RVd Induction Impresses in Myeloma, But 4-Drug Regimens Mark the Future

The 3-drug induction regimen of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) led to impressive overall survival (OS) outcomes and a very good partial response (VGPR) or better in nearly 90% of patients with newly diagnosed multiple myeloma, according to a retrospective analysis published in the Journal of Clinical Oncology.¹

The overall response rate (ORR) was 97.1% after induction therapy. Following transplantation, the ORR was 98.5%, including a ≥VGPR of 89.9% and a stringent complete response (sCR) rate of 33.3%, at a median follow-up of 67 months. The 5- and 10-year OS rates were 57% and 29%, respectively, for high-risk patients, and 81% and 58% for standard-risk patients.

Despite these impressive outcomes, the myeloma paradigm is already looking beyond 3-drug combos to emerging 4-drug standards. For example, data from the phase II GRIFFIN trial showed that after a median follow-up of 22.1 months, the sCR rate was 45.4% with RVd and 62.6% with daratumumab (Darzalex) plus RVd (D-RVd; odds ratio [OR] 1.98; 95% CI, 1.12-3.49; P = .0177) in patients with in patients with transplant-eligible, newly diagnosed myeloma.²

The overall CR rate (sCR + CR) also improved with D-RVd (79.8% vs 60.8%; P = .0045), and the proportion of patients achieving minimal residual disease (MRD) negativity was twice as high with D-RVd. At 24 months, both regimens led to rates of progression-free survival (PFS) exceeding 85% and rates of OS exceeding 90%.

While the data suggest a potential new 4-drug standard, lead investigator Peter M. Voorhees, MD, of the Levine Cancer Institute in Charlotte, cautioned during his presentation of the results at the 2019 ASH Annual Meeting that additional data are still needed

"These results support D-RVd as a potential new standard of care for transplant-eligible newly diagnosed multiple myeloma," said Voorhees. "We need to confirm that the MRD negative rates that were seen in the daratumumab arm are sustained. Most importantly, we need to make sure this improved depth of response translates into an improvement in progression-free survival."

The addition of daratumumab to a similar 3-drug regimen of bortezomib, thalidomide, and dexamethasone (D-VTd) had previously demonstrated improved response rates and PFS as induction and consolidation therapy for transplant-eligible patients with newly diagnosed myeloma in the phase III CASSIOPEIA trial. Based on these findings, the FDA approved the D-VTd quadruplet in September 2019 for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).³

Retrospective RVd Findings

The retrospective RVD analysis included 1000 transplantation-eligible and -ineligible patients with newly diagnosed myeloma treated with RVD induction therapy. Patients were treated between January 2007 and August 2016. The median patient age was 61.21 years (range, 16.32-83.05), 54.6% were male, 63.3% had standard-risk cytogenetics, and 25.1% had high-risk cytogenetics.

The median duration of induction therapy was 3.91 months and the median number of RVD cycles received was 4 (range, 2-15). The median time from diagnosis to ASCT was 5.52 months (range, 1.87-130.83). Among patients who received transplant, 75.1% had upfront ASCT and 16.8% had deferred ASCT. The data cutoff date was May 31, 2019.

The 97.1% ORR after induction therapy included a ≥VGPR rate of 67.6% and an sCR plus CR rate of 35.9%. The 98.5% ORR after ASCT included a ≥VGPR rate of 89.9%, and an sCR plus CR rate of 71%. Among all evaluable patients (n = 977) the ORR was 98.6%, the ≥VGPR rate was 86.8%, and the sCR plus CR rate was 67.5%.

For the entire cohort, the estimated median PFS was 65 months (95% CI, 58.7-71.3). Among high- and standard-risk patients, the median PFS was 40.3 months and 76.5 months, respectively. The median OS was 126.6 months, 78.2 months, and not yet reached for the overall, high-risk, and standard-risk groups, respectively.

Among the overall population, 753 patients received maintenance therapy, of whom 600 (60.7%) were treated with lenalidomide maintenance therapy alone based on standard-risk cytogenetics. Another 107 (10.7%) patients received IMiD and PI maintenance, primarily with RVD. Overall, the ≥VGPR rate was 91% among the maintenance population, compared with 74.4% in those who did not receive maintenance (P <.0001). The median PFS was 65.45 months with maintenance and 47.02 months without (P = .005). The median OS was 129.84 and 81.15 months, respectively (P <.0001).

"This study includes the largest cohort of patients treated with RVD reported to date with long follow-up and demonstrates the ability of 3-drug induction regimens in patients with newly diagnosed multiple myeloma to result in a substantial survival benefit," the authors of the retrospective study concluded.

References

1. Nisha S 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 [published online ahead of print April 16, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02515
2. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019;134(suppl 1;abstract 691). doi: 10.1182/blood-2019-123456
3. Genmab Announces U.S. FDA Approval of DARZALEX® (daratumumab) in Combination with Bortezomib, Thalidomide and Dexamethasone for Frontline Multiple Myeloma. Genmab. Published September 26, 2019. Accessed September 26, 2019. https://bit.ly/2nzRy05.