Commentary

Article

D-VRd Propels Toward SOC Status in Transplant-Ineligible, Newly Diagnosed Multiple Myeloma

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Saad Z. Usmani, MD, MBA, FACP, FASCO, expands on data from the CEPHEUS trial of D-VRd in transplant-ineligible/-deferred, newly diagnosed multiple myeloma.

Saad Z. Usmani, MD, MBA, FACP, FASCO

Saad Z. Usmani, MD, MBA, FACP, FASCO

Deep responses and sustained minimal residual disease (MRD)–negativity rates achieved with the addition of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) to standard bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd; D-VRd) indicate the regimen’s efficacy for transplant-eligible patients with newly diagnosed multiple myeloma, as well as for patients who are either ineligible for or have deferred autologous stem cell transplant, according to Saad Z. Usmani, MD, MBA, FACP, FASCO.1

As reported during the 21st International Myeloma Society (IMS) Annual Meeting, the phase 3 CEPHEUS trial (NCT03652064) met its primary end point of improved MRD-negativity rates at a sensitivity level of 10–5 among patients treated with D-VRd (n = 197) vs VRd alone (n = 198), at 60.9% vs 39.4%, respectively (odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P < .0001). Moreover, the rate of complete response (CR) or better rate with D-VRd was 81.2% compared with 61.6% in the VRd arm (OR, 2.73; 95% CI, 1.71-4.34; P < .0001). Notably, 48.7% of patients achieved sustained MRD negativity with D-VRd vs 26.3% of those who received VRd alone (OR, 2.63; 95% CI, 1.73-4.00; P < .0001).

These data supported the submission of a supplemental biologics license application to the FDA on September 30, 2024, seeking the approval of D-VRd for this patient population. If approved, D-VRd would represent the first therapy in newly diagnosed multiple myeloma to gain FDA approval from a study using MRD-negativity rate as the primary end point.2

“Although [the OS data are] still immature, they complement what we found in the [phase 3] MAIA study [NCT02252172] with daratumumab plus lenalidomide and dexamethasone [D-Rd]. Both trials support the use of either a daratumumab-based quadruplet or triplet as the standard of care [SOC] for patients who are transplant-ineligible or who deferred [transplant],” said Usmani, who serves as chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York.

In an interview with OncLive®, Usmani highlighted key efficacy and safety data from the CEPHEUS trial; contextualized this investigation of D-RVd among other trials evaluating daratumumab-based quadruplets and triplets in myeloma; and discusses the potential role for this regimen in the newly diagnosed myeloma treatment paradigm.

OncLive: What was the rationale for evaluating the addition of daratumumab to VRd in the CEPHEUS trial?

Usmani: The CEPHEUS trial is a randomized phase 3 study in transplant-ineligible or transplant-deferred patients. Subcutaneous daratumumab plus VRD was approved [by the FDA in July 2024] for the transplant-eligible patient population in the newly diagnosed setting based on data from the [phase 3] PERSEUS trial [NCT03710603]. The CEPHEUS trial is [being conducted in] a different patient population and builds on the inclusion of daratumumab in frontline treatments.

Previously, results [from the final analysis of] the MAIA trial showed that D-Rd was the preferred regimen in that patient population, with a median OS of 7.5 years. We also have used VRd for this patient population, so triplets are being used in the transplant-ineligible setting. [Overall, CEPHEUS] was a build-up to see whether daratumumab plus VRd would improve the depth of response and progression-free survival [PFS] for patients [in the transplant-ineligible/deferred setting.]

What should be known about the design and methodology of CEPHEUS?

Patients had to have newly diagnosed [disease and be] either transplant-ineligible or -deferred. Their ECOG performance status had to be [between] 0 and 2. Their frailty score by International Myeloma Working Group [IMWG] criteria had to be 0 or 1. A total of 395 patients were randomly assigned 1:1 to [either the SOC or D-VRd arm.] The SOC arm received VRd for 8 cycles as part of an induction regimen, [followed by] Rd as maintenance. The [experimental regimen] added subcutaneous daratumumab to the 8 cycles of induction VRd as well as the Rd maintenance regimen. The primary end point of the trial was overall MRD negativity, with key secondary end points being PFS, sustained MRD negativity, rate of CR or better, and overall survival [OS].

The study population was a median of 70.0 years of age. In total, 62.9% and 66.7% of the patients [in the D-VRd and VRd arms, respectively, were classified] as fit [according to] IMWG frailty criteria, and the rest of the patients were [classified as] intermediate fit. According to the International Staging System, 28.4% [and 27.8%] of the [D-VRd and VRd] patient populations [had stage III disease]. [Furthermore, 12.7% and 13.6%] of the [D-VRd and VRd] patient populations [had high-risk cytogenetics].

What efficacy data were presented at IMS?

The primary end point for the trial was met. The overall MRD-negativity rate at a 10–5 sensitivity was 60.9% in the D-VRd arm compared with 39.4% in the VRd arm. The rate of CR or better was again statistically significant with D-VRd, at 81.2% vs 61.6% [with VRd]. Notably, 48.7% of patients achieved sustained MRD negativity with D-VRd vs 26.3% of those who received VRd. The MRD-negativity rate at a sensitivity of 10–6 was also superior in the D-VRd arm [vs the VRd arm], at 46.2% vs 27.3%, respectively.

The median PFS, after a median follow-up of 58.7 months, had not been reached in the D-VRd arm. In the VRd arm, the median PFS was 52.6 months. The 54-month PFS rates [were] 68.1% in the D-VRd arm compared with 49.5% [in the VRd arm], with a HR of 0.57.

What was the regimen’s overall safety profile in the trial?

Hematologic adverse effects [AEs] are commonly seen in myeloma across the board. Numerically, [the rates of these AEs were] higher in the D-VRd arm [vs the VRd arm]. Upper respiratory tract infection rates were overall numerically higher [in the D-VRd arm vs the VRd arm], at 39.6% vs 32.8%. [The rate of] COVID-19 infections was higher [with D-VRd vs VRd], at 38.1% compared with 24.6%, respectively, but the [incidence of] second primary malignancies was numerically lower [with D-VRd vs VRd], at 7.6% vs 9.2%, respectively.

Importantly, the sensory neuropathy rates were similar between the 2 study arms, at 55.8% in the D-VRd arm compared with 61.0% in the VRd arm. The [experimental arm of the] study had a long treatment exposure, so the median duration of treatment in the D-VRd arm was 56.3 months compared with 34.3 months in the VRd arm. That is a median of 22 months more of treatment in D-VRd arm.

[The rates of] grade 3/4 treatment-emergent AEs [TEAEs] were 92.4% vs 85.6% [with D-VRd vs VRd, respectively]. [The rates of] grade 5 AEs, when adjusted for treatment exposure, were comparable across the 2 arms. Grade 5 non–COVID-19 TEAEs were [reported in] 10.7% vs 7.7% [of patients in these respective arms.] Lastly, quality of life [QOL] improved across both arms of the study in a similar fashion, showing that there was no change or detriment [in QOL] due to daratumumab being added to VRd.

What are the key takeaways from this research?

Subcutaneous daratumumab added to VRd generated an excellent depth of response that was statistically significant and superior to VRd alone. D-VRd also improved PFS, and the OS data appear to be trending in favor of D-VRd.

The CEPHEUS trial primarily [enrolled] transplant-ineligible patients who were fit or intermediate-fit, so perhaps that’s how oncologists can distinguish which regimen to use for [a given] patient. Investigators [will continue] to evaluate prespecified patient subsets, MRD negativity, [sustained responses] at the 10–6 [sensitivity] level, and how best to analyze the patient subsets of interest, such as patients with extramedullary disease, as well as those with high-risk cytogenetic abnormalities.

References

  1. Usmani SZ, Facon T, Hungaria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-63.
  2. Johnson & Johnson files for U.S. FDA approval of Darzalex Faspro-based quadruplet regimen for newly diagnosed multiple myeloma patients for whom transplant is not planned. News release. Johnson & Johnson. September 30, 2024. Accessed October 7, 2024. https://www.investor.jnj.com/news/news-details/2024/Johnson--Johnson-files-for-U.S.-FDA-approval-of-DARZALEX-FASPRO-based-quadruplet-regimen-for-newly-diagnosed-multiple-myeloma-patients-for-whom-transplant-is-not-planned/default.aspx
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