August 26, 2022

Jordyn Sava

The triplet regimen of lenalidomide, bortezomib, and dexamethasone plus autologous stem cell transplantation and lenalidomide maintenance therapy significantly improved progression-free survival compared with RVd alone in patients with newly diagnosed multiple myeloma, with notable benefit observed in those with high-risk cytogenetics.

Paul Richardson, MDThe triplet regimen of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) plus autologous stem cell transplantation (ASCT) and lenalidomide maintenance therapy significantly improved progression-free survival (PFS) compared with RVd alone in patients with newly diagnosed multiple myeloma, with notable benefit observed in those with high-risk cytogenetics.¹

Findings come from the phase 3 DETERMINATION trial (NCT01208662) presented at the 2022 International Myeloma Society Annual Meeting by Paul Richardson, MD. Data revealed that after a median follow-up of 76 months, the median PFS was 46.² for patients administered RVd alone vs 67.5 months for patients administered RVd and ASCT (HR 1.53; 95% CI, 1.23-1.91; P< 0.0001).

The estimated 5-year PFS rates were 41.5% and 55.6%, respectively. The median PFS was 17.1 vs 55.5 months (HR 1.99; 95% CI, 1.21-3.26) for patients with high-risk cytogenetics and 53.2 vs 82.3 months (HR 1.38; 1.07-1.79) in those with standard-risk cytogenetics.

No overall survival (OS) advantage has been observed at this point.

“The primary end point was clearly met, and it exceeded our expectations with a 21-month difference between early-transplant vs delayed with a median follow-up well, in excess of 76 months. This was highly significant. The use of early transplant in the setting of RVd induction therapy had strikingly superior PFS vs RVd alone. This was notably seen in the high-risk group compared to the standard risk,” stated Richardson, clinical program leader and director for Clinical Research, Jerome Lipper Multiple Myeloma Center, institute physician at Dana-Farber Cancer Institute, and RJ Corman professor of Medicine at Harvard Medical School, during the presentation.

High-dose melphalan plus ASCT is the standard of care in transplant-eligible myeloma, and triplet regimens are associated with high rates of deep response and prolonged clinical benefit, which is often maintained with lenalidomide maintenance. As such, investigators conducted the DETERMINATION trial to determine whether these approaches can be used to improve outcomes.

In the randomized, phase 3 trial, 729 patients with newly diagnosed multiple myeloma between the ages of 18 and 65 years were enrolled with 722 randomized to receive either RVd alone (arm A) or RVd plus ASCT (arm B).

Patients were required to have documented symptomatic myeloma, with organ damage related to myeloma with laboratory assessments performed within 21 days of registration, myeloma measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains, and ECOG performance status of 0, 1, or 2, and a negative HIV blood test.

Those enrolled were given 3 cycles of RVd followed by stem cell mobilization and were randomized to either 5 more cycles of RVd (n = 357; arm A) or 200 mg/m2 of intravenous (IV) melphalan plus ASCT and 2 cycles of RVd (n = 365; arm B).

In both arms, the 21-day cycle of RVd was comprised of 25 mg of oral lenalidomide on days 1 through 14, 1.3 mg/m2 of IV or subcutaneous bortezomib on days 1, 4, 8, and 11, and 20 mg of oral dexamethasone in cycles 1 through 3 and then 10 mg thereafter on days 1, 2, 4, 5, 8, 9, 11, and 12. Additionally, patients in both arms were given between 10 mg of lenalidomide maintenance daily for the first 3 months followed by a dose of 15 mg daily after until either disease progression or intolerance.

The primary end point of the trial was PFS with secondary end points including response rates, duration of response (DOR), time to progression, overall survival (OS), quality of life, and safety. The data cut-off was December 10, 2021.

A total of 357 were randomized to receive RVd-alone and 365 to receive RVd plus ASCT. The median age of those enrolled was 57 in arm A and 55 in arm B. In arm A, 56.6% of patients were male vs 58.9% in arm B, and in both arms, the majority of the patients were White (76.4% and 75.8%). Between both arms, 13% of patients had International Staging System stage III disease, and 19.8% and 19.4% in each had high-risk cytogenetics, including t(4;14), t(14;16), and del17p. In the non-transplant and transplant arms, 291 and 289 patients were given lenalidomide maintenance for a median of 36.4 months and 41.5 months. There are 79 and 81 patients still receiving lenalidomide maintenance.

Regarding responses, 46.9% of patients in the transplant arm achieved a complete response or better vs 42% of patients in the nontransplant arm and a very good partial response or better rate was 82.7% vs 79.6%, respectively. The partial response or better rate was 97.5% in arm A vs 95% in arm B, respectively. Additionally, the DOR was longer in the transplant arm at 56.4 months vs 38.9 months with RVd alone.

The rate of minimal residual disease (MRD) negativity at the start of maintenance in 108 and 90 patients at a sensitivity of 10-5 was 39.8% without transplant vs 54.4% with transplant. Patients who achieved MRD negativity had comparable PFS regardless of treatment.

Notably, only 28% of patients treated with RVd alone underwent delayed transplant; others received next-generation novel agents and monoclonal antibodies.

The 5-year cumulative rate of any secondary cancers was 10.8% with transplant vs 9.7% without. Invasive cancers were reported in 6.5% and 4.9% of patients, respectively. Hematologic cancers developed in 3.5% and 1.6% of patients in each respective arm. Additionally, the 5-year OS rates were 79.2% vs 80.7%, respectively (HR 1.10; 95% CI, 0.73-1.65) with 90 and 88 patients having died. The 5-year OS rates were 54.3% vs 63.4% (HR 1.25; 95% CI, 0.75-2.08) in patients with high-risk and 86.2% vs 86.0% (HR 0.99; 0.66-1.47) in patients with standard-risk cytogenetics.

In the RVd-alone arm, 78.2% of patients had grade ≥3 related adverse events (AEs) vs 94.2% in the RVd plus ASCT arm. Then, 60.5% vs 89.9% had grade 3 or greater related hematologic AEs (P < 0.0001) and 10.4% vs 10.7% had secondary malignancies (P =0.002). Additionally, 79.9% vs 69.6% of patients who had discontinued study treatment received subsequent non-protocol therapy and of 279 patients in the RVd-alone arm who had discontinued treatment, 28% had received ASCT as part of any subsequent therapy.

Grade 3 or greater treatment-related adverse events (TRAEs) including mucositis, fatigue, and infections were less common without transplant than with 78.2% vs 94.2%. In the RVd alone group, any grade 5 AEs which were fatal occurred in 0.3% of patients vs 1.6% in the RVd plus ASCT arm.

During maintenance, the rates of hematologic grade 3 or greater TRAEs were 26.1% and 41.9%. Prior to maintenance, serious AEs were 40.3% vs 47.1% compared to 11.3% vs 16.6% during maintenance. To date, there have been no fatalities due to COVID-19 in the study.

Regarding quality of life, patients in the transplant arm experienced a temporary but clinically meaningful decrease during transplant, which improved from baseline throughout maintenance.

The difference in mean change from baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire QLQ-C30 global health status score was fewer than 10 points throughout treatment except at cycle 5 of RVd vs post-ASCT where the mean change was plus 3.0 vs minus 11.1, respectively (P < .0001).

“What is important to note is no overall survival difference, recognizing the median follow-up now is well in excess of 80 months, and it is similar between the 2, but there may be important trends for high-risk again. In that regard, we look forward to further analysis. Similar overall response rates are seen, except in high-risk with a complete response rate that is higher for early transplant,” added Richardson. “MRD is emerging as a very important tool and is a very important predictor. The side effect profile as much as we would expect, and I certainly think it's important to bear that in mind. We'll be exploring the massive impact in our view of quadruplets in this space, as well as other strategies to further improve outcome.”

References

1. Richardson PG, Jacobus, SJ, Weller EA, et al. Lenalidomide-bortezomib-dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression in patients with newly diagnosed multiple myeloma (NDMM), by cytogenetic risk. Presented at the 19th Annual International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-058

2. Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). ClinicalTrials.gov. Updated April 15, 2022. Accessed August 25, 2022. https://clinicaltrials.gov/ct2/show/NCT01208662