Cilta-Cel Achieved PFS Prolongation in Patients With Myeloma and Poor Prognosis

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According to subgroup analysis findings from the phase 3 CARTITUDE-4 clinical trial (NCT04181827), patients with multiple myeloma exhibiting poor prognostic features, experienced significant progression-free survival (PFS) benefit with single-infusion ciltacabtagene autoleucel (cilta-cel; Carvykti).¹

The poor prognostic features observed in patient in the study included, high-risk cytogenetics, soft-tissue plasmacytoma, ISS stage III disease, and triple-class exposure.

Results presented at the 20th International Myeloma Society (IMS) Annual Meeting showed that the 12-month PFS rates in patients in the intent-to-treat (ITT) population with standard (n = 59) or high (n = 105) cytogenetic risk were 89.6% (95% CI, 78.4%-95.2%) and 88.5% (95% CI, 80.7%-93.3%), respectively. Among those with high-risk features, those with greater than 2 cytogenetic abnormalities (n = 34) had a rate of 82.4% (95% CI, 64.9%-91.7%); in those with 17p deletions, t(4;14) translocations, or t(14;16) translocations (n = 59), this rate was 86.4% (95% CI, 74.7%-93.0%).

Moreover, the 12-month PFS rate was 86.7% (95% CI, 68.3%-94.8%) in those with soft-tissue plasmacytoma at baseline (n = 30) vs 90.3% (95% CI, 84.1%-94.1%) in those without (n = 146). Those who were triple-class refractory at baseline (n = 20) experienced a 12-month PFS rate of 90.0% (95% CI, 65.6%-97.4%) vs 89.7% (95% CI, 83.7%-93.5%) in those who were not (n = 156). Patients with prior daratumumab exposure (n = 36) or triple-class exposure (n = 37) experienced 12-month PFS rates of 82.8% (95% CI, 65.7%-91.9%) and 83.3% (95% CI, 66.5%-92.1%), respectively, vs 84.9% (95% CI, 78.2%-89.7%) in all patients.

“Within the cilta-cel as-treated population, the 12-month PFS rate remained greater than 82% in the presence of common markers of poor prognosis, including high-risk cytogenetics and triple-class refractoriness,” lead study author Salomon Manier, MD, PhD, a professor of medicine at Centre Hospitalier Universitaire de Lille, in Lille, France, said in an oral presentation of the data. “Data in patients with prior daratumumab or triple-class exposure also suggest that cilta-cel is effective when used in this patient population.”

Eligible patients enrolled onto CARTITUDE-4 included those who had developed lenalidomide resistance with prior exposure to 1 to 3 lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. Additionally, patients were required to have an ECOG performance status of 0 or 1.

Patients were randomly assigned to either cilta-cel or physician’s choice of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd).² In the cilta-cel arm, patients underwent apheresis followed by at least 1 cycle of bridging therapy and lymphodepletion, which consisted of 300 mg/m2 of cyclophosphamide plus 30 mg/m² of fludarabine for 3 days. Subsequently, patients received a single infusion of cilta-cel at a target dose of 0.75 × 10⁶ CAR-positive viable T cells/kg. Those in the standard-of-care (SOC) arm received PVd in 21-day cycles or DPd in 28-day cycles until they experienced disease progression.

The study’s primary end point was PFS. Important secondary end points included complete response or better, overall response rate, minimal residual disease negativity, overall survival, and patient-reported outcomes. Investigators also examined safety and pharmacokinetics.

Of the 419 patients who comprised the ITT population, 208 were randomized to cilta-cel and underwent apheresis; 176 of these patients received the CAR T-cell therapy. Moreover, 208 of the original 211 patients randomized to SOC received PVd or DPd. Thirty-two patients in the cilta-cel arm were unable to receive cilta-cel due to disease progression or death.

Previously reported primary results from the CARTITUDE-4 trial demonstrated that cilta-cel reduced the risk of death or disease progression by 74% compared with the SOC in patients with lenalidomide-refractory multiple myeloma who had received 1 to 3 prior lines of therapy.² The median PFS not reached in the cilta-cel arm (95% CI, 22.8-not estimable) vs 11.8 months (95% CI, 9.7–13.8) with SOC (HR, 0.26; 95% CI, 0.18-0.38; P < .0001).

Investigators conducted a prespecified subgroup analysis of patients with high-risk features in the ITT population and reported outcomes at the 2023 IMS Annual Meeting. The data cutoff date for the analysis was November 1, 2022 and the median follow-up was 15.9 months (range, 0.1-27.3).

The treatment arms were noted to be well balanced at baseline. Most patients in the cilta-cel and SOC arms had high-risk cytogenetics (59.4%; 62.9%) and stage I disease by International Staging System (ISS) criteria (65.4%; 62.6%) as opposed to stage II (28.8%; 30.8%) or stage III (5.8%;6.6%) disease. Among those in the cilta-cel arm, 22.0% had 2 or more high-risk features vs 23.3% of those in the SOC arm.

Soft tissue plasmacytoma was present in 21.2% and 16.6% of patients in the cilta-cel and SOC arms, respectively. Most patients had 2 prior lines of therapy (39.9%; 41.2%), followed by 1 prior line (32.7%; 32.2%) and 3 prior lines (27.4%; 26.5%). Bortezomib was previously received by 97.6% of those in the cilta-cel arm vs 97.2% of those in the SOC arm; 24.5% and 25.6% of patients, respectively had prior exposure to daratumumab. Moreover, triple-class exposure was noted in 25.5% and 26.1% of patients, respectively. Of those who were refractory to prior therapy in the cilta-cel arm, 98.6% were refractory to their last line of therapy, 23.1% were refractory to daratumumab, and 14.4% were triple-class refractory; these percentages were 98.6%, 21.3%, and 15.6%, respectively, in the SOC arm. DPd was the most frequently administered bridging therapy in both arms (87.5%; 86.7%).

Additional analysis also showed that cilta-cel improved median PFS vs SOC treatment in all subgroups analyzed, including those with these high-risk features. In those with 2 or more abnormal markers, the HR for PFS was 0.33 (95% CI, 0.17-0.64); in those with del(17p), t(14;16), or t(4;14), it was 0.26 (95% CI, 0.15-0.45).

Moreover, the HR for PFS in patients with ISS stage III disease was 0.33 (95% CI, 0.11-0.95). In those with soft-tissue plasmacytomas, the HR for PFS was 0.39 (95% CI, 0.21-0.75). Those with a high tumor burden experienced a HR for PFS of 0.27 (95% CI, 0.13-0.56). Additionally, the HR for PFS for those who were triple-class refractory was 0.15 (95% CI, 0.05-0.39); in those with prior exposure to daratumumab or bortezomib it was 0.23 (95% CI, 0.12-0.44) and 0.27 (95% CI, 0.19-0.39), respectively.

The observed benefits with cilta-cel in this population with poor prognostic features are consistent with the overall ITT population, affirming the effectiveness of a single infusion of cilta-cel in a wide range of clinically relevant multiple myeloma subgroups, according to Manier.

_References:

_{1. Manier, S. Additional analysis of CARTITUDE-4: Cilta-cel vs standard of care (PVd or DPd) in lenalidomide-refractory patients with multiple myeloma and 1-3 prior lines of therapy. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-47.}

_{2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379}