CAR-T will ‘play a very important role’ in multiple myeloma treatment landscape
Click Here to Manage Email Alerts
The FDA approval of the first ever chimeric antigen receptor T-cell therapy for multiple myeloma in 2021 laid the groundwork for others to follow.
Idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) — or ide-cel — a B-cell maturation antigen (BCMA)-directed, genetically modified, autologous CAR T-cell therapy, was approved for patients who previously received at least four lines of therapy, including a proteasome inhibitor immunomodulatory therapy in an anti-CD8 monoclonal antibody.
“CAR T-cell therapy is going to play a very important role in the multiple myeloma therapeutic landscape,” Saad Z. Usmani, MD, MBA, FACP, hematologist-oncologist and chief of myeloma service at Memorial Sloan Kettering Cancer Center, said during an interview with Healio.
“Currently, two CAR T-cell therapy products target the surface marker BCMA — ide-cel and ciltacabtagene autoleucel [Carvykti; Janssen, Legend Biotech], or cilta-cel,” Usmani continued. “We use both products for patients with advanced multiple myeloma. Both target BCMA, but cilta-cel differs slightly in that the CAR T cells grab onto two sections of BCMA rather than one.”
Most patients with previously treated multiple myeloma are considered eligible for CAR T-cell therapy, unless they have prior comorbidities, such as heart disease, lung disease or renal insufficiency, or significant organ compromise.
“At the moment, we only have a small number of slots allotted to us every month at treatment centers by the drug companies because of supply chain logistic issues,” Usmani said. “Depending on where patients are in their disease course, if their disease is progressing rapidly, we know that it can take up to 6 weeks for CAR T cells to be manufactured, so perhaps that patient is not the ideal patient to go on CAR T-cell therapy and we may have to give them something different to control their disease first. We pay attention to whether patients have the approved criteria, whether their disease is being controlled enough that they can wait 5 to 6 weeks for CAR T-cell therapy.”
Benefits
Both ide-cel and cilta-cel have demonstrated significant response rates in clinical trials.
The KarMMa trial included 128 patients (median age, 61 years; 59% men) assigned to ide-cel at one of three dose levels. Patients had received a median six previous therapies, most (84%) were triple refractory to prior treatments and 88% received bridging therapy.
After median follow-up of 13.3 months, results showed ide-cel demonstrated an overall response rate of 73% (95% CI, 65.8-81.1) and a complete response rate of 33% (95% CI, 24.7-40.9). Median time to complete response was 2.8 months and 65% of patients with a stringent complete response remained in remission for at least 1 year.
“For ide-cel, response rates are well above 70% — this was quite unprecedented when this was reported a couple of years back,” Usmani said. “Then we saw that cilta-cel had response rates of 98%, which is even better in that data set compared with ide-cel —median PFS is still not reached with cilta-cel whereas it is just at 1 year for ide-cel.”
The phase 1b/phase 2, single-arm, CARTITUDE-1 trial included 97 patients (median age, 61 years; 59% men; 71% white) with relapsed or refractory multiple myeloma who previously received at least three lines of therapy.
Results showed an overall response rate of 98% (95%, 92.7-99.7) at median follow-up of 18 months and a stringent complete response rate of 78% (95% CI, 68.6-86.1). Moreover, median duration of response was 21.8 months.
“To put this into context, we would normally expect patients who have four or more prior lines of treatment to only have a PFS of about 3 to 4 months, so both products are highly effective,” Usmani said.
Risks
Despite the benefits of CAR T-cell therapy in this patient population, there are also risks associated with the therapy.
“The most common adverse event we see in patients receiving CAR T-cell therapy is low blood count, which does recover and is also a function of chemotherapy as well,” Usmani said. “But because of the low blood count, patients can be at higher risk for infection. Cytokine release syndrome can happen in most patients. Essentially, we are introducing CAR T cells that have been genetically modified and they get activated and a lot of inflammatory cytokines are released during that process that leads to cytokine release syndrome where people can have low blood pressure and fevers that mimic infection.”
However, these adverse events are reversible fairly quickly, he added.
“These adverse events are managed differently; we are very proactive about managing it as soon as it happens,” Usmani said. “We also look out for neurotoxicity in these patients, which can be mild to moderate for the most part in patients with general confusion or coordination issues. However, in severe cases, patients can be unconscious or have seizures. So, we watch out for these things, especially neurotoxicity early on during the first 3 weeks of treatment. We’ve gotten very good at managing and mitigating all these side effects and patients recover well from them.”
Looking ahead
Both CAR T-cell therapies are now being examined in clinical trials in the early relapse setting and also in the newly diagnosed setting.
“This is what I’m most excited about,” Usmani said. “There are two randomized clinical trials in the newly diagnosed setting for patients who are transplant eligible as well as transplant ineligible, where we are going to be administering CAR T-cell therapies. I’m really looking forward to participating in those trials.”
The ultimate hope is to move the field forward by introducing these innovative therapies to our patients with newly diagnosed disease, he continued.
“There are next generation CAR T cells being developed and strategies being developed where we can actually manufacture the product much faster than we have been able to, and all of those innovations will help more therapies move into the front-line setting,” Usmani said.
References:
- Berdeja JG, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00933-8.
- Munshi NC, et al. N Engl J Med. 2021;doi: 10.1056/NEJMoa2024850.
For more information:
Saad Z. Usmani, MD, MBA, FACP, can be reached on Twitter at @szusmani.
Collapse
Click Here to Manage Email Alerts