Looking to Novel Immunotherapeutics in Relapsed/Refractory Multiple Myeloma

Marc J. Braunstein, MD, PhD

Treatments that activate the body’s innate or adaptive immune response have become a focus of research in multiple myeloma, according to Marc J. Braunstein, MD, PhD, who cited CAR T-cell therapy, bispecific antibodies, and cereblon E3 ligase modulators (CELMoDs) as 3 such examples that are showing high response rates in heavily pretreated patients.

“It’s important to encourage patients to go on clinical trials, because many of our studies have been very successful, especially those using novel agents that are based on firm basic science. At NYU, we have a number of ongoing clinical trials in the relapsed/refractory setting, including those evaluating allogeneic CAR T cells, and combination agents, including bispecific antibodies in the relapsed/refractory setting,” said Braunstein.

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Braunstein, assistant professor in the Department of Medicine at NYU Long Island School of Medicine, course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discussed the evolution and promise of immunotherapeutics in multiple myeloma.

OncLive: What is coming down the pike in multiple myeloma?

Braunstein: The most excitement in the field is for novel immunotherapeutic approaches, and these include primary antigen receptor T cells or CAR T cells, which have been approved for other hematologic malignancies, such as lymphoma, and also the bispecific antibodies, which also work by activating T-cell immunity against multiple myeloma, although it’s not a cellular therapy.

At my institution at NYU, we are opening an allogeneic CAR T-cell therapy study, and this is something that could potentially be an off-the-shelf product, where the T cells are derived from another individual and are modified to go back and attack the myeloma.

In terms of CAR T cells, we’ve seen a lot of excitement around various studies that have a product that targets BCMA, which is a highly specific antigen expressed in multiple myeloma plasma cells. T cells are harvested from the patient for autologous yield, and then they are modified so that they express a receptor that will target the BCMA antigen on the surface of plasma cells. They also have a co-stimulatory domain, which activates T cells to destroy the myeloma plasma cells.

Three major products are advancing through clinical trials, one of which [that is being evaluated in the CARTITUDE-1 study] caught a lot of attention at the 2019 ASH Annual Meeting and Exposition. Updated data from the study were presented at the 2020 ASH Annual Meeting and Exposition by [Deepu Madduri, MD, of Mount Sinai]. The study is looking at an anti-BCMA CAR T cell, and at a median follow-up of 9 months, there was an impressive 95% objective response rate [ORR] and a 56% complete response rate in patients who progressed through multiple lines of therapy.

In terms of the bispecific antibodies, several are in clinical trials targeting various antigens on the surface of myeloma, including CD38, FcRL5, BCMA, a key coupled protein receptor called GPRC5D, and ones in preclinical studies targeting RASi and BAFF, which are proliferative signaling factors for plasma cells.

One bispecific antibody called teclistamab targets BCMA, and the idea is that it binds to the BCMA antigen on the surface of plasma cells and CD3 on the surface of T cells and activates them so that they lice the plasma cells that are in proximity. A phase 1 study was presented by Alfred Garfall, MD, of Penn Medicine and colleagues looking at this agent, and in patients who were triple or penta-class refractory, it showed impressive ORRs in the range of 70% to 80% at the randomized phase 2 dose.

There’s a lot of excitement, not just at finding new targets, but also new approaches to target myeloma plasma cells, using various agents that activate the body’s innate or adaptive immunity against myeloma, or using autologous or allogeneic T cells that have been modified, that can go back and target the myeloma.

In addition, data presented at the 2020 ASH Annual Meeting and Exposition by Niels van de Donk, MD, of VU University Medical Center, and colleagues looking at CELMoDs, which are kind of like novel immunomodulators that are oral agents that are active in patients who are refractory to lenalidomide [Revlimid] or pomalidomide [Pomalyst]. Dr van de Donk and colleagues presented phase 1/2 data looking at the agent called iberdomide, which is an oral CELMoD, in combination with other agents in relapsed/refractory patients and showed meaningful response rates in patients at the phase 2 dose.

We’re definitely moving further away from conventional chemotherapy, although that still plays a role in patients who have highly refractory or resistant disease. We’re going to see a number of exciting approvals for relapsed/refractory multiple myeloma, including some of the agents I mentioned, such as bispecific antibodies, as well as primary antigen receptor T cells.

How will these agents be integrated into practice without a clear sequencing strategy?

One unanswered question in the field of multiple myeloma is how to sequence therapies, and in a way that really individualizes therapeutic regimens to specific patients. These include high-risk patients who have high-risk cytogenetics, or very resistant disease and have proven clinical high-risk disease. We need to find the best induction regimens as well as find the best combination regimens for those patients in the relapsed/refractory setting.

We’re going to have other options for cellular therapies, in addition to autologous stem cell transplant [ASCT], including CAR T cells and natural killer [NK] cells. The question is whether a patient will go for one or the other or sequence those [approaches]. For example, go for ASCT followed by a CAR T-cell therapy.

There’s also a lot of excitement in the field about maintenance therapy for patients who are going to go on continuous therapy since we know that multiple myeloma is very challenging to cure. It can sometimes behave like a chronic disease, and that’s in part due to the use of maintenance therapy. We have an ongoing randomized phase 3 study comparing daratumumab [Darzalex] and lenalidomide with lenalidomide alone as maintenance therapy for patients who are minimal residual disease positive after transplant.

We’re going to see the use of various novel agents in the maintenance setting. There are a lot of unanswered questions that we can begin to answer using novel agents, as well as real-world data. It’s a really exciting time in the field now that we have so many options and can formulate these studies to address important questions.