The FDA approval of another quadruplet-based therapy will help clinicians further tailor frontline therapy for patients with newly diagnosed, transplant-ineligible multiple myeloma, with patient and disease factors guiding treatment decisions to balance efficacy and quality of life, according to Marc J. Braunstein, MD, PhD.
On January 27, 2026, the FDA approved daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).1
SC Daratumumab Plus VRd in Newly Diagnosed, ASCT-Ineligible Myeloma
- The FDA approved subcutaneous daratumumab plus VRd for patients with newly diagnosed multiple myeloma who are ineligible for ASCT.
- Data were supported by findings from the phase 3 CEPHEUS trial, which showed a statistically significant improvement in MRD-negativity rate with daratumumab plus VRd vs VRd alone.
- With multiple approved regimens in the frontline, ASCT-ineligible setting, treatment selection should be guided by patient fitness and disease characteristics.
The regulatory decision was supported by data from the phase 3 CEPHEUS trial (NCT03652064), which showed that patients treated with subcutaneous daratumumab plus VRd (n = 197) experienced a minimal residual disease (MRD)–negativity rate of 52.3% compared with 34.8% for those given VRd alone (n = 198; P = .0005). A statistically significant improvement in progression-free survival (PFS) was also observed with the quadruplet (HR, 0.60; 95% CI, 0.41-0.88; P = .0078).
“[Treatment selection] comes down to tailoring the various options we have to patients' various features. For an older patient, you can get a very meaningful PFS benefit while sustaining a good quality of life during that time with either [a triplet or quadruplet],” Braunstein said. “However, with quadruplet-based regimens that include a monoclonal antibody, the PFS is superior.”
In an interview with OncLive®, Braunstein outlined the clinical implications of the FDA approval of subcutaneous daratumumab plus VRd for patients with newly diagnosed, transplant-ineligible multiple myeloma; detailed the efficacy and safety data for this regimen; discussed patient and disease factors that can influence treatment selection for this patient population; and looked ahead to other novel therapies and combinations that could impact frontline therapy in the future.
Braunstein is an associate professor in the Department of Medicine at NYU Grossman Long Island School of Medicine, director of the Fellowship Program, Hematology/Oncology, at NYU Langone Health - Long Island, and course co-director of the Hematology-Oncology System at NYU Grossman Long Island School of Medicine.
OncLive: What are the clinical implications of the FDA approval of subcutaneous daratumumab plus VRd for patients with newly diagnosed multiple myeloma who are not eligible for ASCT? What data supported this decision?
Braunstein: Multiple myeloma treatment continues to evolve, and the guidelines continue to segregate patients according to their eligibility for transplant, although the recommended guidelines for those 2 groups are increasingly converging on common approaches. The data [subcutaneous daratumumab plus VRd in] patients who are transplant eligible comes from the [phase 3] PERSEUS study [NCT03710603],2 which showed improvement of PFS with the daratumumab quadruplet. There's also data for isatuximab-irfc [Sarclisa]–based quadruplets, as well.
We were involved in a phase 3 CEPHEUS study that looked at transplant-ineligible patients, or those who were willing to defer up-front ASCT. This study had a primary endpoint of MRD negativity at a 10-5 [sensitivity]. [Data] showed that at a median follow-up of [58.7] months, the MRD-negativity rate was superior with daratumumab plus VRd vs VRD alone, with rates of 60.9% [in the experimental group] vs 39.4% in the control group.3 That was significant.
The data between the transplant-eligible and -ineligible groups are both support the efficacy of anti-CD38 quadruplet regimens in newly diagnosed multiple myeloma. The CEPHEUS study was done during the peaks of the COVID-19 pandemic, so there were increased rates of COVID-19 and pneumonia. However, the latest version of the National Comprehensive Cancer Network Guidelines recommend the quadruplet regimens for transplant-ineligible patients with multiple myeloma as category 1 [recommendations] for those who are less than 80 years of age and are not frail.4 That's generally my approach, as well, for those patients who are not frail and can tolerate an anti-CD38–based quadruplet.
Based on data from CEPHEUS and clinical experience utilizing subcutaneous daratumumab plus VRd in the transplant-eligible setting, what is the safety profile of this regimen?
We know that as we add more agents into the mix, patients are going to have a greater risk of bone marrow suppression. We're dealing with a population that is typically on the older side [in terms of] the median age of diagnosis for multiple myeloma. Therefore, [these patients] may have less [bone marrow] reserve to bounce back from suppression or from infections that can result from neutropenia.
With all our patients with multiple myeloma, we have to tailor our treatments to our assessment of their fitness and to their preferences, as well. We have multiple myeloma frailty scores that can be used in real-world practice and can help gauge how fit a patient is in a quantitative way. There is a real risk of increased infections and bone marrow suppression [with daratumumab plus VRd]. However, these are very manageable and are adverse effects [AEs] that we're accustomed to dealing with in the multiple myeloma field. [Selecting a quadruplet regimen] comes down really to assessing how fit your individual patient is and whether you think they'll be able to tolerate the regimen.
Isatuximab plus VRd is another approved frontline quadruplet in the newly diagnosed, transplant-ineligible setting.5 With 2 quadruplets now approved for this patient population, what factors can help inform therapy selection for those deemed appropriate for a quadruplet or a lower-intensity option?
Our precision medicine approach in multiple myeloma is to assess the pathologic features of the myeloma in the individual patient, including features such as their frailty and comorbidities, and to assess the potential AEs of our various treatment options. There are various options to treat newly diagnosed multiple myeloma, including a monoclonal antibody–based triplet regimens, as well. For example, the [phase 3] MAIA trial [NCT02252172], which looked at daratumumab plus Rd vs Rd [alone], showed a survival advantage [with the triplet].
With quadruplets now representing a standard of care in the frontline space, what is the next step needed to integrate novel strategies or agents into the newly diagnosed setting?
The ecosystem of novel immunomodulatory approaches for multiple myeloma is expanding, and that includes T-cell–redirecting therapies, such as CAR T-cell therapy and bispecific antibodies. With the bispecific antibodies, the landscape is increasing now, too. We have [bispecific antibodies] targeting BCMA being explored in the frontline setting. There were data presented at the 2025 ASH Annual Meeting and Exposition of using single-agent linvoseltamab-gcpt [Lynozyfic], for example, as induction for patients with newly diagnosed myeloma.6 There are also ongoing studies, looking at CAR T-cell therapy up-front compared with ASCT.
It's very clear that CAR T cells and bispecific antibodies work extremely well in multiple myeloma. They modify the tumor microenvironment and increase T-cell fitness for targeting the myeloid plasma cells. Clearly, there seems to be emerging data that they work better before T-cell exhaustion [occurs] in earlier lines of treatment.
We had data presented at ASH 2025 on the [phase 3] MajesTEC-3 trial [NCT05083169] that showed that combining teclistamab-cqyv (Tecvayli) with subcutaneous daratumumab in the second-line setting and beyond produced very high response rates compared with daratumumab-based triplets.7
[Things are trending] that we'll be using bispecific antibodies and CAR T cells earlier right now. [NYU Langone Health] is involved in the [phase 3] MajesTEC-7 trial [NCT05552222], which is looking at teclistamab or talquetamab-tgvs [Talvey] combined with daratumumab and lenalidomide for [patients with] newly diagnosed, transplant-ineligible multiple myeloma. Just given the incredible efficacy of these T-cell–redirecting therapies in earlier lines of therapy, I think this will become the new standard. Our current approach is using immunomodulatory drugs or proteasome inhibitors will probably be used in later lines of therapy.
References
- FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. January 27, 2026. Accessed January 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-newly
- Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054
- Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7
- NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 5.2026. Updated January 9, 2026. Accessed January 30, 2026. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
- FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed September 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple
- Orlowski R, Shah M, Chakraborty R, et al. Safety and efficacy of linvoseltamab as a simplified monotherapy first-line regimen in NDMM: Initial Results from the window of opportunity Phase 1/2 LINKER-MM4 trial. Blood. 2025;146(suppl 1):697. doi:10.1182/blood-2025-697
- Mateos M-V, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or Bortezomib (DPd/DVd) in patients (Pts) with relapsed refractory multiple myeloma (RRMM): Results of majestec-3. Blood. 2025;146(suppl 2): LBA-6. doi:10.1182/blood-2025-LBA-6
