Daratumumab Treatment Advancements in Newly Diagnosed Multiple Myeloma

A phase 3 clinical trial, PERSEUS (NCT03710603), published by The New England Journal of Medicine showed benefit in the treatment of patients with newly diagnosed (ND) multiple myeloma (MM) using monoclonal antibody daratumumab (Darzalex; Janssen Biotech, Inc and Genmab A/S) in combination with standard treatments.¹ The study results found that patients who received subcutaneous administration of daratumumab were more likely to have minimal residual disease (MRD), progression-free survival (PFS), and overall better treatment outcomes.

Subcutaneous administration of daratumumab combined with VRd therapy may offer a less invasive, yet highly effective option for patients. Image Credits: © WavebreakMediaMicro - stock.adobe.com

Daratumumab is a monoclonal antibody immunotherapy treatment that targets CD38, a glycoprotein that is overexpressed on the surface of malignant MM cells. When CD38 is highly expressed, it can compromise patient treatment responses as well as enhance the survival and growth of malignant cells. Daratumumab targets and binds to CD38 to trigger multiple mechanisms that encourage the destruction of MM cells, such as increasing cytotoxicity through recruitment of natural killer cells, macrophages, and complement proteins. Furthermore, daratumumab shows capabilities in modulating immune responses to decrease immune suppression, potentially allowing for improved patient responses to treatment.²

The PERSEUS trial investigated daratumumab in combination with bortezomib (Velcade; Millennium/Takeda and Janssen Pharmaceutical Companies), lenalidomide (Revlimid; Bristol-Myers Squibb), and dexamethasone (D-VRd, Decadron; Pfizer CentreOne) to treat patients with NMDD. The primary endpoint of the study was PFS with secondary endpoints including post-consolidation MRD negativity rate, overall response rate, time to response, duration of response, and overall survival.¹

The randomized clinical trial involved 700 people with NDMM who were eligible for stem cell transplantation across 14 countries in Europe and Australia. Patients were randomly assigned to receive standard regimens—induction therapy with VRd, consolidation therapy with VRd, maintenance therapy with lenalidomide, and stem cell transplant—with or without subcutaneous daratumumab. Patients who received daratumumab received it as part of induction, consolidation, and maintenance therapies. The treatment outcomes were measured for a median of approximately 4 years.³

The findings showed that daratumumab in combination with VRd was overall more effective than standard treatments with higher rates of complete response and MRD negativity, with 84% of patients exhibiting PFS at 4 years (hazard ratio = .42; 95% confidence interval, .30 to .59; P<.001). Additionally, the number of patients with a complete response to treatment was greater than the number who did not receive daratumumab (87.9% vs. 70.1%, P<.001), as well as MRD-negativity status (75.2% vs. 47.5%, P<.001).^3,4

Ongoing clinical trials continue to explore the efficacy and success of daratumumab and other immunotherapies for treatment of patients with NDMM. Isatuximab (Sarclisa; Sanofi-aventis), another key monoclonal antibody that targets CD38, was shown to increase PFS and reduce MRD in the phase 3 IMROZ clinical trial (NCT03319667).² Another key study, ADVANCE (NCT04268498) further explores use of daratumumab with a different 3-part combination of carfilzomib (Kyprolis; Amgen, Inc), lenalidomide, and dexamethasone.³

These promising results from the PERSEUS trial underscore the potential of daratumumab in changing treatment for patients with NDMM. As ongoing research continues to expand the use of immunotherapies, daratumumab combined with VRd therapy may offer a less invasive, yet highly effective option for patients, transforming standard of care practices and improving long-term outcomes.

REFERENCES

1. Stichting European Myeloma Network, Janssen Research & Development, LLC. A phase 3 study comparing daratumumab, VELCADE (bortezomib), lenalidomide, and dexamethasone (D-VRd) vs VELCADE, lenalidomide, and dexamethasone (VRd) in subjects with previously untreated multiple myeloma who are eligible for high-dose therapy. Clinicaltrials.gov. September 26, 2022. Accessed May 30, 2024. https://www.clinicaltrials.gov/study/NCT03710603
2. 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
3. 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
4. Sonneveld, P, Dimopoulos, M. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. December 12, 2023. doi:10.1056/NEJMoa2312054