Quadruplet Therapy Significantly Improved Outcomes in Transplant-Ineligible Myeloma

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Myeloma specialist and cellular therapist Dr. Saad Usmani, Chief of the Myeloma Service at MSK

A five-year study has found that adding daratumumab (D) to the current standard-of-care triplet therapy bortezomib, lenalidomide, and dexamethasone (VRd) produced deeper and more durable minimal residual disease (MRD) responses compared to VRd alone in patients with newly diagnosed, transplant-ineligible multiple myeloma.

Myeloma specialist and cellular therapist Dr. Saad Usmani, Chief of the Myeloma Service at MSK, was the lead author of the paper published on February 5, 2025, in Nature Medicine ([1]) that reported final progression-free survival (PFS) results for the international phase 3 CEPHEUS study (NCT03652064).

At a median follow-up of 59 months, 60.9% of patients in the D-VRd group experienced sustained MRD-negativity 10-5 with a complete response or better compared to 39.5% for patients in the VRd group, with an odds ratio of 2.37 (p< 0.0001). (1)

“The deeper responses translated to a significant, 43% lower risk of disease progression or death for patients in the D-VRd group compared to those in the VRd group,” said Dr. Usmani. “The trial results support D-VRd becoming the new standard of care for patients with newly diagnosed transplant ineligible or transplant-deferred multiple myeloma.”

Transplant-Ineligible and Transplant-Deferred Newly Diagnosed Multiple Myeloma

Patients with newly diagnosed multiple myeloma who may experience unacceptable toxicity from high-dose chemotherapy induction followed by autologous stem cell transplantation are considered transplant-ineligible.

There is also a growing rationale for deferring transplantation for an increasing number of select patients with newly diagnosed multiple myeloma, given the availability of several effective treatment regimens that can achieve deep responses with no evidence of MRD. (2)

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How the CEPHEUS Trial Results Build on Previous Advances

Daratumumab is a human immunoglobin G1-kappa monoclonal antibody that targets CD38 expressed on the surface of multiple myeloma tumor cells and other hematopoietic cells. It provides direct antitumor and immunomodulatory activity. (3) (4) (5) (6) (7) (8) (9) Dr. Usmani led the initial studies that led to the approval of daratumumab for patients with relapsed multiple myeloma. (10) (11) (12)

For transplant-ineligible newly diagnosed multiple myeloma, the current standard of care is triplet therapy with either VRd or daratumumab plus lenalidomide and dexamethasone (D-Rd).

Previously, MSK participated in the international phase 3 MAIA trial (NCT02252172) that led to the approval of D-Rd as a standard-of-care treatment option for this patient population. Dr. Usmani was the senior author of the paper published in The New England Journal of Medicine in May 2019 that reported the MAIA trial results. (13)The U.S. Food and Drug Administration (FDA) approved DR-d for newly diagnosed transplant ineligible multiple myeloma in June 2019, (14) and Dr. Usmani and colleagues presented the final survival analysis at the European Hematology Association Congress in July 2024. (15)

“D-Rd demonstrated a significant PFS benefit over Rd and established a new overall survival (OS) benchmark of 7.5 years in the MAIA trial,” said Dr. Usmani. “Adding D to VRd in the CEPHEUS trial was the next logical step to see if it would lead to deeper responses and greater survival benefits.”

Separately, in the phase 3 PERSEUS trial (NCT03710603), D-VRd demonstrated that frontline treatment in transplant-eligible patients significantly improved PFS and increased depth of response versus VRd. (16) The FDA approved D-VRd for this patient population in July 2024. (17)

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CEPHEUS Trial Design

For the CEPHEUS trial, investigators randomly assigned 395 patients with transplant-ineligible newly diagnosed multiple myeloma or for whom transplant was not planned as initial therapy to treatment with eight cycles of D-VRd or VRd followed by D-Rd or Rd until disease progression. The study took place at MSK and more than 110 international sites between December 2018 and October 2019. (1)

The primary endpoint was the MRD-negativity 10-5  rate by next-generation sequencing. Secondary endpoints included a rate of complete response (CR) or better, PFS, and sustained MRD-negativity 10-5. (1)

The median patient age was 70 years. The percentage of patients with International Staging System stage III disease was 28.1%, and 13.2% had high cytogenic risk. In the D-VRd group, 11.7% of patients had an Eastern Cooperative Oncology Group performance status score of 2 versus 7.1% in the VRd group. (1)

The median duration of study treatment was 54 months for the D-VRd group, 22 months longer than 34.3 months for the VRd group. The median number of treatment cycles for the D-VRd cohort was 59, greater than 37 for the VRd cohort. Dose intensities were similar between groups. (1)

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CEPHEUS Study Results

At a median follow-up of 59 months, 60.9% of patients in the D-VRd group experienced MRD negativity 10-5 with a complete response or better. (1)

Disease progression or death occurred in 63 patients (32%) in the D-VRd group versus 91 patients (46%) in the VRd group. Treatment with D-VRd significantly improved PFS compared with VRd, with a hazard ratio of 0.57 (p=0.0005). Median PFS was not reached for D-VRd and was 52.6 months for VRd. The estimated 54-month PFS rates were 68.1% for D-VRd and 49.5% for VRd, respectively. (1)

The CR rate was significantly higher for the D-VRd cohort at 81.2% compared with 61.6% for the VRd cohort, with an odds ratio of 2.73 (p<0.0001). (1)

OS data are immature, and follow-up continues. At the time of reporting trial results, OS was trending in favor of D-VRd versus VRd, with a hazard ratio of 0.85. Note that the COVID-19 pandemic affected OS rates, causing 24 of 111 deaths (21.6%) in total, including 15 patients in the D-VRd group and 9 in the VRd group. Sensitivity analyses that adjusted for the impact of deaths due to COVID-19 showed a more pronounced treatment benefit for D-VRd versus VRd. (1)

In terms of safety, adverse events were consistent with the known safety profiles for all four drugs in the quadruplet therapy. The most common grade 3 or 4 treatment-emergent adverse events (TEAEs) were neutropenia and thrombocytopenia. The incidence of grade 2 peripheral neuropathy was lower in the D-VRd group than the VRd group, and the incidence of grade 3 or 4 peripheral neuropathy was similar between groups. The rate of grade 5 TEAEs was higher in the D-VRd group than the VRd group due to more grade 5 COVID-19 events and nearly two additional years of treatment exposure. The incidence of second primary malignancies was also lower in the D-VRd group. (1)

“Results from CEPHEUS, together with results from PERSEUS, indicate that D-VRd should be the new standard of care for newly diagnosed multiple myeloma, regardless of transplant eligibility,” Dr. Usmani said. “The CEPHEUS results also add further validity to using MRD negativity as an accelerated approval endpoint for predicting PFS outcomes in newly diagnosed multiple myeloma.”

Dr. Usmani recently played a central role in the FDA’s April 2024 decision to accept MRD negativity as an intermediate clinical endpoint for the accelerated approval of new drug regimens and indications in multiple myeloma clinical trials. Read more.

Results for the CEPHEUS clinical trial were presented at the 21st International Myeloma Society Annual Meeting in September 2024. The trial was sponsored by Johnson & Johnson. Access disclosures for Dr. Usmani.

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  1. 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 study. Nature Medicine. February 5, 2025.
  2. Mo CC, Hartley-Brown MA, Midha S, Richardson PG. Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy. Cancers (Basel). 2023;15(24):5709.
  3. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840-1848.
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  6. Overdijk MB, Jansen JH, Nederend M, et al. The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor-Mediated Cross-Linking. J Immunol. 2016;197(3):807-813.
  7. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384-394.
  8. Adams HC 3rd, Stevenaert F, Krejcik J, et al. High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action. Cytometry A. 2019;95(3):279-289.
  9. Casneuf T, Adams HC 3rd, van de Donk NWCJ, et al. Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab. Leukemia. 2021;35(2):573-584.
  10. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37-44.
  11. Usmani SZ, Nahi H, Mateos MV, et al. Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma. Blood. 2019;134(8):668-677.
  12. Mateos MV, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370-e380.
  13. Facon T, Kumar S, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019;380(22):2104-2115.
  14. U.S. Food and Drug Administration. FDA approves daratumuab for multiple myeloma ineligible for autologous stem cell transplant. June 27, 2019. Accessed February 2, 2025 at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-multiple-myeloma-ineligible-autologous-stem-cell-transplant
  15. Facon T, Kumar S, Orlowski RZ, et al. Final survival analysis of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: MAIA study. Abstract P968: European Hematology Association Hybrid Congress 2024.
  16. 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.
  17. U.S. Food and Drug Administration. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. July 30, 2024. Accessed February 2, 2025 at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple
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