Paul G. Richardson, MD
The use of autologous stem cell transplantation (ASCT) early in the course of treatment showed a significant 21.4-month gain in median progression-free survival in younger, newly diagnosed patients with multiple myeloma compared with patients who received chemotherapy without an initial transplant. However, no overall survival benefit has yet been seen using ASCT early compared with keeping it in reserve. These findings from the phase III DETERMINATION trial were presented by Paul G. Richardson, MD, and colleagues during the Plenary Session at the 2022 ASCO Annual Meeting (Abstract LBA4).
'Positive Trend' in Multiple Myeloma
There have been a large number of newer drugs and regimens approved for use in the treatment of multiple myeloma in the past decade. As a result of the relatively long overall survival seen in this disease, many clinical trials have not yet shown an overall survival benefit with one regimen vs another.
Previous research has shown that for patients who plan to delay ASCT, adding bortezomib to a two-drug therapy improves survival compared with the two-drug therapy alone. As part of first-line therapy, some patients undergo a stem cell transplantation; the procedure is time-consuming and may cause serious side effects, so some patients opt to delay it or not have it at all.
ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO, commented on the study: “The prognosis for patients with multiple myeloma has improved substantially over the last 10 years. These findings add to an overall positive trend for patients with multiple myeloma and provide information relevant to the optimal timing of stem cell transplant in this disease.”
Study Details
In the DETERMINATION trial, patients were randomly assigned to initial treatment with melphalan to aid in collecting stem cells, then ASCT, followed by two cycles of a triplet-combination therapy with lenalidomide, bortezomib, and dexamethasone (RVd) vs three cycles of RVd, followed by stem cell mobilization (collection of stem cells for possible future use if the disease progresses), and then five more cycles of RVd. Both arms received lenalidomide maintenance until disease progression or intolerable drug toxicity. Median progression-free survival was 46.2 months in the nontransplant arm vs 67.6 months in the ASCT arm. Subsequent treatment was necessary for 63% of patients in the nontransplant arm vs 53% of patients in the ASCT arm. Of the patients in the nontransplant arm, 28% underwent a delayed transplant as part of this subsequent treatment.
There were 90 deaths in the nontransplant arm vs 88 deaths in the ASCT arm, resulting in a 4-year overall survival of 84% vs 85%, respectively. These results were not statistically significant. The 5-year overall survival estimates were not different, with a median follow-up now of more than 6 years.
Adverse events were less common without than with ASCT, with overall adverse events occurring in 78% without transplantation vs 94% with ASCT. Blood-borne adverse events occurred in 61% of those who did not receive ASCT vs 90% of those who did. A total of 10% of patients not given ASCT developed secondary malignancies compared with 11% of those with did, with a significantly higher rate of secondary acute myeloid leukemia or myelodysplastic syndromes in patients treated with ASCT.
Initial quality-of-life scores associated with stem cell transplant in the ASCT arm were lower than in the nontransplant arm. However, patients' quality of life subsequently recovered post-transplant.
This study was originally a parallel study to the phase III IFM/DFCI 2009 trial. Whereas this previous trial used lenalidomide as maintenance for only 1 year, lenalidomide was given until disease progression for all patients in the DETERMINATION trial. In a cross-trial comparison, the DETERMINATION study showed about a 12-month improvement in progression-free survival for patients in the nontransplant arm when using lenalidomide until disease progression compared with the use of 1 year of lenalidomide in the IFM/DFCI 2009 trial, confirming the clinical benefit of maintenance lenalidomide.
“The findings from DETERMINATION will have importance for real-world practice and the treatment of younger patients with multiple myeloma by informing providers and patients alike of the important considerations to be made in selecting treatment options in the newly diagnosed, transplant-eligible setting, as well as important implications for future research," said Dr. Richardson, who is Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston. Dr. Richardson also noted that this trial has the highest participation of Black patients of any phase III study in this setting to date at 18%.
The patients in the study continue to be followed for effects on overall survival and long-term safety endpoints. Whole-genome sequencing, additional quality-of-life assessments, and correlative analyses are ongoing.
Disclosure: This study was funded by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute as well as the RJ Corman Multiple Myeloma Research Fund, Celgene/Bristol Myers Squibb and the Millennium/Takeda Pharmaceutical/Biotech Company. For full disclosures of the study authors, visit coi.asco.org.
