Immunotherapies Show Promise in Transforming Early Multiple Myeloma Treatment

Almost a decade ago, the first indications for daratumumab (Darzalex; Janssen Biotech, Inc], a novel monoclonal antibody for treatment approved for multiple myeloma (MM), were rolled out by the FDA. Through the introduction of immunotherapies, the treatment landscape of MM was significantly changed. At the International Myeloma Society (IMS) 21st Annual Meeting in Rio de Janeiro, Brazil, multiple experts highlighted the evolution of immunotherapies such as bispecific and monoclonal antibodies, as well as chimeric antigen receptor (CAR) T-cell therapy, and their enhanced benefit in earlier lines of treatment.¹

Immunotherapies and targeted treatments have become the cornerstone of therapeutic approaches, greatly enhancing the longevity and quality of life for patients with MM. Image Credit: © Pavithiran - stock.adobe.com

The advanced understanding of the crucial role of the tumor microenvironment and immune cells in disease progression of MM. The identification of CD38, a highly expressed protein on the surface of malignant cells, was a crucial advancement in the development of targeted treatments. Daratumumab and isatuximab (Sarclisa; Sanofi) are monoclonal antibodies that target and bind to CD38 proteins that demonstrate significant improvements in minimal residual disease (MRD) negativity and progression-free survival. Results from multiple trials, namely the IMROZ (NCT03319667) and PERSEUS (NCT03710603), led to their approval as quadruple therapies with bortezomib (Velcade; Takeda Pharmaceuticals), lenalidomide (Revlimid; Bristol Myers Squibb), and dexamethasone (VRd).^2,3

Jayr Schmidt, MD, head of the Hematology and Cell Therapy department at A.C.Camargo Cancer Center, Brazil, highlighted the significant results of the PERSEUS, MAIA (NCT02252172), IMROZ, and CEPHEUS (NCT03652064) trials evaluating treatment with daratumumab plus VRd (D-VRd); daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone; and D-VRd versus VRd, respectively. The MRD negativity data from these trials were notable, demonstrating significant improvements in patients with previously untreated MM.^4,5

In a discussion of monoclonal antibody daratumumab, Schmidt referenced data from the multicenter, open-label, randomized phase 3 CEPHEUS trial presented at the meeting. According to the study, the primary end point showed a benefit of around 60% improvement in MRD negativity for D-VRd arm versus 39% in the VRd arm. Similar results were observed in the PERSEUS trial. In the D-VRd arm, 75% of patients achieved MRD-negativity compared with 47.5% with VRd alone. The trial is notable for its PFS results indicating that 84.3% of patients in the D-VRd arm were progression-free at 48 months.⁶

“The PERSEUS trial, which combined daratumumab with VRD followed by daratumumab maintenance, the quads compared to a triplet as a phase 3 trial,” said Schmidt. “And then we saw that it showed benefit in the primary end point for [PFS]. It also showed some very interesting data about MRD negativity and some very interesting results in the high-risk population.”

The observed success of quadruple treatments in early treatment lines prior to stem cell transplantation shows great promise; however, challenges such as high-risk cytogenetics and extramedullary disease remain in the front line and are associated with lower response and survival rates, especially for relapsed or refractory patients. This led to the development of bispecific antibodies teclistamab (Tecvayli; Janssen Biotech, Inc) targeting BCMA and talquetamab (Taley; Janssen Biotech, Inc) targeting GPRC5D for patients with poor treatment response or relapsing.

Teclistamab is a T-cell redirecting bispecific antibody that targets CD3 and BCMA antigens on the surface of MM cells. Its success in the relapsed/refractory setting has been observed in the series of MAJESTIC trials where it demonstrated deep, durable remissions and improved PFS, namely in the MAJESTIC-1 study (NCT04557098). Of the 165 enrolled participants with relapsed/refractory MM (77.6% with triple-class refractory disease), there was an overall response rate of 63% with an MRD-negativity rate of 46% in those who achieved a complete response or better.⁷

Talquetamab, like teclistamab, also targets CD3 antigens; however, instead of BCMA, it redirects T-cells to mediate destruction of GPRC5D-expressing cells. In the MonumenTAL trials, its success is seen as a standalone therapy, with increasing improvements when used as a combination treatment. In the ongoing MonumenTAL-3 trial (NCT05455320), researchers are evaluating use of talquetamab with daratumumab and pomalidomide (Pomalyst; Bristol Myers Squibb) and initial findings show positive responses in heavily pretreated patients.⁸

However, bispecific antibodies are strongly associated with numerous adverse effects (AEs), the most common being cytokine release syndrome (CRS) and neutropenia. There is also the additional challenge of increased risk of infections. Cesar Rodriguez, MD, associate professor at Icahn School of Medicine at Mount Sinai, discussed mitigating these AEs through spacing out therapy once patients have achieved remission or partial response. By spacing out the doses rather than reducing them, health care professionals have observed improvements with the taste changes and nail and skin toxicities associated with talquetamab treatment.

“Infection rates is cumulative as long and increases to up to 70% as long as the patient main stays on therapy,” he said. “So, ways of mitigating the risk of infections and infections that don't require hospitalization, has been spacing of the therapy once they've achieved the desired response. With a subset group of patients having spaced out the therapy from weekly dosing to every other weak dosing, they've had achieved a remission or a partial response, and we see that the incidence of infections decreases.”

Beyond monoclonal antibodies and bispecifics, the development of CAR T-cell therapy has further advanced the MM treatment landscape. By manufacturing a patient’s T-cells and equipping them with targeted antigens, treatments can be more accurately and effectively tailored to the individual’s unique disease characteristics. For patients with triple-class refractory disease who have failed multiple prior lines of treatment, CAR T shows promise in clinical trial settings with lower CRS rates and reduced toxicities.

Susan Bal, MD, assistant professor of medicine at University of Alabama at Birmingham, cited the KarMMA-2 trial (NCT03601078) evaluating use of idecabtagene vicleucel (ide-cel), a BCMA-directed CAR T-cell therapy, in patients who underwent 3 or more lines of prior treatment.⁹

“What we saw is that in this study, the overall response rate (ORR) in about 128 triple class refractory patients constitute a high number of patients, and we see a response rate of 72% for the general population. Median overall survival [OS] was anywhere between 8.8 to 11.1 months, and those patients who had deeper responses tended to do better,” she explained.

Ciltacabtagene autoleucel (cilta-cel) is another available CAR T-cell product that targets BCMA and is effective in heavily pretreated patients, demonstrating clinically meaningful benefits in PFS, OS, and ORR. Compared with ide-cel, cilta-cel is associated with enhanced clinical benefit and deeper response.

Despite its success, CAR T-cell therapy comes with its own host of challenges outside of potential toxicities. The manufacturing of CAR T-cells can be a lengthy process, making it difficult for some patients to receive timely treatment. Additionally, it is not easily accessible for patients in rural areas with little access to advanced, specialized medical centers. CAR T, due to lack of availability and clinical research, is usually reserved for later lines of treatment after use of other agents. However, there is growing discussion about the benefit of using CAR T, as well as immunotherapies, in early lines, particularly for high-risk patients with worse disease.

The discussion surrounding bringing these therapies to earlier lines is controversial with health care professionals citing issues with lack of substantial research into use of these agents in untreated patients, as well as availability concerns when opening these treatments up to populations across disease stages. Immunotherapies and targeted treatments have become the cornerstone of therapeutic approaches, greatly enhancing the longevity and quality of life for patients with MM. However, continued research is needed to determine the risk-benefit of these therapies for patients with newly diagnosed, untreated MM.

REFERENCES

1. Rodriguez C, Schmidt J, Bal S, et al. Industry symposium supported by janssen: moving t cell directed therapies to earlier lines. International Myeloma Society 21 Annual Meeting. September 26, 2024. Rio de Janeiro, Brazil

2. Clinical benefit of sar650984, bortezomib, lenalidomide and dexamethasone combination in ndmm patients not eligible for transplant (imroz). ClinicalTrials.gov Identifier: NCT03319667. Updated April 8, 2024. Accessed September 20, 2024. https://clinicaltrials.gov/study/NCT03319667

3. ClinicalTrials.gov. A study of amg 510 (sotorasib) in combination with panitumumab, with and without chemotherapy, in subjects with advanced solid tumors with kras g12c mutation. ClinicalTrials.gov Identifier: NCT03710603. Updated April 26, 2023. Accessed July 30, 2024. https://clinicaltrials.gov/ct2/show/NCT03710603

4. Study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in participants with previously untreated multiple myeloma. ClinicalTrials.gov Identifier: NCT02252172. Updated September 19, 2024. Accessed September 26, 2024. https://clinicaltrials.gov/study/NCT02252172

5. A study comparing daratumumab, velcade (bortezomib), lenalidomide, and dexamethasone (d-vrd) with velcade, lenalidomide, and dexamethasone (vrd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. ClinicalTrials.gov Identifier: NCT03652064. Updated September 19, 2024. Accessed September 26, 2024. https://clinicaltrials.gov/study/NCT03652064

6. Sonneveld P, Dimopoulos M, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. December 12, 2023. doi: 10.1056/NEJMoa231205

7. A study of teclistamab in participants with relapsed or refractory multiple myeloma (majestec-1). ClinicalTrials.gov Identifier: NCT04557098. Updated September 19, 2024. Accessed September 26, 2024. https://clinicaltrials.gov/study/NCT04557098

8. A study comparing talquetamab in combination with daratumumab or in combination with daratumumab and pomalidomide versus daratumumab in combination with pomalidomide and dexamethasone in participants with multiple myeloma that returns after treatment or is resistant to treatment (monumental-3). ClinicalTrials.gov Identifier: NCT05455320. Updated September 19, 2024. Accessed September 26, 2024. https://clinicaltrials.gov/study/NCT05455320

9. An efficacy and safety study of bb2121 in subjects with relapsed and refractory multiple myeloma and in subjects with high-risk multiple myeloma (karmma-2). ClinicalTrials.gov Identifier: NCT03601078. Updated February 9, 2024. Accessed September 26, 2024. https://clinicaltrials.gov/study/NCT03601078