Addition of Transplant to RVd and Lenalidomide Maintenance Led to PFS Boost for Treatment-Naïve Myeloma

Results of the phase 3 DETERMINATION trial (NCT01208662) showed superior progression-free survival (PFS) was possible when lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) was followed by autologous stem cell transplant (ASCT) and lenalidomide maintenance compared with RVd and lenalidomide maintenance alone, according to data presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.^1,2

At a median follow-up of 76 months, the median PFS was 46.2 months in the nontransplant arm vs 67.6 months in the transplant arm (HR 1.53; 95% CI, 1.23-1.91; P < .0001). The estimated 5-year PFS rates were 41.5% and 55.6%, respectively.

“What we were able to demonstrate was that there was a highly significant improvement in PFS with the use of early ASCT,” said lead author Paul G. Richardson, MD, clinical program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

Additional findings illustrated no difference in OS between arms; the estimated 5-year OS rates were 79.2% and 80.7% in the in the non-transplant and transplant arms, respectively.

“Our results provide support for personalized treatment approaches,” Richardson noted. “What I mean by that is if we do not see a benefit in OS and you can delay transplant to use it in a tailored fashion you can have an equally efficacious outcome in OS. We can give patients that option.”

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 understand whether these approaches can be used collectively up front to improve outcomes.

In the trial, patients with newly diagnosed multiple myeloma between the ages of 18 and 65 years received 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).

Each 21-day cycle of RVd comprised 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.

Patients in both arms received between 10 mg of lenalidomide maintenance daily for the first 3 months followed by a dose of 15 mg daily thereafter until progression or intolerance.

The primary end point was PFS and had 90% power to detect a PFS HR of 1.43 for arm A vs B with an α = 0.05 on stratified 2-sided log-rank test. Secondary end points included response rates, duration of response (DOR), time to progression, overall survival (OS), quality of life, and safety. Data cut-off was December 10, 2021.

The median age was 57 years in arm A and 55 years in arm B; 14% and 13% had International Staging System stage III disease, and 18% each had high-risk cytogenetics including t(4;14), t(14;16), and del17p. In the nontransplant and transplant arms, 291 and 289 patients received lenalidomide maintenance; 79 and 81 patients are still receiving lenalidomide maintenance.

With regard to responses, 46.9% of patients in the transplant arm achieved a complete response or better vs 42% of patients in the nontransplant arm. The very good partial response or better rate was 82.7% vs 79.6%, respectively. The partial response or better rate was 97.5% vs 95%, respectively.

Moreover, the DOR was longer in the transplant arm at 56.4 months vs 38.9 months with RVd alone.

“The prognosis for patients with multiple myeloma has improved substantially over the last 10 years,” said ASCO chief medical officer and executive vice president Julie R. Gralow, MD, FACP, FASCO, said during a press briefing. “This trial gives very important information on the benefit and toxicity [of the RVd regimen] so we can have informed discussions with patients. I think duration of response matters to a lot of patients, some [of whom] would rather go a long time others would rather put off a very toxic treatment [such as] ASCT until they might need it later. These data off information that informs a discussion with the patient and helps patients make informed decision.”

The rate of minimal residual disease MRD negativity at a sensitivity of 10-5 was 39.8% without transplant vs 54.4% with transplant. However, Richardson noted that 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.

Grade 3 or greater treatment-related adverse effects including mucositis, fatigue, and infections were less common without transplant than with at 78.2% vs 94.2%.

Regarding quality of life, patients in the transplant arm experienced a temporary but clinically meaningful decrease in 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).

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.

“This was a key toxicity outcome that we monitored carefully,” Richardson said. “We were able to show that there was no difference in the rate of secondary cancers between the arms; however, we did see a higher instance of acute myeloid leukemia and myelodysplastic syndrome was seen with the use of transplant.”

Richardson noted that since this trial was initiated in 2010, triplet therapies have been leveraged as the backbone for quadruplet therapies incorporating monoclonal antibodies and next-generation novel therapies for patients with multiple myeloma. “[Results from studies evaluating quadruplet therapies] are extremely exciting and promising…and by virtue of that this informs our decision-making even more and there are certain research tools such as [minimal residual disease] that can guide us to the best choices for our patients.”

References

1. Richardson PG, Jacobus SJ, Weller E, et al. Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): the phase 3 DETERMINATION trial. J Clin Oncol. 2022;40(suppl 17):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4
2. Autologous stem cell transplant as part of initial therapy showed improved progression-free survival in newly diagnosed multiple myeloma patients. News release. ASCO. June 3, 2022. Accessed June 3, 2022. https://bit.ly/3x8Igbq