Dara-Based Regimens Benefit Patients With NDMM Irrespective of Frailty

A post hoc analysis of the phase 3 CEPHEUS (NCT03652064) and MAIA (NCT02252172) trials found that daratumumab (Darzalex)-based regimens were associated with clinical benefit vs the respective control regimens in patients with newly diagnosed, transplant-ineligible multiple myeloma, r regardless of changes in frailty status.¹

Data presented at the 22nd Annual International Myeloma Society (IMS) Meeting and Exposition showed that over the course of both studies, most patients had stable frailty status, some patients deteriorated, and a small proportion improved over 48 months. Worsening of frailty status was due to increases in both ECOG performance status and age, according to lead study author Hira S. Mian, MD, MSc, FRCPC.

For both studies, investigators assessed frailty status at baseline, 12 months, 24 months, 36 months, and 48 months, with patients having frailty scores ranging from 0 to 5. Scores of 0 or 1 were considered non-frail; scores of 2 to 5 were deemed frail; and scores of 3 to 5 were considered ultra-frail.

Specifically, among evaluable patients in the CEPHEUS trial, frailty scores at baseline included 0 (n = 80), 1 (n = 126), 2 (n = 72), and 3 (n = 11). By month 48, these scores among evaluable patients were 0 (n = 24), 1 (n = 74), 2 (n = 58), and 3 (n = 21); a small proportion of patients worsened to a score of 4.

Overall, patients in MAIA had higher frailty scores, including those considered ultra-frail. At baseline, frailty scores included 0 (n = 146), 1 (n = 250), 2 (n = 196), 3 (n = 106), and 4 (n = 28); a small proportion had a frailty score of 5. At month 48, frailty scores were 0 (n = 59), 1 (n = 89), 2 (n = 91), 3 (n = 64), and 4 (n = 26); no patients had a score of 5 at this time point.

Although Mian highlighted the clinical benefit observed with daratumumab during this post hoc analysis, she also explained that further research is necessary in this space. “We need additional data—prospective data—looking at dynamic frailty in larger phase 3 trials,” said Mian, who is an associate professor of oncology in the Faculty of Health Sciences at McMaster University in Hamilton, Ontario, Canada.

How Was the Frailty Analysis Conducted?

To conduct this post hoc analysis, investigators included patients from CEPHEUS and MAIA to retrospectively assess frailty at time points during the first 2 years of therapy. Notably, patients from CEPHEUS were included in this analysis only if they were transplant ineligible; those who deferred transplant were excluded.^1,2

When investigators analyzed frailty status at baseline, 12 months, 24 months, 36 months, and 48 months, the IFM simplified frailty score was used, determined by Charleson comorbidity index at baseline, current patient age, and ECOG performance status.¹

During the post hoc analysis, investigators examined progression-free survival (PFS) outcomes, minimal residual disease (MRD)–negativity rates, and safety across different frailty subgroups.

CEPHEUS Breakdown and Post Hoc Data

The multicenter, randomized, open-label CEPHEUS study evaluated daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) vs VRd alone in patients with newly diagnosed multiple myeloma who were ineligible for transplant or for whom transplant was not planned as the initial therapy (transplant deferred).²

Previously reported data from CEPHEUS showed that the study met its primary end point, with patients treated with D-VRD achieving an MRD-negativity rate of 60.9% compared with 39.4% for those given VRd (OR, 2.37; 95% CI, 1.58-3.55; P < .0001).

Notably, data from CEPHEUS supported the submission of a supplemental biologics license application seeking the approval of D-VRd for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or have deferred autologous stem cell transplant (ASCT); however, the FDA issued a complete response letter to the application in August 2025, citing observations from facility inspections.³ The CRL was not related to efficacy or safety data from CEPHEUS.

In the frailty analysis, data showed that 34% of evaluable patients with data available at 48 months experienced a change in frailty status.¹ Changes included non-frail to frail (n = 52; 28%) and frail to non-frail (n = 10; 6%). Forty-eight percent of patients (n = 88) were nonfrail from baseline to month 48, and 18% (n = 33) were frail from baseline to month 48.

Among patients who were nonfrail at baseline, reasons for deterioration at month 48 included increase in both age and performance status (9.7%), increase in age (11.7%), and increase in ECOG performance status (3.9%).

Additionally, D-VRd consistently improved the rates of patients who experienced MRD negativity with a complete response (CR) or better across frailty subgroups and different time points. PFS was also improved across these subgroups during this 2-year period.

Notably, frailty changes over the course of 48 months were associated with changes in PFS outcomes. For patients who were frail at baseline and non-frail at month 48, the 48-month PFS rate was 100% (95% CI, 100%-100%) in the D-VRd arm (n = 6) vs 75.0% (95% CI,12.8%-96.1%) in the VRd arm (n = 4). Conversely, in patients who were nonfrail at baseline and frail at 48 months, the 48-month PFS rates were 82.6% (95% CI, 60.1%-93.1%) and 73.2% (95% CI, 51.8%-86.2%) for D-VRd (n = 23) and VRd (n = 29), respectively.

Regarding safety in the D-VRd arm, at least 1 serious treatment-emergent adverse effect (TEAE) occurred in 33.3% of patients who were frail at baseline and non-frail at month 48; 30.4% of patients who were non-frail at baseline and frail at month 48; 34.0% of patients who were nonfrail at both baseline and month 48; and 50.0% of patients who were frail at both baseline and month 48. These respective rates in the VRd arm were 75.0%, 51.7%, 34.1%, and 45.5%.

In the D-VRd arm, TEAEs led to discontinuation of study treatment in 16.7% of patients who were frail at baseline and non-frail at month 48; 8.7% of patients who had worsening frailty at month 48; 2.1% of patients who had stable non-frailty; and 13.6% of patients with stable frailty. These rates in the VRd arm were 25.0%, 27.6%, 14.6%, and 18.2%, respectively.

MAIA Overview and Post Hoc Findings

This open-label, randomized phase 3 trial evaluated D-Rd vs Rd in patients with ASCT-ineligible, newly diagnosed multiple myeloma, and findings from this study supported the June 2019 FDA approval of D-Rd for this patient population.⁴

Findings supporting the approval demonstrated that patients treated with D-Rd achieved a median PFS that was not reached vs 31.9 months for those given Rd alone (HR, 0.56; 95% CI, 0.43-0.73; P <.0001.).

In the post hoc analysis, findings revealed that 26% of patients with data available at month 48 experienced changes in frailty status over the course of the study.¹ Specifically, 21% of patients (n = 69) were frail at month 48 after being nonfrail at baseline, and 5% (n = 15) improved from frail to non-frail by month 48. Forty percent (n = 133) of patients were nonfrail at both baseline and month 48, and 34% (n = 114) were frail at both time points.

The primary reasons for deterioration of frailty status at month 48 included increase in both age and ECOG performance status (7.3%), increase in age (6.8%), and increase in ECOG performance status (3.3%).

Similar to CEPHEUS, data from MAIA showed that D-Rd improved both MRD-negativity rates and PFS across frailty subgroups and time points.

At 48 months, the respective PFS rates were 100% (95% CI, 100%-100%) and 88.9% (95% CI, 43.3%-98.4%) among patients treated with D-Rd (n = 6) and those treated with Rd (n = 9) who improved to nonfrail status. These rates were 92.9% (95% CI, 79.5%-97.6%) and 65.4% (95% CI, 44.0%-80.3%) for D-Rd and Rd, respectively, among patients who worsened to frail status by month 48.

Safety data at month 48 showed that in the D-Rd arm, at least 1 serious TEAE occurred in 33.3% of patients with improving frailty status; 53.5% of patients with worsening frailty status; 38.8% of patients with stable nonfrailty; and 56.8% of patients with stable frailty. These respective rates were 22.2%, 53.8%, 32.1%, and 50.0% in the Rd arm.

TEAEs did not lead to treatment discontinuation in any patients in the D-Rd or Rd arms who had improved frailty at month 48. TEAEs led to treatment discontinuation in 18.6%, 3.8%, and 8.1% of patients in the D-Rd arm who had worsening frailty at month 48; stable nonfrailty; and stable frailty, respectively. These respective rates were 34.6%, 15.1%, and 22.5% in the Rd arm.

“The incidence of related serious TEAEs and TEAEs leading to study discontinuation were generally similar or lower in patients receiving daratumumab…regardless of changing frailty,” Mian concluded.

Disclosures: Mian reported receiving research funding from AbbVie, Janssen, and Pfizer; honoraria from Amgen, Bristol Myers Squibb, Sanofi, and Takeda; and serving as a member of the board of directors for AbbVie, Amgen, Bristol Myers Squibb, Janssen, Pfizer, and Sanofi.

REFERENCES:

1. Mian H, Facon T, Cook G, et al. Dynamic frailty analysis of transplant-ineligible patients with NDMM in the phase 3 MAIA and CEPHEUS trials of daratumumab + lenalidomide-dexamethasone and bortezomib-RD. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-21.

2. 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

3. Update on U.S. regulatory review of supplemental biologics license application. News release. Johnson & Johnson. August 1, 2025. Accessed September 18, 2025. https://tinyurl.com/yhnc2vzf

4. FDA approves daratumumab for multiple myeloma ineligible for autologous stem cell transplant. FDA. Updated June 28, 2019. Accessed September 18, 2025. https://tinyurl.com/3avjsnpb