Benefit of Dara-Rd Maintained Across Age Groups in Transplant-Ineligible NDMM

Laahn Ho Foster, MD

Associate Professor

University of Virginia School of Medicine

Charlottesville, VA

Targeted Oncology: What is the role of RVd (lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM)?

Laahn Ho Foster, MD: RVd is an excellent regimen based on the SWOG S0777 study [NCT00644228], looking at RVd vs Rd [lenalidomide plus dexamethasone].¹ The way that RVd was used was for 8 cycles, basically 6 months, and then it was followed by Rd maintenance. The Rd [arm] was just Rd [for 6 cyles of 28 days] and then was continued on a maintenance schedule. We could see the difference in how patients responded to RVd vs Rd. [At median follow-up of 84 months], they did better on RVd with a median progression-free survival [PFS] of 41 months vs 29 months with Rd [HR, 0.742; 96% CI, 0.594-0.928; P = .003].¹

And [for overall survival (OS)] they have a separation of results [HR, 0.709; 96% CI, 0.543-0.926; P =.0114].¹ The thing about this study is that this was a younger population. The difference between this and the MAIA study [NCT02252172], is that the patients in the study were younger, [many of whom were] less than the age of 65. The Kaplan-Meier curves show how they did and the patients who were older than 65 tended to do worse [with a median PFS of 65 months in those 65 or older vs not reached in those younger than 65 years old].¹

What adverse events are of most concern with RVd, and what has been done to mitigate them?

The neuropathy is a concern. With this regimen no one uses bortezomib twice weekly at this point. There was a lot of neuropathy [on the trial], but going down to the once weekly dosing of bortezomib has mitigated that risk.²

RVd-lite is a modification of how RVd is given.³ They’ve extended the cycles of it, so instead of [lenalidomide being given on the first] 21 days and [bortezomib] twice weekly, you’re getting weekly bortezomib and a lower dose of lenalidomide [(15 mg vs 25 mg) on a 35-day cycle].²

What other option is available for treating newly diagnosed multiple myeloma in patients not intended to receive a stem cell transplant?

The other option [for these patients] is dara-Rd [daratumumab (Darzalex), lenalidomide, and dexamethasone] supported by the MAIA study, looking at dara-Rd vs Rd. Again, just note that this is an older population with a median age of 73 years old [vs 63 years in the SWOG S0777 study].^2,4

The overall response rates [in the MAIA study] were over 90% for dara-Rd, 93% vs 82% for Rd, and the depth of response [was demonstrated by] the complete response (CR) rate [which showd] more than 51% achieved a CR or better, and that’s compared with approximately 30% for the Rd arm.⁵ The minimal residual disease negativity rates show it was approximately 32% for dara-Rd vs 11% for Rd.

[Further], the PFS is significantly longer with the dara-Rd [HR, 0.55; 95% CI, 0.45-0.67; P < .0001], and it also looks like there’s an OS benefit in these patients who are treated with dara-Rd vs Rd [HR, 0.65; 0.52-0.80; P < .0001].⁶

What impact did daratumumab have on the toxicities these patients experienced?

It didn’t seem that the addition of daratumumab changed the safety profile [of the therapy] all that much.^4,7 There was a little bit more in terms of cytopenias that you’ll notice, and there was a bit more in terms of diarrhea [57% any-grade with dara-Rd vs 46% any-grade with Rd].

What additional analyses of the MAIA data give insight into the use of dara-Rd?

[In a post hoc analysis] we can see the outcomes in frail patients on dara-Rd. They separated [patients by] whether they were frail vs not frail. The patients who were not frail, as you would expect, did better than the patients in the frail cohort [with a HR of 0.48 favoring dara-Rd in the non-frail cohort and a HR of 0.62 favoring dara-Rd in the frail cohort].⁸

We can see the differences in how patients did in the younger group vs the older group for PFS [in those] less than 75 years old [with a 60-month PFS rate of 57.4% for dara-Rd vs 33.6% for Rd], and in those patients less than 70 years old [with a 60-month PFS rate of 67.2% vs 28.7%, respectively].⁸ There are separations [between] how patients did with dara-Rd vs Rd, and of course, the patients who were younger seemed to do better than the older subgroup.

REFERENCES:

1. Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8

2. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X

3. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182(2):222-230. doi:10.1111/bjh.1526

4. Facon T, Kumar SK, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249

5. Facon T, Kumar SK, Plesner T, et al. Overall survival results with daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: Phase 3 MAIA study. Presented at 2021 Congress of the European Hematology Association; June 9-17, 2021; Virtual. LB1901. Accessed March 29, 2024. https://tinyurl.com/5xhzsbrw

6. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6

7. Kumar SK, Moreau P, Bahlis NJ, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): Updated analysis of the phase 3 MAIA study. Blood. 2022;140(suppl_1):10150-10153. doi:10.1182/blood-2022-163335

8. Facon T, Kumar SK, Weisel K, et al. Daratumumab plus lenalidomide and dexamethasone in patients with transplant-ineligible newly diagnosed multiple myeloma: MAIA age subgroup analysis. Blood. 2022;140(suppl_1):10133-10136. doi:10.1182/blood-2022-163555