Daratumumab Plus RVd as Induction Therapy Improves Responses, Survival in Newly Diagnosed Myeloma

Nisha S. Joseph, MD

The addition of daratumumab (Darzalex) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Dara-RVd) as induction therapy demonstrated improved responses and progression-free and overall survival (OS) compared with RVd alone in patients with newly diagnosed multiple myeloma who are at least 65 years old, according to institutional findings presented during the 21st IMS Annual Meeting.¹

Results showed that post-induction therapy for patients 65 years and older, the stringent complete response (sCR) rates with Dara-RVd and RVd were 11.0% compared with 4.4%, respectively; complete response (CR) rates were 6.1% vs 26.3%, very good partial response (VGPR) rates were 73.2% vs 35.1%, VGPR or better rates were 90.3% vs 65.8%, and partial response (PR) rates were 9.8% vs 30.7%, respectively. A total 0.9% of patients on RVd had progressive disease (PD).

In the posttransplant setting, the sCR rates with Dara-RVd and RVd were 27.83% compared with 28.4%, respectively; CR rates were 7.8% vs 35.8%, VGPR rates vs 60.0% vs 18.5%, VGPR or better rates were 95.6% vs 82.7%, and PR rates were 3.5% vs 14.6%, respectively. No patients on Dara-RVd had stable disease (SD) vs 0.59% of those on RVd; 0.87% and 0.29% of patients, respectively, had PD.

Additional results showed that, in the overall cohort, the median progression-free survival (PFS) with Dara-RVd was not reached (NR) vs 67.5 months with RVd (P <.001); the 1-year PFS rates were 98% vs 93%, respectively, and 2-year PFS rates were 93% vs 82%, respectively. Similarly, the median OS with the addition of daratumumab was NR vs 128.9 months without (P = .034); the 1-year OS rates were 99% vs 97% with Dara-RVd vs RVd, respectively; 2-year OS rates were 94% vs 91%, respectively.

The survival benefit with Dara-RVd was seen regardless of age. For patients 65 years and older, the median PFS was NR with Dara-RVd compared with 59.3 months (95% CI, 50.4-68.2) with RVd alone (P = .003). In those younger than 65 years old, the median PFS with Dara-RVd was NR vs 70.1 months (95% CI, 60.7-79.6) with RVd (P = .001).

“Both RVd and Dara-RVd are the largest reported cohorts of consecutive and uniformly treated real-world patients with data, and despite the expected limitations of a retrospective analysis, our data is quite consistent with what we are seeing in the randomized setting,” lead study author Nisha S. Joseph, MD, an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia, said in an oral presentation during the meeting. “We can clearly see here that patients 65 years and older can and do benefit from this regimen and approach. It also highlights the potential utility of transplant in patients who are otherwise transplant eligible despite age.”

RVd has been utilized as a standard induction therapy at Winship Cancer Institute of Emory University since 2007, followed by Dara-RVD since 2018, Joseph explained. This led to researchers creating a database of more than 1300 patients who were treated with these regimens before autologous stem cell transplant (ASCT) and risk-stratified maintenance treatment.² These data steered to a comparative analysis of outcomes between 326 patients with newly diagnosed multiple myeloma who were treated with induction Dara-RVd and 1000 patients with RVd. Results were consistent with other randomized findings with the regimens improving PFS and depth of response.³

Joseph cited the PERSEUS trial (NCT03710603), in which Dara-RVd demonstrated a PFS benefit across patient subgroups with newly diagnosed multiple myeloma except for those who were 65 years and older (n = 181; 25.5%; HR, 0.97; 95% CI, 0.52-1.81) and non-White patients (n = 56; 7.8%).⁴

At the meeting, Joseph presented the subgroup analysis from the institution’s database of patients at least 65 years old who were treated with Dara-RVd vs RVd, with the hypothesis that adding daratumumab to RVd would lead to increased depth of response and improved PFS vs RVd in the older patient population.

To be eligible for enrollment, patients had to have transplant-eligible, newly diagnosed, standard- or high-risk multiple myeloma who received either Dara-RVd or RVd as induction therapy and were eligible to receive maintenance therapy.

In the RVd group, lenalidomide was administered at 25 mg on days 1 to 14 every 21 days; bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days; and oral dexamethasone on days 1, 8, and 15 every 21 days. In the Dara-RVd group, daratumumab was given intravenously or subcutaneously on days 1, 8, and 15 every 21 days for cycles 1 to 4 and day 1 only if cycles 5 and 6 were given; lenalidomide was given at 25 mg on days 1 to 14 every 21 days; bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days; and oral dexamethasone on days 1, 8, and 15 every 28 days.

Following transplant, those with standard-risk myeloma received lenalidomide maintenance until PD; those with high-risk disease received maintenance therapy with a proteasome inhibitor and immunomodulatory drug for 3 years or until PD.

The primary end point was CR rate or greater, and secondary end points were overall response rate, VGPR or greater, PFS, and OS.

Baseline characteristics were mostly similar between the 2 arms. In the RVd arm (n = 1000), the median age was 61 years (range, 16-83) and more than half of patients were male (54.6%); patients were White (62.0%), Black (36.3%), or Asian (1.7%). Most patients had IgG isotype (61.6%) and International Staging System (ISS) stage 1 disease (45.8%) and Revised ISS (R-ISS) stage 2 disease (48.7%). Moreover, 82.2% of patients had standard-risk disease and 17.8% had high-risk disease. Patients had t(11;14) disease (13.0%), t(4;14) disease (4.8%), t(14;16) disease (2.8%), del(17p) disease (10.0%), +1q21 disease (15.9%), del(13) disease (25.7%), or double-hit disease (6.7%).

In the Dara-RVd arm (n = 326), the median age was 62 years (range, 23.5-79) more than half of the patients were male (55.5%), and patients were either White (55.2%), Black (41.7%), or Asian (3.1%). Again, the majority of patients had IgG isotype (65.2%) and ISS stage 1 disease (49.6%) and R-ISS stage 2 disease (47.6%). Most patients had standard-risk disease (84.6%); 15.4% of patients had high-risk disease. Patients had t(11;14) disease (21.4%), t(4;14) disease (4.4%), t(14;16) disease (1.0%), del(17p) disease (5.7%), +1q21 disease (26.5%), del(13) disease (33.8%), or double-hit disease (5.5%).

A total of 326 evaluable patients were treated with Dara-RVd induction between April 2018 and August 2022, 125 of whom were at least 65 years old. One thousand patients were evaluated and treated with RVd, 335 of whom were at least 65 years old.

The median follow-up was 19.1 months for Dara-RVd and 87 months for RVd; the data cutoff date was December 31, 2022.

Further findings showed that, in patients who were 65 years and older with standard-risk disease, the median PFS was NR with Dara-RVd vs 59.4 months (95% CI, 49.8-69.0) with RVd (P = .007). In those with high-risk disease who were 65 years and older, the median PFS was NR and 42.7 months (95% CI, 30.1-55.3), respectively (P = .324). Joseph said this was not a clear PFS benefit; she noted that there were 13 patients with high-risk disease who were 65 years and older, “so clearly there is not enough numbers to adequately answer that question.”

Joseph concluded by underscoring that questions remain regarding the role of lenalidomide monotherapy and risk-stratified maintenance therapy for select patients with newly diagnosed multiple myeloma.

Disclosures: Joseph did not cite any disclosures.

References

1. Joseph NS, Kaufman J, Gupta V, et al. Efficacy of Dara-RVD induction therapy in newly diagnosed myeloma (NDMM) patients ≥65 years of age. Presented at: 21st International Myeloma Society Annual Meeting & Exposition; September 25-29, 2024; Rio de Janeiro, Brazil. Abstract OA-51.
2. Joseph NS, Kaufman JL, Dhodapkar MV, et al. Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol. 2020;38(17):1928-1937. doi:10.1200/JCO.19.02515
3. Joseph NS, Kaufman JL, Gupta VA, et al. Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients. Blood Cancer Journal. 2024;14(159). doi:10.1038/s41408-024-01120-9
4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Eng J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054