Quadruple Therapies Including Immunotherapy Agents Show Benefit in Multiple Myeloma

Multiple myeloma (MM) is the second most common hematological cancer, and it originates from malignant plasma cells within the bone marrow, leading to overproduction of abnormal cells that cause suppressed immune function, brittle bones, and organ dysfunction. Standard-of-care practice for the treatment of MM traditionally includes chemotherapy followed by autologous stem cell transplantation (ASCT). However, continued research into MM therapy has discovered the potential for utilizing quadruple therapies, a 4-part drug combination treatment that includes a CD38 immunotherapy agent, according to C. Ola Landgren, MD, PhD, based on research presented at the 2024 American Society of Clinical Oncology Annual Meeting.

The promising outcomes observed with CD38-targeted immunotherapies show the potential of quadruple therapy in reshaping the treatment landscape for MM. Image Credit: © k_e_n - stock.adobe.com

The treatment landscape for MM is constantly changing, prompting researchers to explore efficacy of double, triple, and quadruple therapies, providing patients with MM with a more dynamic treatment approach. Quadruple therapy involves the addition of a CD38-targeted antibody to the foundation of small molecule drugs, which typically consists of a proteasome inhibitor, an immunomodulatory drug, and a steroid.¹ CD38 is a transmembrane glycoprotein responsible for enzyme activity on the surface of cells and is highly expressed in malignant cells. Increased expression of CD38 is associated with immune suppression, therapy resistance, and the growth and survival of malignant cells.²

Monoclonal antibodies, such as isatuximab (Sarclisa; Sanofi-aventis) and daratumumab (Darzalex; Janssen Biotech, Inc and Genmab A/S), are immunotherapies that bind to CD38 to help the immune system better target and attack malignant cells. These treatments enhance cytotoxicity of malignant cells, activate natural killer cells, and increase phagocytic activity of monoctyes, as well as modulate the tumor microenvironment to make cancer cells more susceptible to immune system attacks.^3,4

Multiple studies have shown the success of these immunotherapy treatments for patients with MM, newly diagnosed (ND) MM (NDMM), and relapsed or refractory MM. In phase 3 of the PERSEUS (NCT03710603) randomized clinical trial for NDMM, findings showed that patients treated with daratumumab had high levels of progression-free survival, with 84% of those who received daratumumab plus standard treatment free of cancer progression after 4 years. Additionally, daratumumab-treated patients were more likely to achieve minimal residual disease (MRD) negativity after treatment.^5,6

The promising outcomes observed with CD38-targeted immunotherapies show the potential of quadruple therapy in reshaping the treatment landscape for MM. For instance, the adoption of quadruple therapies may reduce the need for procedures such as ASCT or bone marrow transplants, which typically entail high-dose chemotherapy regimens. Furthermore, quadruple therapies can also detect MRD negativity early on, allowing for more accurate assessment of patient response to treatment.¹

Future studies aim to further research use of isatuximab and daratumumab in treatment of patients with MM, while also evaluating newer bispecific monoclonal antibody immunotherapies, which target cell surface proteins such as BCMA, GPRC5D, and FcRH5.¹

“This is where the field is right now,” Landgren said in an interview with Pharmacy Times. “The future is looking bright for patients with [MM].”

REFERENCES

1. Quadruple therapies and the future of multiple myeloma treatment. EurekAlert!. May 23, 2024. Accessed May 28, 2024. https://www.eurekalert.org/news-releases/1045887

2. Gozzetti A, Ciofini S, Simoncelli M, et al. Anti CD38 monoclonal antibodies for multiple myeloma treatment. Hum Vaccin Immunother. 2022;18(5):2052658. doi:10.1080/21645515.2022.2052658

3. FDA accepts isatuximab for priority review for treatment of transplant-ineligible multiple myeloma. Pharmacy Times. May 28, 2024. Accessed May 28, 2024. https://www.pharmacytimes.com/view/fda-accepts-isatuximab-for-priority-review-for-treatment-of-transplant-ineligible-multiple-myeloma

4. Maura F, Boyle EM, Coffey D, et al. Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens. Nat Cancer. 2023;4(12):1660-1674. doi:10.1038/s43018-023-00657-1

5. Trial results support adding daratumumab to initial treatment for multiple myeloma. National Cancer Institute. January 19, 2024. Accessed May 28, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2024/multiple-myeloma-darzalex-plus-vrd

6. Pieter Sonneveld, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. The New England Journal of Medicine. December 12, 2023. doi:https://doi.org/10.1056/nejmoa2312054