clinical topic updates
Continuous Antimyeloma Therapy and Optimal Use of the Immunomodulatory Agents
Continuous antimyeloma therapy has been shown to prolong disease control and has replaced the fixed-duration approaches of the past. Ideal properties of therapies that are to be used long-term include ease of use and tolerability.
Edward W. and Betty Knight Scripps Professor of Medicine
“Lenalidomide and pomalidomide can both be used long-term. We know that daratumumab can be used long-term/continuously as well, and the same is true for bortezomib when used every other week.”
In the continuous therapy paradigm, we prescribe the form of maintenance therapy that was used in clinical trials. So, for example, for a transplant-ineligible patient, the 2 main choices are VRd (bortezomib, lenalidomide, and dexamethasone) or DRd (daratumumab, lenalidomide, and dexamethasone). If you choose VRd, then you will use lenalidomide as maintenance therapy, based on the SWOG trial. If you choose DRd, then you are actually going to use both daratumumab and lenalidomide as maintenance therapy, based on the MAIA trial. And I would point out that these are different protocols, so one cannot, for example, compare DRd with VRd and say that DRd has a 60-month progression-free survival while the other has only 48 months. That is, with VRd, you are using 6 months of a triplet followed by lenalidomide alone, whereas with DRd, you are using a triplet until progression.
In transplant-eligible patients, even if we used a quadruplet for induction (eg, daratumumab plus VRd) followed by transplant, then the recommended maintenance is lenalidomide for standard-risk multiple myeloma and bortezomib plus lenalidomide for high-risk multiple myeloma. To include daratumumab in that space, we would need a randomized clinical trial showing that daratumumab is superior to lenalidomide or that daratumumab adds something to lenalidomide. A current study in the United States is evaluating whether daratumumab plus lenalidomide is more effective than lenalidomide alone as post-transplant maintenance therapy in patients with multiple myeloma.
Regarding the optimal use of immunomodulatory agents in a continuous fashion, one thing to consider is that these agents are relatively easy to use and do not cause too much toxicity. Lenalidomide and pomalidomide can both be used long-term. We know that daratumumab can be used long-term/continuously as well, and the same is true for bortezomib when used every other week. Recent data on maintenance therapy with oral ixazomib are also available. So, that is 5 different agents to choose from, depending on the clinical circumstance. Another consideration is dose optimization. These agents must be used at a dose that enables patients to live a normal life. And if that means 10 mg for lenalidomide and 2 mg for pomalidomide, so be it. The 3 weeks on, 1 week off schedule with lenalidomide allows the patient to take the drug long-term with minimal side effects.
Cippitelli M, Stabile H, Kosta A, et al. Role of Aiolos and Ikaros in the antitumor and immunomodulatory activity of IMiDs in multiple myeloma: better to lose than to find them. Int J Mol Sci. 2021;22(3):1103. doi:10.3390/ijms22031103
Dimopoulos MA, Jakubowiak AJ, McCarthy PL, et al. Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma. Blood Cancer J. 2020;10(2):17. doi:10.1038/s41408-020-0273-x
Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X
Durie BGM, Hoering A, Sexton R, et al. Longer term follow up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood. 2018;132(suppl 1):1992. doi:10.1182/blood-2018-99-117003
Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249
Palumbo A, Gay F, Cavallo F, et al. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol. 2015;33(30):3459-3466. doi:10.1200/JCO.2014.60.2466
Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia. 2020;34(12):3286-3297. doi:10.1038/s41375-020-0813-1
Siegel DS, Schiller GJ, Song KW, et al. Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure. Br J Haematol. 2020;188(4):501-510. doi:10.1111/bjh.16213
SWOG Cancer Research Network. Phase III study of daratumumab (NSC- 791647) + lenalidomide (LD) or lenalidomide (L) as post-autologous stem cell transplant maintenance therapy in patients with multiple myeloma (MM) using minimal residual disease to direct therapy duration (DRAMMATIC study). Accessed April 1, 2021. https://www.swog.org/clinical-trials/s1803