Determination Trial Confirms Importance of Individualizing Therapy for Newly Diagnosed Multiple Myeloma

In the phase 3 DETERMINATION trial—in which patients with newly diagnosed multiple myeloma were randomly assigned to a standard triplet regimen with and without autologous stem-cell transplantation (ASCT), with all receiving lenalidomide (Revlimid) maintenance therapy until disease progression—patients with ASCT had significantly longer progression-free survival (PFS) versus those who did not, but no difference in overall survival (OS) was observed between the 2 treatment arms.

Results from this trial were presented in a plenary session during the 2022 American Society of Clinical Oncology Annual Meeting by Paul G. Richardson, MD, Director, Clinical Research, and Clinical Program Leader, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, and published in the New England Journal of Medicine to coincide with the presentation (N Engl J Med. 2022;387:132-147).¹

“There are a number of important messages from this study that will inform practice. The most important overarching one is that ‘one size does not fit all.’ This is incredibly exciting for patients because it means you can choose your therapy with a degree of confidence that it won’t necessarily have an impact on their overall survival,” Dr Richardson stated.

Study Description

All patients were assigned to treatment with lenalidomide, bortezomib (Velcade), and dexamethasone and randomized to ASCT (N = 365) or no ASCT (N = 357). All patients received lenalidomide maintenance until disease progression. The median duration of lenalidomide maintenance therapy was 41.5 months in the ASCT arm and 36.4 months in the non-ASCT arm.

Approximately 58% of patients were male and 42% were female. Median age was approximately 56 years. Notably, approximately 19% of participants were African American.

“We had the highest representation of African American [patients] in our trial, above any other phase 3 trial in this setting. That to us was incredibly gratifying to see,” Dr Richardson said.

For the primary end point, significantly longer median PFS was observed in patients with ASCT (67.5 months) compared with those without ASCT (46.2 months; P <.0001). However, the 5-year OS was similar between the 2 arms.

Subgroup analyses indicated less benefit with ASCT in African-American participants, individuals with a body mass index >25 kg/m², and those with higher disease stage. Dr Richardson explained that although the subgroup findings require further follow-up, these data highlight the importance of inclusive clinical trials.

The effect of minimal residual disease (MRD) on PFS was analyzed using tumor samples obtained at the start of maintenance from 90 patients with ASCT and 108 patients without ASCT. In the ASCT group, 54.4% of patients were MRD-negative compared with 39.8% of those without ASCT. The 5-year PFS in MRD-negative patients was similar regardless of their treatment assignment (53.5% with ASCT vs 59.2% without ASCT).

In the ASCT arm, 28% of patients had ASCT as salvage therapy. The remaining patients received other subsequent treatments, including immunomodulatory drugs and proteasome inhibitors. The fact that patients had poststudy treatments may have influenced the lack of an OS difference between the 2 arms.

Significantly more grade ≥3–related hematologic adverse events were reported in the ASCT arm (89.9%) compared with the non-ASCT arm (60.5%; P <.001). In addition, 10 patients with ASCT had acute myeloid leukemia or myelodysplastic syndrome compared with no patients in the non-ASCT arm (P = .002). Patients in the ASCT arm also had reductions from baseline in quality of life surrounding the period of transplant, but these decreases were transient and leveled off over time.

Lessons from the Trial

Invited discussant Joseph Mikhael, MD, MEd, FRCPC, FACP, Chief Medical Officer, International Myeloma Foundation, and Professor, Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, AZ, discussed key takeaways from the trial.

“This study demonstrates to us that ASCT still has a place in the care of patients with multiple myeloma. Historically we’ve thought of this as a frontline approach. This adds further evidence that in the timing of transplant, like any other intervention, there isn’t a perfect sequence, and it doesn’t necessarily have to be used frontline,” he said.

The lenalidomide maintenance data illustrate the importance of selecting a dose that patients can tolerate long-term. “Be flexible in your dosing. Talk to your patients and see how they’re feeling. It’s better to have patients on a lower dose of lenalidomide than to discontinue it,” Dr Mikhael said.

He noted that the age of participants in the study ranged from 18 to 65 years, representing a younger and healthier population than the national average age and health of newly diagnosed patients in the United States.

He emphasized the importance of considering the patient’s individual situation, including insurance issues regarding stem-cell banking, tolerability of treatments, and the timing of transplant in relation to other life events.

“Patient preference is paramount,” Dr Mikhael said. “In a disease we are not curing, we want choices, and we want to individualize those choices.”

Reference

1. Richardson PG, Jacobus SJ, Weller EA, et al; for the DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387:132-147.