Johnson & Johnson's CARVYKTI Emerges as a Potential SOC for Lenalidomide-Refractory Myeloma Following First Relapse

Phase III CARTITUDE-4 study

The Phase III CARTITUDE-4 study, conducted by the Janssen Pharmaceutical Companies of Johnson & Johnson, revealed that CARVYKTI (ciltacabtagene autoleucel; cilta-cel) demonstrated a remarkable 74% reduction in the risk of disease progression or death compared to two standard-of-care (SOC) regimens, pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), in adults with relapsed and lenalidomide-refractory multiple myeloma. These findings were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine.

The CARTITUDE-4 study is particularly significant as it is the first randomized study investigating the efficacy of cell therapy in multiple myeloma as early as after the first relapse. The study enrolled 419 patients who had received one to three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and were lenalidomide-refractory. The patients were randomly assigned to receive either CARVYKTI (208 patients) or SOC treatment (211 patients).

After a median follow-up of 16 months, the median progression-free survival (PFS) was not reached in the CARVYKTI arm, while it was 11.8 months in the SOC arm. At 12 months, the PFS rates were 76% in the CARVYKTI arm and 49% in the SOC arm. The CARVYKTI arm also demonstrated an 85% overall response rate (ORR), with 73% achieving a complete response (CR) or better. In contrast, the ORR in the SOC arm was 67%, with a CR or better rate of 22%. Additionally, in the subset of patients evaluated for minimal residual disease (MRD) status, 88% of patients in the CARVYKTI arm achieved MRD negativity at the 10-5 threshold, compared to only 33% in the SOC arm.

These impressive results highlight the potential of CARVYKTI as a groundbreaking therapy for patients with relapsed and lenalidomide-refractory multiple myeloma who have received one to three prior lines of treatment. CARVYKTI has already gained FDA approval for the treatment of adult patients with relapsed/refractory multiple myeloma following four or more prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, based on data from the Phase Ib/II CARTITUDE-1 trial (NCT03548207).



(n = 208)


(n = 211)

Median PFS, mo (95% CI)

NE (23–NE)

12 (10–14)

12-mo PFS, % (95% CI)

76 (69–81)

49 (42–55)

ORR, n (%)b

176 (85)

142 (67)


152 (73)

46 (22)

10-5 MRD negative,c n (%)

126 (61)

33 (16)

Note: aPer computerized algorithm by constant piecewise weighted log-rank test. bIn 176 patients who received cilta-cel as study tx: ORR, 175 (99%); ≥CR, 152 (86%). cFor MRD-evaluable pts: cilta-cel, 88% (126/144); SOC, 33% (33/101).

The study did not identify any new safety concerns. Grade 3 or 4 adverse events were reported by 97% and 94% of patients, including infections (27%, 25%) and cytopenias (94%, 86%), respectively. In the CARVYKTI arm, 76% of patients experienced cytokine release syndrome (CRS), with only 1% of cases classified as grade 3 and no cases of grade 4 or 5. Five percent of patients reported immune effector cell-associated neurotoxicity syndrome (ICANS), all of which were grade 1 or 2. Additionally, one patient in the CARVYKTI arm experienced a grade 1 movement and neurocognitive treatment-emergent adverse event (TEAE). Out of the total patients, 39 in the CARVYKTI arm and 46 in the SOC arm died, with 10 CARVYKTI and five SOC patients passing away due to TEAEs.

KOL insights

“Use of cilta-cel in earlier lines may lead to improved tolerability. Overall, cilta-cel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma after first relapse” –Expert Opinion.

“The fact that there was not only a significant benefit in PFS but an impressively high percentage of patients achieving MRD-negative disease was very encouraging. In addition, what also [struck] me was that this benefit was achieved with limited treatment versus the continuous treatment and with no additional toxicity concerns. For now, I think the exciting take-home message is that with BCMA-targeting CAR T-cell therapy, we can safely treat patients earlier [in] their disease course with not much concern of additional toxicity and with a promise of high responses including molecular remission” –Expert Opinion.


A single infusion of CARVYKTI demonstrated a significant improvement in PFS compared to standard-of-care treatments in patients with lenalidomide-refractory multiple myeloma who had received one to three prior lines of therapy. The study revealed a 74% reduction in the risk of disease progression or death, accompanied by high rates of CR and MRD negativity. These findings suggest that cilta-cel has the potential to become a key therapy for multiple myeloma patients after their first relapse, offering a favorable benefit-to-risk profile across different patient populations.

On May 25, 2023, Janssen Pharmaceuticals submitted a Type II variation application to the European Medicines Agency (EMA) based on the results of the CARTITUDE-4 study. The application aims to obtain approval for CARVYKTI for the treatment of relapsed and lenalidomide-refractory multiple myeloma at an earlier stage. Given the extensive use of lenalidomide-based therapies as frontline treatments, there is an increasing need for new and effective therapies for patients who become refractory to lenalidomide early in their treatment journey. CARVYKTI has the potential to fulfill this unmet need and provide a valuable treatment option for these patients