Cilta-cel CAR-T provides ‘unprecedented’ benefit for advanced multiple myeloma
Click Here to Manage Email Alerts
Key takeaways:
- Cilta-cel exhibited superior efficacy compared with standard therapy for relapsed and lenalidomide-refractory multiple myeloma.
- Researchers observed consistent clinical benefit with cilta-cel across patient subtypes.
CHICAGO — Ciltacabtagene autoleucel significantly extended PFS compared with standard therapy for adults with relapsed and lenalidomide-refractory multiple myeloma, results from the randomized phase 3 CARTITUDE-4 study showed.
A single dose of the chimeric antigen receptor T-cell therapy reduced the risk for disease progression or death by 74% compared with either of two standard-of-care regimens, according to data presented at ASCO Annual Meeting and published in The New England Journal of Medicine.
“Median overall survival in this patient population is poor, at approximately 9 months,” Binod Dhakal, MD, MS, associate professor of medicine in the division of hematology at Medical College of Wisconsin, told Healio. “Cilta-cel provides benefit lasting almost 3 years, which is unprecedented in this setting.”
Background
Ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech) — often called cilta-cel — is a B-cell maturation antigen-directed CAR T-cell therapy.
The FDA approved the agent last year for treatment of patients with relapsed or refractory multiple myeloma who received four or more previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
Lenalidomide is used extensively as early-line therapy for multiple myeloma in the United States. However, most patients become refractory to treatment.
“This represents a patient population with a clear unmet need commonly seen in clinical practice,” Dhakal said. “The CARTITUDE-1 study [conferred] a median PFS of approximately 3 years in heavily pretreated patients with multiple myeloma, so we aimed to test cilta-cel in earlier lines against effective standard-of-care treatments.”
Methodology
CARTITUDE-4 evaluated the safety and efficacy of cilta-cel vs. one of two standard-of-care regimens — pomalidomide, bortezomib and dexamethasone, or daratumumab (Darzalex, Janssen), pomalidomide and dexamethasone — for 419 adults with relapsed and lenalidomide-refractory multiple myeloma who received one to three previous lines of therapy.
Investigators randomly assigned 208 study participants (median age, 61.5 years; range, 27-78; 55.8% men; 75.5% white) to preconditioning lymphodepletion followed by an infusion of cilta-cel at a target dose of 0.75 × 106 CAR T cells/kg. The other 211 participants (median age, 61 years; range, 35-80; 58.8% men; 74.4% white) received a physician’s choice of standard regimens.
PFS served as the primary endpoint. Secondary endpoints included multiple other efficacy measurements, safety and patient-reported outcomes.
Key findings
Median follow-up was 15.9 months (range, 0.1 to 27.3).
CARTITUDE-4 met its primary endpoint, showing significantly longer PFS in the cilta-cel group (median, not reached vs. 11.8 months; HR = 0.26; 95% CI, 0.18-0.38).
Investigators reported 12-month PFS rates of 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard care group.
Researchers also reported a higher overall response rate (84.6% vs. 67.3%), higher complete response rate (73.1% vs. 21.8%) and longer median duration of response (not reached vs. 16.6 months) in the cilta-cel group.
A higher percentage of patients in the cilta-cel group achieved minimal residual disease-negative status (60.6% vs. 15.6%).
All patients experienced at least one treatment-related adverse event.
Neutropenia was the most common treatment-related toxicity (grade 3/grade 4, 89.9% for cilta-cel vs. 82.2% for standard care).
Three-quarters (76.1%) of patients assigned cilta-cel developed cytokine release syndrome, with 1.1% experiencing grade 3/grade 4 CRS events. Investigators reported no grade 5 CRS events.
Eight study participants (4.5%) experienced grade 1 or grade 2 immune effector cell–associated neurotoxicity syndrome.
‘A new standard’
Cilta-cel provided “uniform benefits” across patient subgroups, Dhakal said.
The CAR-T outperformed standard-care regimens among those with high-risk disease or soft plasma tumors, and regardless of the line of therapy in which it was received, he added.
“We continue to see deep and durable efficacy responses with cilta-cel that have significantly delayed disease progression, and with a manageable safety profile,” Dhakal told Healio. “Cilta-cel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma after first relapse.”
References:
- Dhakal B, et al. Abstract LBA106. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- San-Miguel J, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2303379.
Perspective
Back to Top
Saad Z. Usmani, MD, MBA, FACP
After seeing the remarkable results from the CARTITUDE-1 trial, one of the major remaining questions from a clinical standpoint is whether CAR T-cell therapy can provide acceptable efficacy in earlier lines of therapy, especially in more difficult-to-treat patients.
CARTITUDE-4 focused on adults with lenalidomide-refractory multiple myeloma. In the United States, as well as in many parts of the world, lenalidomide maintenance therapy is used after induction therapy, regardless of whether a patient underwent hematopoietic stem cell transplantation. Lenalidomide maintenance is used until disease relapse or progression or drug intolerance; therefore, many patients become refractory to lenalidomide.
This phase 3 study evaluated cilta-cel against two commonly used regimens among heavily pretreated, evenly matched patient populations.
PFS among adults treated with standard therapies performed as expected. However, a HR of 0.26 and PFS not yet reached is a phenomenal result thus far for cilta-cel.
These are very encouraging results that extend to the different high-risk subgroups evaluated by the study investigators — many of which favored the use of cilta-cel over standard therapy.
As a cell therapist, I am personally excited about these results. The PFS curves are remarkable, and I’m hopeful that we will start seeing a plateau emerge with subsequent follow-up on this trial.
From a safety standpoint, it doesn't look like there were any key concerns. Treatment-related deaths occurred during this trial, but many were due to COVID-19 as this trial enrolled patients during the pandemic.
Based on these results, cilta-cel is likely to move up to an earlier line of therapy option, but we will need to wait for indication changes from the FDA first. If changes are made to the label, I believe they are likely to include adults with lenalidomide-refractory disease who have received one to three prior lines of treatment.
Memorial Sloan Kettering Cancer Center
Perspective
Back to Top
Samer Al Hadidi, MD, MS, FACP
The results of this randomized clinical trial studying earlier use of CAR-T compared with a triple-based regimen in an earlier relapsed setting are extremely important. It is encouraging to see that PFS was superior using CAR-T per the intention-to-treat analysis.
It is critical to point out that early death occurred among patients assigned to cilta-cel, which may reflect lower efficacy for patients with more aggressive disease. The trial did not allow crossover for patients who progressed on the control arm to receive cilta-cel. We also don’t know the subsequent treatments that patients received at the time of disease progression, and we have no data on previous use of autologous stem cell transplantation.
Results from this trial showed that prolonged cytopenia — more than 60 days from the time of infusion — occurs. Long follow-up data will be needed to better understand the timeline of improvement/resolution, as well as long-term outcomes.
Clinicians who are considering using cilta-cel as earlier therapy need to acknowledge the relatively long time needed for manufacturing. The median time from first apheresis to cilta-cel infusion was 79 days (range, 45-246 days). The impact of such a long manufacturing turnaround period must be considered when treatment decisions are made because patients with aggressive relapse may not be able to wait for CAR T cells to be produced.
With excitement building about the potential benefit of earlier use of CAR-T in multiple myeloma — as evidenced by improved responses and PFS in this clinical trial — we need to ensure equitable access to such therapies and improve manufacturing capabilities to better match the expected incremental demand. Efforts need to be focused on providing these therapies for patients in most need. Regardless, I am excited to see these promising randomized clinical trial results of earlier use of CAR-T in multiple myeloma. I am hopeful that longer-term outcomes allow us to better understand if such responses will be reflective of longer survival and/or improved quality of life.
Winthrop P. Rockefeller Cancer Institute
Healio | Cell Therapy Next Peer Perspective Board Member
Collapse
Click Here to Manage Email Alerts