Immune Engager Therapies Demonstrate Promise Following Relapse on Ide-Cel in Multiple Myeloma

Murali Janakiram, MD, MS

Patients with multiple myeloma who received immune engager therapies (IETs) following relapse with idecabtagene vicleucel (ide-cel; Abecma) had better progression-free survival (PFS) compared with those who received non-IETs, according to data from a retrospective, multicenter, real-world observational study.¹

According to results presented at the 2024 Transplantation & Cellular Therapy Meetings, for those who received IET after the first relapse the overall response rate (ORR) was 38.0% vs 22.3% with other therapies (P = .1). The median PFS was 106 days with IET compared with 66 days with other therapies (P = .004).

“In this large retrospective multicenter cohort looking at post-relapse outcomes of ide-cel, the median PFS was 60 and 47 days, showing that relapsing myeloma post CAR [chimeric antigen receptor] T-cell therapy has a dismal outcome with very low [complete response] and VGPR [very good partial response] rates,” said Murali Janakiram, MD, MS, associate professor, department of hematology & hematopoietic cell transplantation at City of Hope, in his oral presentation.

CAR T-cell therapies have shown high efficacy in malignancies including multiple myeloma, but there are not strong data on subsequent therapies, particularly with IET. Janakiram said there are several potential concerns with giving back-to-back IETs, such as T-cell exhaustion, lymphopenia, or cytopenia that can preclude collection for subsequent CAR T-cell therapy or initiation of other IET, and increased risk of infections.

In the phase 3 KarMMa-3 trial (NCT03651128), BCMA (B-cell maturation agent)-directed ide-cel was compared with standard therapies, which did not include IETs. At a median follow-up of 18.6 months, the median PFS was 13.3 months with ide-cel vs 4.4 months with standard therapies (HR, 0.49; 95% CI, 0.38-0.65; P < .001).²

The retrospective, multicenter, observational study included 145 patients with multiple myeloma treated with ide-cel in 11 centers in the United States.¹ The median age of the patients prior to ide-cel treatment was 64 years, and 44% of patients had extramedullary disease. They had received a median of 6 lines of therapy (IQR, 5-8) and 83% had prior autologous stem cell transplant. Three months after receiving ide-cel, 55% had a VGPR or better, and at 6 months, 45% had VGPR or better. The median PFS in these patients who all had documented relapse was 150.5 days.

At the first relapse following ide-cel treatment, the mean M protein spike was 0.21 mg and the median involved light chains was 124 mg/L. Extramedullary or paramedullary disease was present in 57% of patients at relapse.

The ORR was 24.9% and the median PFS was 60 days for all patients treated with subsequent therapies after the first relapse. The most common subsequent therapy used was non-cytotoxic including daratumumab (Darzalex) and selinexor (Xpovio), in 33% of patients. IETs were used in 29% and cytotoxic chemotherapy was used in 15%. Targeted therapy was used in 5.6% and external beam radiation alone was used in 4.9%.

Among those receiving IET, the most common were the BCMA-directed bispecifics teclistamab-cqyv (Tecvayli) or elranatamab-bcmm (Elrexfio), making up 65% of these patients. This was followed by belantamab mafodotin (Blenrep) in 20%. Other IETs included talquetamab-tgvs (Talvey) in 5% and natural killer (NK) cell therapy in 10%.

A Kaplan-Meier curve for PFS comparing IET vs non-IET therapy showed a higher probability of progression on IET in the first 30 to 45 days, but this trend reversed and IET showed a trend of superior PFS than non-IET afterward. Janakiram said this can be attributed to IET taking a longer time to begin acting. “Once myeloma starts responding, you see a much better stabilization of disease with IET,” he said.

Janakiram acknowledged that these data may reflect the available agents at the time they were collected. “I think this data set has the potential to change over time as therapies are going to be approved and newer therapies are going to be approved.”

Bispecifics have only recently been approved in this setting, and initially only BCMA-directed IETs were available even though talquetamab, which targets GPRC5D, might now be used if there was loss of BCMA expression after CAR T-cell therapy. He said PFS could potentially have been higher in the IET group if non-BCMA therapy was available to more patients, though repeat BCMA targeting may be viable since BCMA loss in post CAR T cell studies has been low.

Additionally, most patients treated with ide-cel are already refractory to approved non-cytotoxic therapy options, so outside of clinical trials of mezigdomide or iberdomide, prior lines of therapy would be recycled despite limited efficacy. Belantamab mafodotin was taken off the market in 2022 after not showing overall survival benefit as a single agent. Another limitation Janakiram discussed was that the study was of academic centers which had greater access to IETs compared with other oncology practices.

Sixty-three patients in the tracked cohort had a second relapse; 43% of these had extramedullary or paramedullary disease on relapse. In these patients, 43% received non-cytotoxic therapy, 30% received IET, and 24% received cytotoxic chemotherapy. The ORR was 26.9% and median PFS was 47 days during treatment for a second relapse. In the second relapse cohort, 19 patients received IET, including 12 (63%) who received BCMA-directed bispecific, 1 (5.3%) who received talquetamab, 4 (21%) who received belantamab, and 2 (11%) who received other therapy including NK cell therapy.

In addition to the observations of the efficacy of IET in the first relapse, the median PFS was 66 days for IET vs 44 days for non-IET for the second relapse (P = .3). However, the ORR for IET in the second relapse was only 21% compared with 29.5% for EIT vs non-IET, respectively (P = .69).

Janakiram said that more research is needed into the impact of CAR T-cell therapy on subsequent therapies, particularly T-cell and B-cell exhaustion as well as the role of monoallelic and biallelic mutations in the function of BCMA. However, these results support the use of IET over other treatment options following CAR T-cell therapy.

“IET is associated with better median PFS after ide-cel therapy and should be considered as a first choice if available,” concluded Janakiram.

References

1. Janakiram M, Khouri J, Castaneda O, et al. Immune engager therapies are associated with better outcomes in post ide-cel relapse in MM- an analysis of the US MM Immunotherapy Consortium database. Presented at: 2024 Transplantation and Cellular Therapies Meeting; San Antonio, TX; February 21-24, 2024. Abstract 39.
2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614