ASCO 2023: Studies Clarify Role of Immunotherapy in Multiple Myeloma

Four studies presented at the ASCO Annual Meeting 2023 further clarify the role of immunotherapy in the treatment of multiple myeloma (MM).

Results from the phase 3 CARTITUDE-4 trial suggested that a chimeric antigen receptor (CAR) T-cell therapy could be used earlier in the course of MM treatment.¹ The study showed that ciltacabtagene autoleucel (cilta-cel) improved progression-free survival (PFS) when compared to standard care in MM patients who had received 1 to 3 prior lines of therapy.

The phase 3 DSMM XVII study showed that a monoclonal antibody improves upon standard care in transplant-eligible patients with newly diagnosed MM.² Adding elotuzumab to carfilzomib, lenalidomide, and dexamethasone (KRd) improved outcomes in this trial.

The phase 3 DREAMM-3 trial suggested that belantamab mafodotin may not have a place as monotherapy in MM.³ The bispecific antibody did not significantly improve PFS when compared to pomalidomide and low-dose dexamethasone in patients with relapsed or refractory MM in this trial.

On the other hand, the phase 1/2 RedirecTT-1 trial showed positive results with 2 bispecific antibodies — talquetamab and teclistamab.⁴ Researchers found that combining talquetamab and teclistamab was safe, and the combination produced response rates rivaling those seen with CAR T-cell therapies. This was the first time results with 2 bispecific antibodies were reported in patients with a hematologic malignancy.

“I think we’re seeing what we’d hoped to see, that this new era of introducing bispecifics and CAR-T therapy very late in the disease cycle is now moving to earlier treatment,” said Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation and a professor at the Translational Genomics Research Institute in Phoenix.

“[T]he path to cure is not an overnight phenomenon, but I think everyone in the field agrees that these major moves where we’re seeing unprecedented response rates is definitely a very important step toward cure,” he said.

CARTITUDE-4: Cilta-Cel Improved PFS vs Standard Care

Cilta-cel significantly prolonged PFS when compared with standard treatment in the phase 3 CARTITUDE-4 study.¹ These results are expected to change the approved indication for cilta-cel, moving it from fifth-line or later treatment to second-line or later treatment in MM.

In this trial (ClinicalTrials.gov Identifier: NCT04181827), researchers compared cilta-cel with either pomalidomide plus bortezomib and dexamethasone (PVd) or daratumumab plus pomalidomide and dexamethasone (DPd).

The trial included 419 MM patients who had received 1 to 3 lines of prior treatment, including a proteasome inhibitor and an immunomodulatory agent, and had lenalidomide-refractory disease. The patients were randomly assigned to receive cilta-cel (n=208) or standard care with PVd or DPd (n=211).

The overall response rate was higher with cilta-cel than with standard care — 84.6% and 67.3%, respectively (odds ratio, 3.0; 95% CI, 1.8-5.0; P <.0001). The median duration of response was not reached and 16.6 months, respectively.

The median PFS was not reached in the cilta-cel arm and was 11.8 months in the standard care arm (hazard ratio [HR] 0.26; 95% CI, 0.18-0.38; P <.0001). The 12-month PFS rate was 76% and 49%, respectively.

Cilta-cel provided a PFS benefit in all subgroups, including difficult-to-treat patient populations, said study presenter Binod Dhakal, MD, of the Medical College of Wisconsin in Milwaukee.

“The responses are deeper and more durable compared to standard of care,” he added. “And all the data suggests that cilta-cel could be a new standard of care for patients who are lenalidomide-refractory and after the first relapse.”

Overall survival (OS) data are still immature, but there was a trend toward improved OS in the cilta-cel arm (HR, 0.78; 95% CI, 0.5-1.2; P =.26). There were 39 deaths in the cilta-cel arm and 47 deaths in the standard care arm.

Common grade 3-4 adverse events (AEs) were hematologic AEs (94.2% in the cilta-cel arm and 86.1% in the standard care arm) and infections (26.9% and 24.5%, respectively). There were 10 deaths due to treatment-emergent AEs in patients receiving cilta-cel (7 due to COVID-19) and 5 in patients receiving standard care (1 due to COVID-19).

In the cilta-cel arm, 76.1% of patients had cytokine release syndrome, and 4.5% had immune effector cell-associated neurotoxicity syndrome. Neurotoxicity was seen in 20.5% of patients receiving cilta-cel, and grade 3-4 neurotoxicity was seen in 2.8%.

“The higher neurotoxicity, I think, needs to be appreciated when it comes to cilta-cel,” said Stefan Knop, MD, of Würzburg University Medical Center in Germany, who was not involved in the CARTITUDE-4 trial. “But of course, patients who have not exploited, let’s say, 5 lines of therapy do tolerate aggressive treatments way better than those who are at the very end of that journey.”

Dr Dhakal also noted that cilta-cel appeared more tolerable when used as an earlier line of therapy.

Based on these findings, the manufacturers of cilta-cel have submitted a supplemental biologics license application for cilta-cel to treat patients with relapsed or refractory MM after at least 1 prior line of treatment.⁵

DSMM XVII: Elotuzumab Improved Upon KRd Induction

Elotuzumab plus KRd might be a new standard induction therapy, according to Dr Knop, who presented results from the phase 3 DSMM XVII trial at ASCO 2023.²

The trial (ClinicalTrials.gov Identifier: NCT03948035) included 579 adults (aged 18 to 70 years at baseline) with newly diagnosed MM who were eligible for transplant. They were randomly assigned to receive induction with elotuzumab plus KRd (n=291) or KRd only (n=288).

In both arms, patients received 6 cycles of induction. Those who had stable disease or better underwent autologous stem cell transplant with high-dose melphalan. They then received 4 cycles of KRd with or without elotuzumab, followed by maintenance with elotuzumab-lenalidomide or lenalidomide alone.

Nearly 92% of patients received all 6 cycles of induction. Patients who received elotuzumab plus KRd had a higher rate of very good partial response or better with minimal residual disease (MRD) negativity than patients who received KRd only — 49.8% and 35.4%, respectively (P =.0005).

MRD negativity rates, regardless of response status, were 52.6% for patients receiving elotuzumab plus KRd and 37.5% for those receiving KRd only (P =.0003).

The rate of grade 3 or higher AEs was 74.7% in the elotuzumab arm and 66.3% in the KRd arm. Five patients in the elotuzumab arm had fatal AEs, as did 8 in the KRd-only arm.

Dr Knop noted that elotuzumab plus KRd “has a manageable safety profile in fit patients up to 70 years old.”

This article originally appeared on Cancer Therapy Advisor