Autologous stem cell transplant (ASCT) added to triple therapy improves progression-free survival (PFS) but not overall survival (OS) in patients with newly diagnosed multiple myeloma (MM), according to preliminary data from the phase 3 DETERMINATION trial presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine.
These findings suggest ASCT remains an important treatment for patients with MM, but that it can be timed to better suit the needs of individual patients, without the potential concern that patients will miss an OS benefit if it is not undertaken early in their treatment course.
Remarkable Efficacy of Triple Induction Regimens Is a Key Factor
“It’s well established that autologous stem cell transplant with high-dose melphalan is a standard of care in transplant eligible patients,” says Paul G. Richardson, MD. “But the optimal use of novel agent induction treatment, integrating transplant and the use maintenance in younger patients, continues to evolve. Part of the reason for that is the remarkable efficacy of triplet induction regimens and the more recent addition of monoclonal antibodies.”
The DETERMINATION trial randomly assigned 722 adults (aged 18-65) with symptomatic MM 1:1 to receive triplet therapy (ie, lenalidomide, bortezomib, dexamethasone) plus lenalidomide maintenance until progression (N=357) or triplet therapy plus ASCT followed by lenalidomide maintenance until progression (N=365). Black patients made up approximately 20% of the study population, which is the highest proportion included in any phase 3 MM studies undertaken to date. The study’s primary endpoint was PFS; secondary endpoints included response rates, duration of response, time to progression, OS, QOL, and safety.
Overall Survival Was Similar Between Groups
At a median follow-up of 76 months, 328 disease progression events or deaths had occurred. The risk of such events was 53% higher in the ASCT arm versus the non-ASCT arm. The median PFS was 46.2 months versus 67.5 months in these cohorts, respectively, demonstrating a 21-month delay in disease progression events with the addition of ASCT to triplet induction and lenalidomide maintenance. When assessing PFS by subgroup, however, the benefit of adding ASCT to triplet therapy and lenalidomide maintenance was not pronounced in Black patients, those with International Staging System (ISS) stage 3 disease, and those with revised ISS stage 3 disease. Despite the significantly improved PFS in the ASCT armoverall, OS was similar between groups, with a 5-year survival rate of 80.7% in the ASCT arm and 79.2% in the non-ASCT arm.
“Similarly, the overall response rates and quality of responses were equivalent, as assessed by a central response review committee,” Dr. Richardson notes. “Very interestingly and encouragingly, there was a higher rate of minimal residual disease (MRD)-negativity to the responses in the transplanted arm. Set against that were the higher toxicity rates and a transient but clinically meaningful decrease in QOL during transplant. Fortunately, these later improved from baseline and through the duration of maintenance.”
Adverse Events More Common in the ASCT Arm Vs the Non-ASCT Arm
The percentage of patients with a partial response or better was 97.5% in the ASCT arm and 95.0% in the non-ASCT arm, with 82.7% and 79.6%, respectively, having a very good partial response. The percentage of patients with a complete response was 46.8% in the ASCT arm and 42.0% in the non-ASCT arm (Table).
Treatment-related adverse events (TRAEs) of grade 3 or higher and hematologic TRAEs of grade 3 or higher were more common during all treatment phases in the ASCT arm versus the non-ASCT arm, with the former occurring in 94.2% versus 78.2% of patients, respectively, and the latter occurring in 89.9% versus 60.5% of patients, respectively.
‘DETERMINATON Trial Supports Personalized Approaches’
During the maintenance phase, hematologic TRAEs of grade 3 or higher were observed in 41.9% of the ASCT arm and 26.1% of the nonASCT arm. Long-term toxicities included equivalent rates of second cancers between the two arms overall, but a significantly higher rate of treatment-related myelodysplasia and acute myeloid leukemia against early transplant, with 10 cases in the early ASCT arm versus none in the delayed or non-ASCT arms.
“Above all, [the DETERMINATION trial] supports personalized approaches, not least because we see no overall survival difference to date, and this observation allows the option of considering keeping transplant in reserve for selected patients,” Dr. Richardson says. “As we think about future directions in myeloma, we are very fortunate to have a plethora of exciting treatment options. The quadruplets incorporating monoclonal antibodies are becoming well established and performing extremely well in the upfront setting. We have CAR-Ts, bispecifics, antibody-drug conjugates, and next generation novel agents, all of which are providing us with the opportunity and potential to do better when used earlier in the course of a patient’s disease.”
