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CAR T Bridging for MM: Module

CME

The Role of Bridging Therapeutic Strategies for Patients With Multiple Myeloma Receiving CAR T-Cell Therapy

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: July 17, 2023

Expiration: July 16, 2024

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Potential for Earlier CAR T-Cell Therapy

There are a number of strategies that in the future that may help limit some of the toxicity from bridging chemotherapy and even potentially mitigate the need for bridging therapy.

First and foremost is the potential use of CAR T‑cell therapy in earlier lines of treatment. There have been a number of publications and presentations, including from the phase II KarMMa‑2 study21,22 and the phase II CARTITUDE‑2 study,23 in which patients who had early relapse after initial therapy and received CAR T‑cell therapy as part of second-line after receiving a salvage‑based therapy. This may be a good strategy for entering into CAR T‑cell therapy during remission instead of explosive relapse.

Both the phase III KarMMa‑324 and CARTITUDE‑425 studies potentially could lead to the use of CAR T‑cell therapies in earlier lines of therapy. Patients in this setting are more sensitive to salvage‑based therapies, giving them a much better chance of going into CAR T‑cell therapy in a good response with low disease burden, potentially improving their outcomes. 

There are several ongoing studies that intend to treat patients using CAR T‑cell therapy as part of frontline therapy. The phase I KarMMa-4 trial (NCT04196491; not recruiting) will treat patients with newly diagnosed, high‑risk MM after induction therapy with consolidation therapy of ide-cel. The randomized phase III CARTITUDE‑5 trial (NCT04923893; recruiting) is comparing cilta-cel vs bortezomib/lenalidomide/dexamethasone (with lenalidomide/dexamethasone maintenance) in patients who are ineligible for transplant. All patients will receive 6 cycles of induction with bortezomib/lenalidomide/dexamethasone before randomization, and patients in the CAR T-cell therapy cohort will receive 2 cycles of bridging therapy.

Finally, the phase III CARTITUDE‑6 study (NCT05257083; not yet recruiting) will compare cilta-cel vs daratumumab/bortezomib/lenalidomide/dexamethasone followed by autologous stem cell transplant in patients with newly diagnosed MM. The CAR T-cell therapy cohort will receive 6 cycles of induction with daratumumab/bortezomib/lenalidomide/dexamethasone.

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KarMMa-3: Phase III Trial of Ide-cel vs SoC in R/R MM

In the phase III KarMMa-3 trial, patients with R/R MM (N = 386) were randomized 2:1 to receive ide-cel or SoC therapy.24 Patients were stratified based on age, number of lines of therapy, and presence of high risk genetics. All patients had received 2-4 prior lines of therapy (median: 3), and they had to be refractory to their previous line of therapy. 

Patients who were assigned to a SoC therapy received one of 5 regimens: daratumumab/bortezomib/dexamethasone; daratumumab/pomalidomide/dexamethasone; elotuzumab/pomalidomide/dexamethasone; carfilzomib plus dexamethasone; or ixazomib/lenalidomide/dexamethasone. Per protocol, patients randomized to CAR T-cell therapy could receive 1 cycle of these SoC treatments as bridging therapy if necessary, but no information is available on actual bridging therapy received.

In all patients, high risk cytogenetics was seen in 43.5% and extramedullary disease in 24.0%, 65.5% were triple class refractory, and 85% of patients had previous transplant. 

The primary endpoint was PFS, with key secondary endpoints including ORR and OS.

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KarMMa-3: Treatment Response and PFS

Patients who received ide-cel had a significantly longer PFS (13.3 vs 4.4 months; HR: 0.49; 95% CI: 0.38-0.65; P <.001) compared with those who received SoC therapy.24 CAR T-cell therapy led to increased ORR (71% vs 42%; P <.001) and CR (39% vs 5%) and better DoR (14.8 vs 9.7 months) compared with SoC therapy. 

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KarMMa-3: Safety

In terms of safety, toxicity was what we would expect after CAR T-cell therapy compared with those who received SoC therapy.24 Hematologic toxicity was seen in 90% of patients (87% grade 3/4), CRS in 88% (4% grade 3/4, 1% grade 5), and neurologic toxicity in approximately 15% of patients (3% grade 3/4) after ide-cel treatment. There was a higher level of hematologic toxicity with CAR T-cell therapy compared with SoC. 

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CARTITUDE-4: Phase III Trial of Cilta-cel vs SoC

In the phase III CARTITUDE-4 trial, patients with R/R MM (N = 419) were randomized 1:1 to receive cilta-cel or SoC (pomalidomide/bortezomib/dexamethasone or daratumumab/pomalidomide/dexamethasone).25 Eligible patients had received 1-3 prior lines of therapy including a proteasome inhibitor and an IMiD, and they had to be refractory to lenalidomide. Participants could not have had any previous BCMA-targeted therapy or CAR T-cell therapy. 

This current analysis was conducted after a median of 15.9 months of follow-up.

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CARTITUDE-4: Efficacy With Cilta-cel

This trial met its primary endpoint of PFS, with median not reached for cilta-cel vs 11.8 months for SoC (HR: 0.26; 95% CI: 0.18-0.38; P <.0001).25 The response rate for the cilta-cel arm was 84.6%, including 73.1% CR or better and 60.6% with MRD negativity. The intention-to-treat population includes patients who did not receive cilta-cel infusion, mostly because of disease progression during the bridging and LD phases. Among 176 patients who received cilta-cel, 175 had a response (ORR: 99.4%), 152 had CR or better (86.3%), and 126 were MRD negative (71.6%). Median DoR has not been reached for the intention-to-treat or as-treated populations. These outcomes are similar or even slightly better than those seen with cilta-cel in CARTITUDE-1.

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CARTITUDE-4: Safety With Cilta-cel

The safety profile was similar to that seen with cilta-cel in CARTITUDE-1.25 Cytopenias, CRS, and neurotoxicity occurred at lower rates than in CARTITUDE-1, suggesting a better safety profile for cilta-cel when used as an earlier line of treatment. All cases of CRS and ICANS resolved with treatment. Of note, there were several deaths related to COVID-19; the investigators noted the emergence of COVID-19 variants and changing of mandated restrictions in different locations during the time period of the trial.

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