patient care perspectives

Safety and Tolerability of Long-Term, Continuous Treatment for Multiple Myeloma

by Sagar Lonial, MD, FACP

Overview

In both transplant and nontransplant populations, a careful balance between disease control, side effects, and quality of life must be maintained. Triplets are preferred from the perspective of disease control, and measures can be taken to improve tolerability so that long-term outcomes are not compromised.

Expert Commentary

Sagar Lonial, MD, FACP

Chair and Professor
Department of Hematology and Medical Oncology
Anne and Bernard Gray Family Chair in Cancer
Chief Medical Officer
Winship Cancer Institute
Emory University School of Medicine
Atlanta, GA

“I think that there are ways to modify the approach to make it a little easier or more convenient for patients, but it really depends on the risks and side effects that patients are experiencing.”

Sagar Lonial, MD, FACP

The continuous therapy paradigm has been evolving. Consider the randomized IFM 2009 trial, which involved patients with newly diagnosed multiple myeloma receiving lenalidomide, bortezomib, and dexamethasone (RVd) induction therapy followed by either autologous stem cell transplantation (ASCT) plus RVd (RVd-ASCT) or RVd alone. The median progression-free survival (PFS) in this trial was approximately 47 months in the transplant group vs 35 months in the RVd-alone group. However, neither group in this trial received continuous lenalidomide maintenance therapy, as is the current practice in the United States. Instead, both groups received just 1 year of lenalidomide therapy.

The US version of IFM 2009 has not yet met its primary end point. However, in March 2020, our group published results from a series of 1000 consecutive patients with newly diagnosed multiple myeloma who received RVd induction therapy, transplantation, and then continuous lenalidomide maintenance therapy. Our estimated median PFS was 65 months for the entire cohort. Thus, with continuous maintenance, we saw a prolongation of the duration of remission by roughly 1 year. In fact, the estimated median PFS for standard-risk patients was 76.5 months with continuous lenalidomide therapy, or a prolongation that is closer to 2 years.

So, what about treatment toxicity? I tell my patients that we should stop continuous therapy if their quality of life is significantly diminished. But if we can manage those side effects, it becomes worth doing. Medications such as colestipol or colesevelam can reverse gastrointestinal symptoms in the vast majority of cases. For patients who have too much fatigue or other symptoms, it is necessary to balance the benefits of continuous therapy with the downsides of toxicity management. If a patient does not tolerate lenalidomide, you could consider ixazomib. However, while it may have some benefits in high-risk disease, the data do not support generally substituting ixazomib for lenalidomide.

Although there is a concern that lenalidomide maintenance therapy can increase the cumulative risk of a secondary hematologic malignancy, that risk may be offset by the survival benefits. In our series of 1000 consecutive patients, the rate of secondary primary malignancies was approximately 3% to 4%. The 1-week break from lenalidomide at the end of a cycle, which is typically done in the United States, seems to reduce that risk of a secondary malignancy as well.

Now, say that you have an older patient who was never a transplant candidate who was treated with RVd. The following question arises: Do you need all 3 drugs until disease progression? If the patient is frail, for instance, you can refer to the phase 3 SWOG S0777 study, which examined bortezomib, lenalidomide, and dexamethasone (VRd) vs Rd. In that trial, the lenalidomide was continued, but the bortezomib was stopped at 8 cycles. This is probably a more patient-friendly approach for those who have high-risk disease. Our center has advocated for the use of triplet therapy. I think that there are ways to modify the approach to make it a little easier or more convenient for patients, but it really depends on the risks and side effects that patients are experiencing.

References

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

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

Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial [abstract 143]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Roussel M, Hebraud B, Hulin C, et al. Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma. Leuk Lymphoma. 2020;61(6):1323-1333. doi:10.1080/10428194.2020.1719091

Zweegman S, Stege CAM, Haukas E, et al. Ixazomib-thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; results from the randomized phase II HOVON-126/NMSG 21.13 trial. Haematologica. 2020;105(12):2879-2882. doi:10.3324/haematol.2019.240374

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