Recommended Maintenance Therapy for Multiple Myeloma: Transplant and Nontransplant Settings
In the nontransplant setting, continuous therapy may involve a doublet or a triplet regimen as tolerated until disease progression. After the more intense induction and autologous stem cell transplantation, post-transplant maintenance therapy might involve a single agent or a doublet regimen. In both settings, continuous lenalidomide-based treatment is a standard.
How would you describe the current paradigm regarding maintenance therapy for different types of patients with multiple myeloma?
Chair and Professor
“Maintenance therapy is certainly a standard in multiple myeloma, and continuous therapy has demonstrated longer durations of remission."
The paradigm of treatment in multiple myeloma right now is continuous therapy. Whether it is maintenance therapy, as in the setting of a post-transplant patient, in a risk-adapted way or continuous therapy in a nontransplant-eligible patient who, for example, has a good induction and then one form of therapy or all of the therapies continue(s) until progression, these are the norms. Maintenance therapy is certainly a standard in multiple myeloma, and continuous therapy has demonstrated longer durations of remission.
In the United States, continuous lenalidomide maintenance is the standard of care, and, in 2020, we published our series of 1000 consecutive patients who received induction with lenalidomide, bortezomib, and dexamethasone (RVd), transplantation, and then continuous lenalidomide maintenance therapy. Our estimated median progression-free survival (PFS) was 65 months for the entire cohort and 76.5 months for those with standard-risk multiple myeloma. Compare that with the IFM 2009 trial, which showed a median PFS of 50 months with RVd plus transplantation and lenalidomide maintenance therapy. The US-based trial that would mirror the IFM 2009 trial is not yet mature, but there is clear value in maintenance therapy, as long as the treatment is tolerable and the patient maintains a healthy quality of life. If patients start encountering toxicities or side effects from the chronic administration of lenalidomide that are not easily managed, provided such individuals have received at least 1 year of maintenance therapy, I am comfortable with either stopping treatment or switching to a different target as maintenance in that clinical situation.
Edward W. and Betty Knight Scripps Professor of Medicine
“Continuous lenalidomide-based treatment is currently the standard for maintenance therapy in both transplant-eligible and -ineligible patients.”
Continuous lenalidomide-based treatment is currently the standard for maintenance therapy in both transplant-eligible and -ineligible patients. For transplant-eligible patients, it is based on multiple clinical trials showing that maintenance with lenalidomide prolongs PFS and improves overall survival (OS). For transplant-ineligible individuals, we know from the SWOG S0777 trial that patients were randomized to RVd vs lenalidomide plus dexamethasone, and the results of that trial reflect the fact that every participant received lenalidomide until progression. So, although it was not termed as maintenance therapy, it basically served as maintenance therapy.
Similarly, in the daratumumab, lenalidomide, and dexamethasone MAIA trial, the combination was to continue until the occurrence of disease progression or unacceptable side effects. Therefore, lenalidomide is a constant as much as patients can tolerate it. In high-risk individuals, data from the HOVON-65/GMMG-HD4 trial, also from single-institution studies, indicate that adding bortezomib was very valuable. Our group feels that, for all patients who are high risk, in addition to lenalidomide, we would add bortezomib, which is administered every other week. There are some patients who may have had bortezomib as the initial therapy; such individuals can continue the same at a lower dose.
Kraft Family Professor of Medicine
“The benefits of PFS and OS have to be balanced against the side effects. If we can use MRD to identify patients in whom we can safely stop maintenance, we will not only prolong PFS and OS but also improve their quality of life.”
I agree with my colleagues that lenalidomide really is a standard of care, especially with standard-risk multiple myeloma. As of now, it is given continuously until relapse. It is US Food and Drug Administration approved because it prolongs not only PFS but also OS in the post-transplant setting. Dr Lonial’s group has nicely shown at Emory University (and it is our practice as well) that the addition of bortezomib to lenalidomide in high-risk patients has value. The reason is that, although lenalidomide may confer a benefit alone, it is not enough; however, if you add a proteasome inhibitor, you can, to some extent, abrogate the early relapses that are the hallmark of high-risk disease.
Currently, there are many ongoing trials that are evaluating other agents, particularly CD38 monoclonal antibodies, in the maintenance setting. Minimal residual disease (MRD) is currently measured by multicolor flow cytometry, gene sequencing, and positron emission tomography/computed tomography. There is also a longitudinal component (ie, 2 time points of MRD negativity separated by at least a 1-year duration) as a clinical trial end point. There are now discontinuation trials where maintenance is being discontinued in patients with durable MRD negativity. It is a bit like the past, when imatinib achieved molecular emissions in chronic myeloid leukemia for the first time and discontinuation trials followed. We may be in a similar situation now in multiple myeloma, and it is now critical to determine whether we can discontinue maintenance therapy in patients with durable MRD negativity.
Dose adjustments have been made to address issues of toxicity in patients taking lenalidomide maintenance. Diarrhea is treated symptomatically. There is also a low but real incidence of secondary malignancy in patients receiving lenalidomide maintenance therapy post transplant. The benefits of PFS and OS have to be balanced against the side effects. If we can use MRD to identify patients in whom we can safely stop maintenance, we will not only prolong PFS and OS but also improve their quality of life.
Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750
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, 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 Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8
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
Goldschmidt H, Lokhorst HM, Mai EK, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018;32(2):383-390. doi:10.1038/leu.2017.211
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 [published correction appears in J Clin Oncol. 2020;38(23):2702]. J Clin Oncol. 2020;38(17):1928-1937. doi:10.1200/JCO.19.02515
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Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014;28(3):690-693. doi:10.1038/leu.2013.335