Durable Responses With Anti-BCMA CAR T-cell for Multiple Myeloma

Neil Osterweil

December 09, 2020

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD, of Mount Sinai Medical Center in New York, and colleagues.

"We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What's even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff," she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.

Combined Data

For the 2020 ASH annual meeting, Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.

Safety Data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.

Neurotoxicity Mechanism Questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

"We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells," Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

"We did see some nerve palsies and peripheral motor neuropathy, but it wasn't that many patients, and it's really hard to compare what happened here with the bi-specifics, as every product is very different," she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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