patient care perspectives

Risk-Adapted Post-Transplant Maintenance Therapy in Multiple Myeloma

by Kenneth C. Anderson, MD

Overview

Post-transplant lenalidomide maintenance therapy has improved outcomes in standard-risk and high-risk patients with multiple myeloma. As investigators look to maintain progression-free survival (PFS) status in high-risk patients, lenalidomide-based combinations continue to be of interest.

Expert Commentary

Kenneth C. Anderson, MD

Kraft Family Professor of Medicine
Harvard Medical School
Director, LeBow Institute for Myeloma Therapeutics
Director, Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Boston, MA

“The ability to use novel drugs in combination in the transplant paradigm has remarkably improved outcomes. Once we can achieve very high rates of MRD negativity, we then have the ability to maintain these responses.”

Kenneth C. Anderson, MD

The ability to use novel drugs in combination in the transplant paradigm has remarkably improved outcomes. Once we can achieve very high rates of minimal residual disease (MRD) negativity, we then have the ability to maintain these responses. In multiple myeloma, lenalidomide as a single agent, 10 mg orally for 21 of 28 days, is US Food and Drug Administration approved. Lenalidomide after autologous stem cell transplantation offers PFS and overall survival (OS) benefits over placebo, as shown in 2 large randomized trials. This is no small benefit. In fact, a meta-analysis including more than 1200 patients, with a median follow-up of 79.5 months, demonstrated that lenalidomide maintenance offers more than 2 years of PFS benefits and 2.5 years of OS benefits over placebo.

There have been attempts to incorporate other agents with lenalidomide in risk-adapted maintenance therapies. One of the earlier experiences was from the Winship Cancer Institute at Emory University with Sagar Lonial, MD, FACP, and his team, where post-transplant RVd (lenalidomide, bortezomib, and dexamethasone) was used in patients who had high-risk multiple myeloma and underwent transplantation, with the goal of avoiding the early relapses that are the hallmark of high-risk disease. This resulted in an OS of 93% at 3 years in that population. More recently, Nisha S. Joseph, MD, and colleagues at the Winship Cancer Institute reported long-term follow-up results in 1000 patients who received RVd, transplant, and risk-adapted maintenance therapy (lenalidomide for standard risk and RVd for high risk). The median PFS for standard-risk patients was 76.5 months; the median OS for standard-risk patients has not been reached. Even in high-risk patients, the median PFS was 40.3 months and the median OS was 78.2 months.

There is other evidence for the use of risk-adapted maintenance post transplant. For example, in the FORTE trial, KRd (carfilzomib, lenalidomide, and dexamethasone) was compared with carfilzomib, cyclophosphamide, and dexamethasone before a transplant. The regimens were compared as consolidation, and then post transplant, there was lenalidomide vs carfilzomib-lenalidomide maintenance. KRd was very effective after transplant, even in the high-risk patients.

Currently, there are ongoing trials of daratumumab incorporated into maintenance in standard-risk and high-risk patients. These trials are in the early stages, but they look appealing. For example, the GRIFFIN trial compared RVd before and after transplant vs daratumumab plus RVd before and after transplant. There was a randomization between daratumumab plus lenalidomide maintenance vs lenalidomide maintenance. In this trial, the daratumumab-plus-lenalidomide maintenance group had more persistent MRD negativity. Thus, for these high-risk patients, there will potentially be other partners for lenalidomide maintenance coming in the future, such as CD38 antibodies.

References

Attal M, Lauwers-Cances V, Marit G, et al; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791. doi:10.1056/NEJMoa1114138

Baertsch M-A, Mai EK, Hielscher T, et al; German-Speaking Myeloma Multicenter Group (GMMG). Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2021;11(1):1. doi:10.1038/s41408-020-00390-3

Devarakonda S, Efebera Y, Sharma N. Role of stem cell transplantation in multiple myeloma. Cancers (Basel). 2021;13(4):863. doi:10.3390/cancers13040863

Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up [published correction appears in Hemasphere. 2021;5(4):e567]. Hemasphere. 2021;5(2):e528. doi:10.1097/HS9.0000000000000528

Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(15 suppl):8002. doi:10.1200/JCO.2019.37.15_suppl.8002

Jackson GH, Davies FE, Pawlyn C, et al; UK NCRI Haemato-Oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57-73. doi:10.1016/S1470-2045(18)30687-9

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

McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35(29):3279-3289. doi:10.1200/JCO.2017.72.6679

McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. doi:10.1056/NEJMoa1114083

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

Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905. doi:10.1056/NEJMoa1402888

Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol. 2019;37(7):589-597. doi:10.1200/JCO.18.00685

Vaxman I, Gertz M. Risk adapted post-transplant maintenance in multiple myeloma. Expert Rev Hematol2019;12(2):107-118. doi:10.1080/17474086.2019.1576521

Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288

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