Immunotherapy Evolution Continues With Innovative Approaches to Multiple Myeloma Treatment
Experts discuss emerging targets in the immunotherapy landscape and how to improve patient outcomes through innovative approaches.
In the 1990s, the only option for patients with multiple myeloma (MM), in early, refractory, and relapsed stages, was chemotherapy, which limited their treatment options to agents that were associated with significant toxicities and proved to be ineffective treatments against this heterogeneous disease. The development of immunomodulatory agents (IMiDs) led to the advent of T-cell-directed therapies including monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), and chimeric antigen receptor (CAR) T-cell therapy. These agents have changed the treatment landscape of MM, offering patients a catalog of therapeutic options that are more effectively tailored to their unique needs.
The triSpecific antibody JNJ-79635322 is first in-class antibody targeting BCMA, GPRC5D, and CD3. Image Credit: © Tatiana Shepeleva - stock.adobe.com
Despite the evident improvements demonstrated by immunotherapies, there is still no cure for MM, and it remains a difficult disease to treat as patients advance through multiple lines of treatment. At the International Myeloma Society 21st Annual Meeting in Rio de Janeiro, Brazil, multiple speakers presented emerging agents and alternative methods of destroying malignant myeloma cells through use of protein degradation and harnessing the capabilities of the immune system. These potential therapeutic approaches may both support and enhance the efficacy of immunotherapies.1
Daratumumab (Darzalex; Janssen Biotech, Inc) was the first mAb approved by the FDA for treatment of MM, which marked a crucial step forward in the evolution of MM therapies. Researchers and specialists were able to target and bind to specific overexpressed proteins, such as CD3, CD38, BCMA, and emerging targets GPRC5D and FcRH5, on the surface of malignant cells. This method offered patients a therapy with more precision, allowing for limited toxicities and damage to surrounding cells. However, patients continued to relapse, and the benefits of progression-free survival (PFS) dwindled with successive lines of therapy.
This challenge led to the development of BsAbs such as teclistamab (Tecvayli; Janssen Biotech, Inc.) and elranatamab (Elrexfio; Pfizer) which have shown significant capabilities in improving PFS (12.5 to 17 months) and response rates (60% to 70%), and CAR T-cell therapies.2 Despite the clinical activity of these agents targeting BCMA, relapses still occur and may involve antigen loss, antigen mutation, and the development of heterogeneity in myeloma cells.
Jordan Schecter, MD, vice president of the Multiple Myeloma Disease Area Stronghold at Johnson & Johnson, introduced the next step: the triSpecific antibody JNJ-79635322, a first in-class antibody targeting BCMA, GPRC5D, and CD3. JNJ-79635322 binds to CD3 on T-cells and BCMA and GPRC5D on myeloma cells and has shown potent and dose-dependent cytotoxicity against myeloma cell lines (BCMA and GPRC5D), as well as anti-tumor activity in mouse models. Schecter and his team injected the mice with JNJ-79635322 and used calipers to measure the tumor growth or non-growth of the tumor. They observed that the doses JNJ-79635322 resulted in a tumor killing on both sides of the animal where there was tumor growth, suggesting its efficacy in MM. When describing the uniqueness of this approach, Schecter noted the goals of this development.
“We are really trying to address the toxicity profile. We're aware that infections are obviously a concern with the BCMA and CD3. Also, the dysphagia that is typical for GPRC5D-targeting antibodies. So, we are looking to strike that good balance between efficacy and safety. We're also looking to optimize the schedule including extended dosing intervals rather than the weekly or every other week,” he explained.
JNJ-79635322 is being investigated in the ongoing phase 1 dose-escalating MMY1001 study (NCT05652335) evaluating patients with relapsed/refractory MM (RRMM) who were previously treated with imminent proteasome inhibitors and anti-CD38 monoclonal antibodies. The trial will test multiple doses, dose levels, and different schedules of administration of JNJ-79635322. With promising results, the study will advance to a second phase to identify that recommended phase 2 dose.3
The continued success of targeting BCMA makes itself evident in clinical trial and practice, validated by the approval of novel agents and ongoing research into ways to target the protein. Another method presented was the use of the BCMA-targeting antibody drug conjugate (ADC) belantamab mafodotin (Blenrep; GlaxoSmithKline). There have been multiple prior attempts to develop ADCs targeting BCMA; however, they are no longer in development. Belantamab mafodotin is the next attempt to offer patients with MM an alternative therapeutic option that utilizes the capabilities of small molecules.
Results from the phase 3 DREAMM7 (NCT04246047) and DREAMM8 (NCT04484623) trials showed that belantamaphodotin can be successfully used with standard of care daratumumab, bortezomib (Velcade; Millennium/Takeda, Janssen Pharmaceutical Companies), and dexamethasone, as well as pomalidomide (Pomalyst; Bristol Myers Squibb) and dexamethasone, respectively.4,5
“Belantamab mafodotin is not just a simple [ADC],” said Joanna Opalinska, senior director of Clinical Development, Oncology at GlaxoSmithKline. “It also has a very strong [antibody-dependent cellular cytotoxicity] and [antibody-dependent cellular phagocytosis] activity, and it induces immunogenic cell death, which makes it a very potent molecule.”
Targeted agents were not the only treatment methods discussed in the session. Alternative approaches presented aim to harness processes such as protein degradation and immune system functions through use of small molecules to support standard of care agents. Iberdomide and mezigdomide (Bristol Myers Squibb) are novel CELMoD E3 ligase modulators capable of degrading substrates at lower concentrations compared with lenalidomide (Revlimid; Bristol Myers Squibb) and pomalidomide; additionally, these molecules have longer chemical structures that allow for stronger, more effective binding and degradation. According to preclinical trials, mezigdomide, in particular, had superior degradation benefits and retains potent anti-proliferative activity in both IMiD-sensitive and IMiD-resistant myeloma cell lines. In the phase 1 CA057-003 study (NCT05552976), the efficacy and safety of mezigdomide in combination with tazemetostat (Tazverik; Epizyme, Inc) and dexamethasone in patients with RRMM is being evaluated.6
Another method of support and enhancement focused on immune system activation and tumor microenvironment reprogramming through use of molecules including checkpoint inhibitors, small molecules, mAbs, cytokines, CAR T-cell engagers, and fusion proteins. Zandra Klippel, MD, global project lead, isatuximab at Sanofi, highlighted belumosudil (Rezurock; Kadmon Pharmaceuticals, LLC), an agent commonly used to treat chronic graft-versus-host disease. Belumosudil inhibits the STAT3 pathway and TH17 cells, which are linked to MM and bone disease. According to preclinical studies, belumosudil can induce apoptosis in myeloma cells, as well as promote T-cell activation.
There are 2 dose-escalation clinical trials evaluating belumosudil as a monotherapy versus in combination with dexamethasone, as well as a third investigating belumosudil with isatuximab and dexamethasone.
“We're still looking to improve the outcomes of the patients that are living with [MM],” said Klippel. “We're [researching whether] we can create rational combinations that stimulate different arms of the immune system that target directly the tumor through different mechanisms. We're hopeful to avoid significant toxicity by using intrinsically more tolerable drugs, but also potentially sequence more effectively regimens.”
The evolution of MM treatments, from traditional chemotherapy to advanced immunotherapies, has significantly altered the landscape for patients. However, despite these advances, MM remains a highly complex and incurable disease. By refining these approaches and combining them with existing treatments, researchers and health care professionals can prolong survival and enhance quality of life for patients with MM.
