Overcoming Treatment Challenges in Multiple Myeloma: Bispecific Antibodies and CAR T-Cell Therapy

Immunotherapies are the cornerstone of treatment for multiple myeloma (MM), demonstrating clinically meaningful improvements in response rates and progression-free survival (PFS) through the use of more precise, targeted therapies. Unlike some other malignancies, MM has the "advantage" of having numerous overexpressed proteins that can be targeted by specific agents to mitigate the proliferation of myeloma cells, including BCMA and emerging targets such as GPRC5D and FcHR5. At the International Myeloma Society 21st Annual Meeting in Rio de Janeiro, Brazil, multiple experts discussed the success of these agents, mechanisms of resistance, and evolving methods of overcoming T-cell exhaustion to improve these therapies and their benefit for patients with MM.¹

The continued development of combination therapies aims to not only improve their safety and efficacy but also increase their availability and affordability. Image Credit: © Animager - stock.adobe.com

The treatment landscape for MM has evolved drastically over the past few decades with the advent of bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cell therapies, which have greatly enhanced longevity and quality of life for patients. With the use of these T-cell redirection therapies, health care professionals have seen significant improvements in patient outcomes, with high response rates ranging from 60% to 90% and PFS lasting from 11 months to 3 years. Clinical trial results show that these benefits are observed in both refractory/relapsed patients and newly diagnosed, untreated patients with MM.

Various approved and investigational BsAbs and CAR T-cells bind to notable targets such as CD38 and BCMA, or the emerging targets GPRC5D and FcHR5. BCMA is a key target for multiple agents, including the approved CAR T products idecabtagene vicleucel (Abecma; Bristol Myers Squibb) and ciltacabtagene autoleucel (Carvykti; Janssen Biotech, Inc.), which demonstrated success in the CARTITUDE-1 (NCT03548207) and CARTITUDE-4 (NCT04181827) trials evaluating patients with advanced, heavily pretreated MM. Additionally, the BsAbs teclistamab (Tecvayli; Janssen Biotech, Inc.) and elranatamab (Elrexfio; Pfizer) have shown significant capabilities in improving PFS (12.5 to 17 months) and response rates (60% to 70%) in the MajesTEC (NCT04557098, NCT05552222) and MAGNETISMM (NCT03269136, NCT04798586, NCT04649359, NCT05014412) trials, respectively.^2-7

Another approved BsAb is talquetamab (Talvey; Janssen Pharmaceuticals), which targets GPRC5D, a protein highly overexpressed in approximately 90% of patients with MM. Multiple CAR T and BsAb GPRC5D-targeting agents are in development, exhibiting promising response rates ranging from 70% to 100%. However, researchers are concerned with the durability of these responses, as shown by a PFS of only 35% at 10 months in CAR T-cell GPRC5D agents.

There are numerous unmet needs and toxicities associated with immunotherapies that require continued research to ensure optimal efficacy and safety. BsAbs and CAR T-cell therapies are associated with toxicity challenges and adverse effects (AEs) that can have serious health implications for patients, especially those with a heavy disease burden. Cytokine release syndrome (CRS), neutropenia, and an increased risk of infections are among the most common complications, along with instances of nail and skin toxicities, which are observed in GPRC5D-targeting agents such as talquetamab. Despite the success of combination treatments, they appear to be associated with a further increased risk of AEs.

"I think the bigger concern with these BCMA combinations is the neutropenia and infection signal," said Ajai Chari, MD, PhD, director of myeloma and professor of Clinical Medicine at the University of California, San Francisco. "For example, when you combine teclistamab, daratumumab [Darzalex; Janssen Biotech, Inc.], and lenalidomide [Revlimid; Bristol Myers Squibb], the rate of grade 3 or higher for neutropenia is 74% [and] 13% for febrile neutropenia."

Several factors can impact the success of immunotherapies in addition to toxicities, including high tumor burden, prior treatment lines resulting in antigen loss, T-cell fitness and exhaustion, and the presence of mutations. Each of these compromises treatment outcomes and can contribute to the development of treatment resistance to BsAbs and CAR T-cell therapies.

MM is an incurable, progressive disease in which outcomes typically worsen with each successive line of therapy. Resistance continues to be a significant obstacle for patients and researchers, especially those who have endured multiple lines of treatment with poor outcomes. The underlying mechanisms of resistance can be linked to the complexity of the tumor microenvironment (TME), tumor location, the presence of mutations, existing patient comorbidities, and exposure to prior lines of therapy, which lead to antigen loss and T-cell exhaustion.

T-cell exhaustion is a physiological process and regulatory mechanism that limits excessive T-cell responses, which can cause damage to surrounding cells and tissues, and it is a major cause of failure for even the most promising therapies. Research shows that T-cell exhaustion plays a role in the progression of MM from monoclonal gammopathy of undetermined significance to smoldering MM, indicating a potential association between T-cell dysfunction and disease progression. Characteristics of exhausted T-cells include reduced proliferative capacity, metabolic fitness, and decreased cytokine production.

"Data shows that CAR T cells with high expression of exhaustion markers are associated with lower rates of complete remission and shorter duration of response," said Hermann Einsele MD, FRCP, clinic director at Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Germany.

Einsele discussed various opportunities for overcoming T-cell exhaustion to decrease the risk of incomplete remission or therapy resistance. In a CRS mouse model performed by his team, they found that dasatinib (Sprycel; Bristol Myers Squibb), a tyrosine kinase inhibitor, could downregulate pro-inflammatory cytokines, prevent CRS-induced death, and reduce the expression of T-bet and TOX, markers of T-cell exhaustion. Another potential therapeutic aid he highlighted was harnessing the capabilities of the gut microbiome to influence T-cell fitness.

"Now we can also learn from microbes, because we know that modulation of the gastrointestinal microbiome has a major impact on CAR T-cell function," Einsele explained. "These microbes also produce metabolites, and we have been studying these metabolites that can actually be used to improve the metabolic fitness of CAR T-cells, reduce CAR T-cell dysfunction, and improve anti-tumor activity."

Another method of overcoming T-cell exhaustion discussed was the development of T-cell receptor-like antibodies capable of targeting intracellular proteins beyond the cell surface, including mutated or abnormally expressed proteins. This expands the pool of available targets beyond the cell surface, which may help overcome antigen escape and loss of target expression by avoiding continuous engagement of a single target, leading to T-cell exhaustion.

"So instead of making a traditional CAR like we do here, what one can do is make a CAR that is targeting a protein not present on the myeloma cell, like fluorescein," said Nikhil Munshi, MD, Kraft family chair, director of Basic and Correlative Science, and professor of Medicine at the Dana-Farber Cancer Institute, Harvard Medical School. "Then we can inject a myeloma-specific antibody like daratumumab or isatuximab [Sarclisa; Sanofi] tagged with fluorescein, which will then lead to the binding of the CAR to fluorescein on the antibody."

Munshi also discussed the potential of small molecule-activated receptors instead of a traditional CAR design. The CAR T-cells would be manufactured to express a receptor that can be activated by a small molecule, allowing for in vivo modulation of the CAR T-cell function without the need for genetic modifications. In a group study, they engineered CAR T-cells to express IL-7 receptor alpha chain, which can be activated by a small molecule. The results showed that activating the small molecule-inducible receptor on the T-cells led to a significant increase in memory T-cell populations.

Even with solutions to overcome T-cell exhaustion, mitigate toxicities, and avoid treatment resistance, challenges still remain that compromise the efficacy of BsAbs and CAR T-cell therapies. The largest obstacle can be simplified to the inability of these treatments to effectively destroy all or enough MM cells to avoid disease recurrence. This is due to the aforementioned interferences, such as the complexity of the TME, tumor location, or the presence of mutations, which contribute to the persistence of MM.

"Post-CAR T-cell, [my lymphoma colleagues] see anywhere between 40% and 50% of patients who are cured of the disease," said Munshi. "What we see in myeloma is not there and still continues to go down. Maybe after waiting for long enough, there might be a tail to the curve, but currently, there's a clear difference. And that's our challenge, that we are not yet curing myeloma, despite this treatment being incredibly effective."

Although the efficacy of these therapies is evident, the management of toxicities remains an important challenge that requires careful patient selection and optimization of supportive care measures. Health care professionals must consider numerous factors when selecting patients for specific therapies, taking factors such as cost, availability, patient preference, and disease characteristics into account. The continued development of combination therapies aims to not only improve their safety and efficacy but also increase their availability and affordability. The introduction of combination treatments, allogeneic CAR T-cells, and potentially academic CAR T-cells offers opportunities for enhanced treatments at more affordable price points.

The transformative impact of immunotherapies on the treatment of MM is undeniable; however, as these therapies advance, barriers persist. The statistically significant response rates and extended survival times are challenged by the realities of resistance, toxicities, and the complexities of T-cell exhaustion. As targeted treatments evolve, there remains a need for continued innovation to address these limitations and refine approaches that extend survival and improve quality of life. With deeper understandings of the tumor microenvironment, mechanisms of resistance, and the integration of novel strategies, there are increasing opportunities to pave the path toward a cure.

REFERENCES

1. Einsele H, Neri P, Donk N, et al. Immunotherapy. International Myeloma Society 21 Annual Meeting. September 27, 2024. Rio de Janeiro, Brazil.

2. A study of jnj-68284528, a chimeric antigen receptor t cell (car-t) therapy directed against b-cell maturation antigen (bcma) in participants with relapsed or refractory multiple myeloma (cartitude-1). ClinicalTrials.gov Identifier: NCT03548207. Updated April 2, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT03548207

3. A study comparing jnj-68284528, a car-t therapy directed against b-cell maturation antigen (bcma), versus pomalidomide, bortezomib and dexamethasone (pvd) or daratumumab, pomalidomide and dexamethasone (dpd) in participants with relapsed and lenalidomide-refractory multiple myeloma (cartitude-4). ClinicalTrials.gov Identifier: NCT04181827. Updated September 19, 2024. Accessed September 27, 2024. https://www.clinicaltrials.gov/study/NCT04181827

4. A study of teclistamab in participants with relapsed or refractory multiple myeloma (majestec-1). ClinicalTrials.gov Identifier: NCT04557098. Updated September 19, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT04557098

5. A study of teclistamab in combination with daratumumab and lenalidomide (tec-dr) and talquetamab in combination with daratumumab and lenalidomide (tal-dr) in participants with newly diagnosed multiple myeloma (majestec-7). ClinicalTrials.gov Identifier: NCT05552222. Updated September 19, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT05552222

6. Pf-06863135 as single agent and in combination with immunomodulatory agents in relapse/​refractory multiple myeloma. ClinicalTrials.gov Identifier: NCT03269136. Updated February 23, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT03269136

7. Magnetismm-2: study of elranatamab (pf-06863135) in japanese participants with multiple myeloma. ClinicalTrials.gov Identifier: NCT04798586. Updated September 27, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT04798586

8. Magnetismm-3: study of elranatamab (pf-06863135) monotherapy in participants with multiple myeloma who are refractory to at least one pi, one imid and one anti-cd38 mab. ClinicalTrials.gov Identifier: NCT04649359. Updated September 23, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT04649359

9. A study to learn about the study medicine (elranatamab) in participants with multiple myeloma that has come back after responding to treatment or has not responded to treatment (magnetismm-9). ClinicalTrials.gov Identifier: NCT05014412. Updated July 30, 2024. Accessed September 27, 2024. https://clinicaltrials.gov/study/NCT05014412