Addition of Stem Cell Transplant Boosts Outcomes for Common Myeloma Regimen

The addition of autologous stem cell transplant (ASCT) and then Revlimid (lenalidomide) maintenance therapy after treatment with Revlimid, Velcade (bortezomib) and dexamethasone — a combination known as RVd — led to improved outcomes for patients with newly diagnosed multiple myeloma compared to those who had RVd then maintenance therapy without undergoing transplant, according to findings from the phase 3 DETERMINATION clinical trial.

At a median follow-up of 76 months, the median progression-free survival was 46.2 months in the nontransplant arm, compared to 67.6 months in the transplant arm. The estimated five-year progression-free survival rates were 41.5% and 55.6%, respectively.

“What we were able to demonstrate was that there was a highly significant improvement in (progression-free survival) with the use of early ASCT,” said lead author Dr. Paul G. Richardson, 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 overall survival between arms; the estimated five-year overall survival 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 (overall survival) and you can delay transplant to use it in a tailored fashion you can have an equally efficacious outcome in (overall survival). 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 Revlimid maintenance.

As such, investigators conducted the DETERIMINATION 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 three cycles of RVd followed by stem cell mobilization (a process that moves stem cells from the bone marrow to blood), and were randomized to either five more cycles of RVd (357 patients; arm A) or 200 mg/m2 of intravenous (IV) melphalan plus ASCT and two cycles of RVd (365 patients; arm B).

Each 21-day cycle of RVd comprised 25 mg of oral Revlimis on days 1 through 14, 1.3 mg/m2 of IV or subcutaneous Velcade 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 Revlimid maintenance daily for the first three months followed by a dose of 15 mg daily thereafter until progression or intolerance.

The main goal of the study was progression-free survival. Secondary end points included response rates, duration of response, time to progression, overall survival, quality of life and safety. Data cut-off was Dec. 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 3 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 Revlimid maintenance; 79 and 81 patients are still receiving Revlimid maintenance.

With regard to responses, 46.9% of patients in the transplant arm achieved a complete response or better, compared to 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 duration of response was longer in the transplant arm at 56.4 months, versus 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, which indicates that very little, if any, disease is left after treatment, was 39.8% without transplant vs 54.4% with transplant. However, Richardson noted that patients who achieved MRD negativity had comparable progression-free survival 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 side 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, which is used to measure quality of life in patients with cancer, 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.

The five-year cumulative rate of any secondary cancers was 10.8% with transplant and 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.”

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