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.