Immunotherapy Is on the Cusp of Major Breakthroughs in Multiple Myeloma

Sagar Lonial, MD

Just a decade ago, immune therapy for multiple myeloma barely existed as an idea. Since then, immune therapy has evolved rapidly and the field is on the verge of major improvements in outcomes, Sagar Lonial, MD, said.

The challenge now, he said, is identifying which patients will most benefit from treatments such as immune checkpoint inhibitors, monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers (BiTE). Furthermore, special populations including older patients, those at high risk, and those with high proliferation, present unique treatment problems. Understanding how to choose a CAR T-cell therapy versus a bispecific agent and learning how to use these agents in sequence and in combination represents the future of myeloma therapy, he said.

“Understanding how to combine these and approach special populations is a challenge,” Lonial said. “How do we understand patients who are immune to these treatments? The high-risk patients may be more immune. How do we make them more sensitive? How do we make them express those proteins that we know can be effective?”

Lonial, the 2020 Giants of Cancer Care® award winner for Myeloma, delivered the Giants Lecture during the 25th Annual International Congress on Hematologic Malignancies. He is the chief medical officer at Winship Cancer Institute of Emory University, as well as chair of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer at the Emory University School of Medicine, in Atlanta, Georgia.

Lonial has been a pioneer in immune therapy for myeloma from the earliest days. He led 3 clinical trials assessing monoclonal antibodies for the treatment of multiple myeloma. In 2015, his research resulted in FDA approval for elotuzumab (Empliciti) and daratumumab (Darzalex) in combination with lenalidomide. Daratumumab was the first anti-CD38 monoclonal antibody approved for the treatment of patients with cancer. He also led the research that led the FDA to grant accelerated approval to belantamab mafodotin-blmf (Blenrep), the first-in-class anti­­–B-cell maturation antigen (BCMA), in August 2020 for adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

New Data Is Creating New Treatment Paradigms

Lonial said anti-CD38 antibodies have become the default first-choice antibody for patients with relapsed/refractory MM. There is a solid collection of evidence showing that these agents improve progression-free survival (PFS) in this patient population.

Data from the phase 3 APOLLO trial (N = 304) demonstrated that daratumumab/hyaluronidase-fihj (Darzalex FASPRO) plus pomalidomide and dexamethasone (Pd) reduced the risk for progression or death by 37% (HR, 0.63; 95% CI, 0.47-0.85; P = .0018) compared with Pd alone in patients with relapsed/refractory multiple myeloma. The median PFS was 12.4 versus 6.9 months in favor of the daratumumab/hyaluronidase-fihj arm.¹

Overall survival data are still developing. At a median follow-up of 16.9 months, 99 (33%) patients had died. HR for OS was 0.91 (95% CI, 0.61-1.35).

Lonial noted that the experimental treatment nearly doubled PFS. He added that the combination will likely have even stronger results when used in an earlier line of treatment.

Investigators are exploring another anti-CD38 antibody, isatuxumab-irfc (Sarclisa), in combination with Pd versus Pd alone. The FDA approved the isatuxumab/Pd combination for adults with relapsed/refractory MM in March 2020 based on data from the ICARIA-MM trial (NCT02990338). Isatuxumab/Pd induced a 40% reduction in the risk for disease progression or death (HR 0.596; 95% CI, 0.44-0.81; P = .0010). Median PFS as 11.53 months in the experimental arm compared with 6.47 months for those who received Pd.²

The science is expanding beyond agents targeting the CD38 antibody. In the past few years, investigators have begun researching BCMA as a novel treatment target due to its highly selective expression in malignant plasma cells. Clinical trial data have shown strong response to multiple BCMA-targeted therapeutics.

Lonial is leading the international, open-label, phase 2 DREAMM-2 study (NCT03525678) evaluating belantamab mafodotin-blmf in patients with relapsed/refractory MM who experienced disease progression after 3 or more lines of therapy, who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory and/or intolerant to an anti-CD38 monoclonal antibody.

Findings from the pivotal DREAMM-2 trial, which showed that belantamab mafodotin elicited an overall response rate (ORR) of 31% (97.5% CI, 21.7-43.6) in patients with relapsed/refractory MM who received the treatment at the recommended 2.5 mg/kg dose. In patients who received belantamab mafodotin at 3.4 mg/kg, the ORR was 35% (97.5% CI, 24.8-47.0).³

The median PFS was 2.8 months in the 2.5-mg/kg cohort and 3.9 months in the 3.4-mg/kg cohorts. Overall survival data were immature at the time of the analysis.

“When it comes to immune therapy circa 2021, we have multiple immune targets, including CD38, SLAMF7, BCMA, GPRC5d, and FCRH5,” Lonial said. “Their expression…is pretty consistent across all the different genetic subgroups. In fact, it’s pretty consistent from diagnosis all the way through to refractory relapse. It’s not like you lose expression of these over time.”

The remaining question for clinicians, he said, is how to use a bispecific, an antibody, or a CAR T-cell therapy. “How do you put them all together with a treatment platform that lets you give fixed-duration therapy, get to MRD negativity and then stop treatment and walk away? Our goal is to get to a point where we don’t give continuous therapy, where we give limited duration therapy, get deep responses, and see how durable those responses are, whether they are patients with multiple myeloma who are high risk or standard risk.”

References

1. Dimopoulos MA, Terpos E, Boccadoro M, et al. Apollo: phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Virtual. Abstr 412.
2. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5
3. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0