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High Marks for CAR T Cells in R/R Myeloma

— Response rates of 70-100% with BCMA-targeted products for heavily treated disease

Ƶ MedicalToday

Three-fourths of patients with heavily treated multiple myeloma responded to chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), results of a pivotal phase II trial showed.

A third of patients achieved complete responses, and most responses were durable, reflected in a median duration of response (DOR) of 10.7 months. Complete responses were associated with a median DOR of 19 to 20 months.

Severe cytokine release syndrome (CRS) or neurologic toxicity occurred infrequently among patients who received the target dose of idecabtagene vicleucel (ide-cel, bb2121), Nikhil C. Munshi, MD, of Dana-Farber Cancer Institute in Boston, reported during the .

"Results support a favorable benefit-risk profile for ide-cel across the target dose range," Munshi said in a recorded presentation. "Ide-cel provides an attractive option for treatment of triple-class exposed relapsed/refractory multiple myeloma."

The study, known as KarMMa, was the largest of three myeloma CAR T-cell trials reported during the virtual meeting, each involving a different BCMA-targeted therapy. The smaller trials showed objective response rates (ORRs) of 90% and 100% with low rates of severe CRS and neurologic toxicity.

The three "fabulous studies" reflect the current exciting but chaotic times in the field of CAR T-cell therapy for relapsed/refractory myeloma, said ASCO invited discussant Krina Patel, MD, of the University of Texas MD Anderson Cancer Center in Houston. She noted that BCMA-targeted therapy was used for the first time in 2014, and more than 60 clinical trials are now underway.

The studies and others like them provide a strong base for continued advances, which should include achieving a true cure for at least a portion of patients with relapsed/refractory myeloma, Patel said. Future studies may focus on other antigen targets, and bispecific therapies offer intriguing possibilities.

"BCMA-specific CAR T cells demonstrate unprecedented response rates for very relapsed/refractory patients and appear to be dose dependent," she continued. "Progression-free survival rates in the setting of a single dose of CAR T cells are very promising and improve with deeper responses and MRD [minimal residual disease] negativity. Safety concerns, such as CRS, are in the majority of cases manageable."

"Patient access is key for the future of CAR T," Patel said. "I would like to say the hope is real and the future is bright [but] I think we need to upgrade all of our CAR T therapies for even better response and do that very soon."

Ide-Cel and KarMMa

Munshi findings for 128 patients who received one of three doses of ide-cel (150-450 × 106 CAR T cells) in the phase II KarMMa trial. Eligible patients had received at least three prior regimens, including prior exposure to an immunomodulator, a proteasome inhibitor, and an anti-CD38 antibody. Patients underwent leukapheresis with or without bridging therapy.

Following cell expansion and processing, patients underwent 3 days of conditioning with fludarabine and cyclophosphamide before receiving a single infusion of ide-cel. The initial response assessment occurred 1 month after infusion.

The trial had a primary endpoint of ORR (null hypothesis ≤50%) and secondary endpoints that included complete response, DOR, progression-free survival (PFS), overall survival (OS), and safety. Median follow-up was 13.3 months and ranged from 18.0 months for patients treated with the lowest doses of ide-cel to 12.4 months for those who received the highest dose.

The patients had a median age of 61, a third had high-risk cytogenetics, half had high tumor burden, and 85% had ≥50% tumor BCMA expression. More than 90% of the patients had undergone prior autologous stem-cell transplantation, and a third of patients had undergone more than one transplant. Munshi said 84% of the patients had triple-refractory disease and 94% were double refractory.

The ORR for all 128 patients was 73% and ranged from 50% for patients who received the lowest ide-cel dose to 82% for those who received the highest dose. The complete response rate was 33% overall and 39% in the subgroup of patients who received 450 × 106 cells.

The median time to initial response was 1 month, and time to complete response was 2.8 months. Munshi said 26% of patients achieved MRD with complete response and 39% achieved MRD status with very good partial response (VGPR) or better.

The entire cohort had a median PFS of 8.8 months, including 12.1 months in patients treated with the highest dose of ide-cel. A preliminary survival analysis yielded a median of 19.4 months, and the 12-month survival rate was 78%.

Grade ≥3 CRS occurred in 4% of patients, 6% in the high-dose subgroup, and the median duration was 5 days. Grade ≥3 neurologic events occurred in 3% of patients and had a median duration of 3 days.

Orva-Cel and EVOLVE

The phase I/II EVOLVE trial followed a with low-dose orvacabtagene autoleucel (orva-cel, 50 and 150 × 106 cells), which showed response rates of 79% and 86% and complete response rates of 43% and 18% of patients, respectively.

EVOLVE included 62 patients with relapsed/refractory myeloma treated with 300 to 600 × 106 cells, Sham Mailankody, MD. The patient population and treatment process were similar to those in the KarMMa trial. Primary objectives were safety/tolerability, recommended phase II dose, and antitumor activity as assessed by ORR.

The patients had received a median of six prior regimens for myeloma, and almost all had a prior autologous stem-cell transplant. More than 90% of the patients had triple-refractory disease.

Across the range of doses evaluated, orva-cel led to an ORR of 92%, including a complete response rate of 36% and ≥VGPR of 68%. All but one patient had some degree of tumor reduction. Responses included some patients with the highest baseline levels of BCMA, said Mailankody. MRD assessment at 3 months showed that 21 of 25 evaluable patients met MRD criteria.

Hematologic toxicity was common, including grade ≥3 neutropenia in 90% of patients, thrombocytopenia in 47%, anemia in 48%, and leukopenia in 32%. Grade ≥3 infections occurred in 13% of patients, and grade ≥3 CRS and neurologic toxicity each occurred in 3% of patients.

JNJ-4528 and CARTITUDE-1

The ongoing CARTITUDE-1 trial followed a showing that use of JNJ-4528 led to a median PFS of 20 months and median OS of 36 months in 57 patients with relapsed/refractory multiple myeloma. Jesus G. Berdeja, MD, of Sarah Cannon Research Institute in Nashville, findings for 29 patients who received a single weight-adjusted dose of JNJ-4528.

Similar to in the other two trials, eligible patients had received at least three prior regimens and had disease that proved refractory to at least two key classes of myeloma therapy. Overall, the cohort's treatment history included a median of five prior lines of therapy.

Berdeja reported that all 29 patients achieved a reduction in tumor burden (as assessed by paraprotein), which reached 100% in all but one case. All but four patients met criteria for stringent complete response. The median time to initial response was 1 month, and time to complete response was 3 months. Response and depth of response were independent of baseline BCMA expression.

After a median follow-up of 11.5 months, 22 of 29 patients remained alive without disease progression. Three patients died: one each from CRS, progressive disease, and acute myeloid leukemia. The 9-month PFS rate was 86%.

Consistent with the other two studies, grade ≥3 CRS and neurotoxicity occurred in 7% and 3% of patients, respectively. Grade ≥3 hematologic toxicity included neutropenia in 100% of patients, thrombocytopenia in 69%, anemia in 48%, leukopenia in 66%, and lymphopenia in 48%. Severe nonhematologic toxicity was limited, as two patients each had increased levels of aspartate aminotransferase and alanine aminotransferase.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The ide-cel study was supported by Bristol-Myers Squibb and Bluebird Bio.

Munshi disclosed relationships with OncoPep, AbbVie, Adaptive Biotechnologies, Amgen, BeiGene, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm Therapeutics, and Takeda.

The orva-cel study was supported by Juno Therapeutics.

Mailankody disclosed relationships with Allogene, Janssen Oncology, Juno Therapeutics, and Takeda.

The JNJ-4528 study was supported by Janssen.

Berdeja disclosed relationships with Amgen, Bioclinica, Bristol-Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Karyopharm Therapeutics, Kite Pharma, Legend Biotech, Prothena, SERVIER, Takeda, AbbVie, Acetylon, Bluebird Bio, Constellation, Curis, Genentech/Roche, Glenmark, Kesios, Lilly, Novartis, Poseida Therapeutics, Sanofi, Teva, and Vivolux.

Primary Source

American Society of Clinical Oncology

Munshi NC, et al "Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma: Initial KarMMa results" ASCO 2020; Abstract 8503.

Secondary Source

American Society of Clinical Oncology

Mailankody S, et al "Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma: Update of the phase I/II EVOLVE study" ASCO 2020; Abstract 8504.

Additional Source

American Society of Clinical Oncology

Berdeja JG, et al "Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen-directed CAR T-cell therapy, in relapsed/refractory multiple myeloma" ASCO 2020; Abstract 8505.