A study aimed at determining the optimal duration of lenalidomide maintenance after autologous stem cell transplantation for multiple myeloma has not answered that question, per se, but has yielded some hints that may inform future clinical trials. The follow-up analysis of the UK NCRI Myeloma XI trial was reported at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition by Charlotte Pawlyn, PhD, of the Institute of Cancer Research and the Royal Marsden Hospital NHS Foundation Trust, London.¹

The investigators found that in the overall population, continued lenalidomide maintenance to 5 years reduced the risk of disease progression. In addition, patients who undoubtedly benefit from continuous maintenance to 5 years or beyond can be identified by measurable residual disease (MRD) status. MRD-negative patients derive benefit from lenalidomide maintenance for at least 3 years, and studies should be designed to understand if some patients might be able to stop treatment safely after this time point. For MRD-positive patients, on the other hand, the data support continuing maintenance until disease progression.

“In this analysis, there is clear evidence that continuing lenalidomide maintenance beyond 3 years is associated with improved progression-free survival in all patients…. The data suggest that for patients who are MRD-negative at the time of starting maintenance therapy, there may be a time after stem cell transplant at which continuing maintenance may no longer have ongoing benefit over observation, but that needs to be addressed in future randomized studies,” Dr. Pawlyn said.

In this analysis, there is clear evidence that continuing lenalidomide maintenance beyond 3 years is associated with improved progression-free survival…

— Charlotte Pawlyn, PhD

Tweet this quote

Important Question

“Several phase III studies and a meta-analysis have demonstrated that lenalidomide maintenance is associated with significantly prolonged progression-free survival and overall survival compared with observation…. The studies were initially planned for patients to continue maintenance until disease progression, but as outcomes for our patients improve and progression-free survival lengthens, it would potentially be preferable for patients to be able to stop therapy earlier if we could identify a time point at which that could be done safely, either in the overall population or perhaps as directed by genetics or MRD status,” she said.

This question was explored in the phase III randomized UK NCRI Myeloma XI trial in 1,248 newly diagnosed “all-comers.” Transplant-eligible patients could be randomly assigned after transplantation to lenalidomide at 10 mg as maintenance (until disease progression or intolerance) or observation. The arms were well balanced, with approximately one-third of patients classified as high-risk.

Significant Maintenance Benefit

After a median follow-up of 44.7 months and a median of about 2 years on treatment, maintenance lenalidomide resulted in a significantly prolonged—even doubling of—progression-free survival vs observation. Median progression-free survival was 64 months with lenalidomide vs 32 months with observation (hazard ratio [HR] = 0.52; P < .001).

“These results confirmed our previously reported findings² from an earlier data cutoff,” Dr. Pawlyn said. “Importantly, the benefit associated with lenalidomide maintenance from the randomization time point remained significant in both standard-risk (HR = 0.40; P < .0001) and high-risk/ultra-high–risk patients (HR = 0.50; P < .0001) and in patients who were either MRD-negative (HR = 0.72; P = .022) or MRD-positive (HR = 0.37; P < .0001) at the time of maintenance randomization.”

Similarly, the time to disease progression or death on the next line of treatment (PFS2) was significantly prolonged. Median PFS2 was not reached with maintenance vs 61 months with observation (HR = 0.66; P < .0001).

Outcomes at Various Time Points

To further explore the question of maintenance duration, the researchers repeated these analyses using multiple landmarks of the data. For each time point—from 2 years after randomization, 3 years after randomization, and so forth—they included all patients remaining on the study and measured outcomes in the overall population and by risk and MRD status.

“If you look across the overall population using these multiple landmarks after the start of maintenance therapy, you can see evidence of a significant benefit for continuing lenalidomide to the 2-year mark (HR = 0.51; P < .0001), 3-year mark (HR = 0.47; P < .0001), and 4-year mark (HR = 0.56; P = .031), although it is no longer statistically significant from the 5-year landmark (HR = 0.83; P = .672),” Dr. Pawlyn reported. The same pattern was seen with PFS2, with evidence of significant benefit beyond 4 years of therapy.

“But it’s important to note that at the current follow-up, there is a high degree of censoring from these later time points; therefore, it’s difficult to be certain whether there is a true loss of treatment effect, or whether we need to wait for longer follow-up. The current data do not indicate a clear time point at which it would be safe to say, ‘That’s the point at which we can stop maintenance’ in the general population,” she cautioned.

Exploring Maintenance by MRD Status

The investigators then questioned whether an earlier stopping point could be justified in certain subgroups. They found that in both standard-risk and high-risk/ultra-high–risk patients, the pattern of benefit from maintenance continued out to at least 5 years. Examination of patients by MRD status, on the other hand, revealed clear differences.

Patients who were MRD-negative at the time of maintenance randomization showed evidence of a significant benefit for continuing lenalidomide beyond 2 years, but the difference lost statistical significance beyond 3 years.  In contrast, MRD-positive patients gained a much greater benefit from lenalidomide maintenance at all time points, with lenalidomide associated with hazard ratios of 0.34 at 2 years, 0.28 at 3 years, and 0.14 at 4 years.

“The reason there are no data at 5 years for patients who are MRD-positive is because of too few patients reaching this time point in the control arm. This emphasizes the importance of continuing lenalidomide maintenance to disease progression for patients who are MRD-positive,” Dr. Pawlyn commented.

“But we know that sustained MRD negativity rather than MRD assessment at a single time point is associated with improved progression-free and overall survival. So rather than looking at MRD status at randomization, the obvious question is whether patients with sustained MRD negativity can stop maintenance earlier,” she said.

To this end, benefit was shown for maintenance in patients with sustained MRD negativity from 6 months to 3 years, but there was less evidence to support continuing lenalidomide beyond that time point. “For patients with sustained MRD negativity, at least 3 years after maintenance starts would be an appropriate time to explore stopping lenalidomide in a randomized setting,” she suggested. “Such studies would provide the evidence needed to change practice.”

Dr. Pawlyn added that continuing lenalidomide maintenance beyond certain time points must be balanced against the risk of cumulative toxicity. Although hematologic toxicity does appear to diminish over time, she said, “the spectrum of all toxicities experienced by the patient, as well as their preferences, should be considered.” 

DISCLOSURE: Dr. Pawlyn has served as a consultant to Janssen, Sanofi, Celgene/BMS, and AbbVie; and has received honoraria and/or travel support from Janssen, Sanofi, and Celgene/BMS.

REFERENCES

1. Pawlyn C, Menzies T, Davies FE, et al: Defining the optimal duration of lenalidomide maintenance after autologous stem cell transplant: Data from the Myeloma XI Trial. 2022 ASH Annual Meeting and Exposition. Abstract 570. Presented December 11, 2022.

2. Jackson GH, Davies FE, Pawlyn C, et al: Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20:57-73, 2019.