Will Carvykti(Ciltacabtagene Autoleucel) become one of the new standards of care for lenalidomide-refractory multiple myeloma

Will Carvykti(Ciltacabtagene Autoleucel) become one of the new standards of care for lenalidomide-refractory multiple myeloma

Introduction to carvykti

Carvykti (Ciltacabtagene Autoleucel, cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) immunotherapy targeting the B-cell maturation antigen (BCMA). According to the phase III CARTITUDE-4 trial, a single infusion of Carvykti significantly prolonged progression-free survival (PFS) compared to standard treatment in patients with lenalidomide-refractory multiple myeloma (MM).

At the European Hematology Association (EHA) 2023 Annual Meeting, Dr. Einsele from the University of Würzburg, Germany, stated, “The trial met its primary endpoint, with Carvykti significantly improving PFS in lenalidomide-refractory MM patients after 1-3 prior lines of therapy, demonstrating a favorable benefit-risk profile across patient subgroups.”

Compared to the control group receiving standard treatment, the Carvykti group had a higher 12-month PFS rate (76% vs. 49%), with a median PFS of 11.8 months in the control group and not reached (NR) in the Carvykti group (HR=0.26; P<0.0001). [EHA 2023, abstract S100]

Subgroup analyses consistently supported the superiority of Carvykti over standard treatment across all key subgroups, with HRs ranging from 0.15 to 0.40.

The overall response rate (ORR) was also higher in the Carvykti group compared to the control group (85% vs. 67%; OR=3.0; P<0.0001), driven primarily by a higher complete response (CR) rate (73% vs. 22%; OR=10.3; P<0.0001). The Carvykti group had a longer median duration of response (DoR, NR vs. 16.6 months) and a higher 12-month DoR rate (85% vs. 63%) compared to the control group.

Carvykti treatment also significantly improved the rates of minimal residual disease (MRD) negativity (at a threshold of 10-5) in the intention-to-treat population (61% vs. 16%; OR=8.7; P<0.0001) and the MRD-evaluable population (88% vs. 33%).

While not yet mature, the overall survival (OS) data trended in favor of Carvykti over standard treatment (HR=0.78; P=0.26), with 39 deaths in the Carvykti group and 47 deaths in the control group. In the Carvykti group (n=176), the 12-month PFS rate was 90%, the ORR was 99% (86% ≥CR), and the MRD negativity rate (at a threshold of 10-5) was 72%.

Safety of Carvykti

The most common treatment-emergent adverse events (TEAEs) were hematological, with up to 90% of patients in the Carvykti group experiencing severe neutropenia. Compared to the standard treatment group, the Carvykti group had higher rates of grade 3/4 anemia (36% vs. 14%), thrombocytopenia (41% vs. 19%), and lymphopenia (21% vs. 12%), but most severe cytopenias resolved to grade ≤2 by day 30.

Dr. Einsele stated, “With appropriate supportive care, the adverse events associated with CAR-T therapy are manageable.”

Ten patients in the Carvykti group died due to TEAEs, seven of whom died from COVID-19, compared to five deaths in the control group, with only one COVID-19-related death. Dr. Einsele emphasized the importance of strict COVID-19 prevention and active treatment for patients receiving CAR-T therapy.

In the Carvykti group, 76% of patients experienced cytokine release syndrome (CRS), and 20% experienced CAR-T cell-related neurotoxicity, ranging from mild to severe but non-fatal cases. Eight patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS), while 30 patients experienced non-ICANS neurotoxicity, such as cranial neuropathies, peripheral neuropathies, and motor and neurocognitive TEAEs (MNTs).

Notably, the incidence and severity of CRS, ICANS, MNTs, and certain cytopenias in this study were lower compared to the CARTITUDE-1 phase Ib/II trial, which enrolled heavily pretreated MM patients who had received ≥3 prior lines of therapy. Dr. Einsele commented, “This highlights the improved tolerability of Carvykti when used earlier in the treatment course.”

Lenalidomide-refractory MM patients: An unmet medical need

The researchers compared Carvykti to effective standard treatments used in the frontline setting, as Dr. Einsele explained, “because less heavily pretreated patients have better T-cell function/CAR-T cell activity.”

A total of 419 patients (median age 61 years, 57% male) were randomized 1:1 to receive Carvykti or standard treatment. Patients in the Carvykti arm received ≥1 cycle of bridging therapy with PVd (Pomalidomide, Bortezomib, Dexamethasone) or DPd (Daratumumab, Pomalidomide, Dexamethasone) before receiving Carvykti infusion 5-7 days after lymphodepletion.

Dr. Einsele pointed out, “The CARTITUDE-4 population represents a common, unmet medical need in clinical practice. The 74% reduction in progression/death, along with high CR and MRD negativity rates, highlight Carvykti’s potential to become the standard of care for lenalidomide-refractory MM patients at first relapse.”

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