas a signature of previously approved CAR T-cell products is that "they can give long-term survival to a large number of patients."
In other words, the durability of responses that has become somewhat of a hallmark of CAR T-cell therapies — and is used to justify use of the word "cure" in those who see an enduring benefit — may not be a characteristic of ide-cel. Hege acknowledged that ide-cel has not yet demonstrated a long-lasting progression-free survival benefit, at least not to the same extent as some of the CD19-directed CAR T-cell therapies for lymphoma approved in recent years. That said, she suggested this may have more to do with the disease than the therapy and indeed may change with longer follow-up.
"Multiple myeloma historically has been less curable [than DLBCL]," she said, adding, "It is premature to conclude that Abecma is not a curative therapy. … We need longer follow-up to know what is the ultimate durability of response in these patients, who achieve an initial stringent complete response, which of course is the first step for durable long-term benefit." As of now, Hege noted that of the 28 percent of patients with initial stringent complete responses, nearly two-thirds have remained in remission a year after treatment.
In parallel with continuing long-term follow-up to quantify the durability of response with ide-cel, Hege said that researchers are interrogating data from patients who did and did not experience disease relapse to get at the mechanisms of resistance to the treatment.
On the other hand, to Greenberger, there may be treatment-related reasons for why ide-cel's progression-free survival does not measure up to previous CAR T-cell therapies. "It could be the target, it could be the affinity of the antibodies, or it could be the duration of the cells," he reasoned.
In recent months, several case studies have described patients with BCMA antigen loss following ide-cel and tried to home in on why this occurs. But Hege and Greenberger both said that antigen loss has been shown to be rare among ide-cel-treated patients. According to Hege, only about 4 percent of patients have had documented antigen loss. Relapses are more likely to have to do with the functional persistence of the CAR T cells, she said.
If the primary reason for the progression-free survival curve drop-off is the persistence of the cells, Greenberger said it might be possible to overcome this resistance mechanism with retreatment, at least in some patients. "It turns out that the duration of the cells are lost over time," he suggested. "And therefore, if the cells are being exhausted or extinguished over time, you may lose the ability to control the disease."
If this is indeed the reason why responses fall off after 8.8 months or so, Greenberger believes this may be overcome by retreating patients with additional courses of ide-cel. In the trial, 28 patients whose cancers progressed after initial treatment were retreated with ide-cel at a higher dose and six responded. "This tells us that putting in more cells might have some benefit," he said.
Hege wasn't as quick to cite retreatment as a potential way to overcome resistance to ide-cel. After all, the FDA approval is for a one-time treatment, and BMS and Bluebird are marketing the treatment as such. Indeed, the one-time nature of the treatment is the aspect that the companies are highlighting as a major advancement in multiple myeloma.
"It's a real paradigm shift in how myeloma is treated, because it's a single, one-time infusion without continuous dose therapies that require (patients) come back to the clinic repeatedly," she said. "It allows patients to go back to being people leading normal lives and not patients who are coming to the clinic every week or every month for ongoing therapy."
In Hege's view, patients in earlier treatment settings may have more enduring responses to ide-cel, because patients who are refractory to fewer lines of therapy tend to do better with therapies generally. BMS and Bluebird are currently conducting additional trials, including the randomized Phase III KarMMa-3 trial, to assess ide-cel in earlier indications.
Competition, cost and access
With the FDA decision for Janssen and Legend's cilta-cel on the horizon, the question as to what advantage, if any, ide-cel might offer to patients over a similar treatment is top-of-mind for many in the field.
LLS's Greenberger said it is difficult to say much about how the two BCMA-directed CAR T-cell therapies would measure up to each other in the absence of more mature data from Janssen's CARTITUDE-1 clinical trial. The most recent cilta-cel data from a study presented at the American Society of Hematology 2020 Annual Meeting showed an overall response rate of 97 percent and a stringent complete response rate of 67 percent. The median duration of response and progression-free survival had not yet been reached at 12.4 months.
"It's still too early to say," Greenberger said. "But the cilta-cel data looks like it might be superior [in terms of progression-free survival] than ide-cel, although there are a whole bunch of caveats around that."
Hege was unwilling to comment on the competitive landscape in light of Janssen's cilta-cel data but said, "BCMA is a great target in multiple myeloma" that could expand options for patients. "[But] what we are is first," she added. "We have the opportunity to be first to the commercial marketplace where we can provide this therapy to as many patients who need it as possible."
As with other FDA-approved CAR T-cell therapies, ide-cel carries an extremely high price tag. According to BMS and Bluebird, the list price for ide-cel is $419,500. Patients and payors see a different price after discounts and other considerations, but the cost is high enough to raise questions about patient access.
"We are committed to ensuring access to patients and will work on that on many fronts," Hege said of BMS's patient-access programs. She did not provide additional detail on these programs but added that the cost is justified by the "value Abecma provides patients in this late-line setting with very few treatment options."
Given the logistical challenges associated with manufacturing and delivering CAR T-cell therapies, such as long turnaround times, Hege also underscored BMS's commitment to transparency with patients about the whole process. This, she said, will be done through a "sophisticated digital interface" that will allow patients and their prescribing physicians to schedule slots for infusions and monitor the progress of manufacturing the patient-specific products.
BMS has committed to a 28-day turnaround time for manufacturing the autologous cell therapies, which the company will do at a Summit, New Jersey-based facility before shipping the BCMA-targeted cells back to patients for infusion.