The invited discussant of the ATLAS trial, Peter M. Voorhees, MD, Professor of Medicine, Chief of the Plasma Cell Disorders Division, at Levine Cancer Institute and Atrium Health/Wake Forest Baptist in North Carolina, applauded the very good outcomes achieved in the study.1 However, he posed the following question: “At what point does the burden of increased treatment outweigh the potential gains in progression-free survival when there is no difference in overall survival?”
Peter M. Voorhees, MD
Dr. Voorhees continued: “Although there was a 44% reduction in the risk of disease progression or death for those assigned to the triplet vs lenalidomide monotherapy, not surprisingly there was no difference in overall survival—an increasingly difficult benchmark to achieve in front-line myeloma studies.”
Based on ATLAS and FORTE,2 which had similar findings, Dr. Voorhees concluded that carfilzomib, lenalidomide, and dexamethasone (KRd)-based maintenance “is a new standard of care for high-risk fit patients who have undergone induction therapy and ASCT.” However, he asked, “in the absence of an overall survival advantage, is lenalidomide enough in standard-risk patients?”
Upfront Treatments Effective, but Considerations Remain
As Dr. Voorhees pointed out, existing induction regimens, front-line ASCT (autologous stem cell transplantation), and lenalidomide maintenance have markedly improved progression-free survival. As a case in point, he described a retrospective study from Emory University involving 1,000 standard-risk patients who received lenalidomide, bortezomib, and dexamethasone (RVd) induction followed by risk-adapted maintenance therapy (751 had upfront transplantation).3 This treatment resulted in a median progression-free survival exceeding 6 years and a median overall survival of 13 years.
“There’s always room for improvement, certainly, but I think we’re doing quite well these days in this particular group of patients,” Dr. Voorhees maintained. “At least for standard-risk patients, progression-free survival is already very good with standard therapy.”
The improvement in progression-free survival as attained under the ATLAS approach also comes at a financial cost, Dr. Voorhees noted. He calculated the total cost of consolidation and maintenance therapies under three scenarios:
- KRd continuation through cycle 36, followed by lenalidomide: It requires 152 infusion visits and costs about $932,101.
- KRd continuation through cycle 8, followed by lenalidomide: It requires 40 infusion visits and costs about $646,268.
- Lenalidomide maintenance: It requires no infusion visits and costs about $544,184.
There is also the growing trend to use monoclonal antibodies upfront, which has shown a benefit in numerous studies, added Dr. Voorhees. CASSIOPEIA4 and GRIFFIN5,6 evaluated the incorporation of daratumumab into bortezomib, thalidomide, and dexamethasone (VTd) and RVd backbones, respectively; in neither study was median progression-free survival reached (after 44 and 39 months of follow-up, respectively), and the rate at 3 years was approximately 80% and 89%. “In CASSIOPEIA, that impressive result was obtained even though half the patients received no maintenance therapy and the other half received daratumumab alone once every 8 weeks for just 2 years,” he added.
“Clearly, KRd performed better than lenalidomide, but again, given the impressive progression-free survival that we are seeing with modern-day induction, even followed by lenalidomide maintenance, I think this multidrug maintenance approach is probably best suited for patients for whom we do not expect a long progression-free survival—specifically those with high-risk cytogenetics,” he concluded.
Regarding MRD-guided de-escalation, Dr. Voorhees said questions remain. Before establishing MRD to adapt treatment decisions, he would like to see a trial that randomly assigns patients at the point of MRD determination.
DISCLOSURE: Dr. Voorhees reported financial relationships with Bristol Myers Squibb, Amgen, Celgene, Novartis, and Janssen.
REFERENCES
1. Dytfeld D, Wrobel T, Jamroziak K, et al: ATLAS: A phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. 2022 ASCO Annual Meeting. Abstract 8001. Presented June 5, 2022.
2. Gay F, Musto P, Rota-Scalabrini D, et al: Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): A randomised, open-label, phase 2 trial. Lancet Oncol 22:1705-1720, 2021.
3. Joseph NS, Kaufman JL, Dhodapkar MV, et al: Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol 38:1928-1937, 2020.
4. Moreau P, Attal M, Hulin C, et al: Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 394:29-38, 2019.
5. Voorhees PM, Kaufman JL, Laubach J, et al: Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood 136:936-945, 2020.
6. Laubach JP, Kaufman JL, Sborov DW, et al: Daratumumab plus lenalidomide, bortezomib, and dexamethasone in patients with transplant-eligible newly diagnosed multiple myeloma: Updated analysis of Griffin after 24 months of maintenance. 2021 ASH Annual Meeting & Exposition. Abstract 79. Presented December 11, 2021.
