Many oncologists historically prescribed indefinite treatment for myeloma patients. Consequently, lenalidomide maintenance therapy became the standard of care after initial induction. However, doctors still debated the exact duration of this treatment. A newly published clinical trial has now answered this critical clinical question. Specifically, the phase 3 ENDURANCE trial compared fixed-duration therapy against continuous therapy.
Trial Design and Patient Demographics
The researchers enrolled 516 patients with standard-risk newly diagnosed multiple myeloma. Importantly, none of these patients underwent up-front autologous stem-cell transplantation. Following induction treatment with a proteasome inhibitor and lenalidomide, researchers randomly assigned the participants. Specifically, 260 patients received indefinite-duration lenalidomide. Conversely, 256 patients received a fixed two-year course of lenalidomide.
Optimal Duration of Lenalidomide Maintenance Therapy
The trial followed patients for a median of 86 months. Interestingly, overall survival did not differ significantly between the two groups. At seven years, the overall survival rate was 68.6% in the continuous group. Similarly, the survival rate was 69.0% in the fixed-duration group. Therefore, continuing treatment beyond two years did not offer any survival benefit. Additionally, progression-free survival rates at seven years showed no statistically significant difference. Specifically, the continuous group achieved 36.1% progression-free survival. Meanwhile, the fixed-duration group achieved 29.7% progression-free survival.
Toxicity and Long-Term Risks
Safety analysis revealed that continuous treatment caused more adverse events. Furthermore, the incidence of grade 3 or higher nonhematologic events was 48.2% in the continuous group. In contrast, only 31.5% of patients in the fixed-duration group experienced these severe toxicities. Moreover, long-term exposure raised the risk of second primary cancers. Specifically, the five-year cumulative incidence of these cancers was 11.2% with continuous treatment. Conversely, the fixed-duration group experienced an incidence of only 8.3%. Thus, stopping therapy after two years reduces toxicity and improves overall quality of life.
Clinical Implications for Practice
This trial fundamentally challenges the current paradigm of indefinite therapy. Consequently, clinicians must rethink how they manage patients with standard-risk multiple myeloma. For many patients, a two-year course represents a safer and cheaper alternative. Indeed, fixed-duration treatment dramatically lowers financial burdens for patients. Additionally, it helps avoid unnecessary long-term toxicities. Ultimately, these results support shared decision-making in clinical practice.
Frequently Asked Questions
Q1: What did the ENDURANCE trial conclude about lenalidomide maintenance therapy?
The trial concluded that fixed-duration maintenance therapy with lenalidomide offers equivalent overall survival to continuous therapy. This finding applies specifically to standard-risk patients who do not undergo an upfront transplant.
Q2: Did the continuous lenalidomide group experience more side effects?
Yes. Indeed, patients on continuous therapy experienced significantly higher rates of grade 3 or higher nonhematologic adverse events compared to those on fixed-duration therapy.
Q3: Was there a difference in second primary cancer incidence between the two groups?
Yes. Specifically, the five-year cumulative incidence of second primary cancers was 11.2% with continuous lenalidomide. Conversely, the fixed-duration group experienced an incidence of only 8.3%.
References
- Kumar S et al. Continuous or Fixed-Duration Maintenance Therapy in Multiple Myeloma. N Engl J Med. 2026 Jul 16. doi: 10.1056/NEJMoa2600157. PMID: 42456135.
- Mian H, Costa LJ. Time to stop? Rethinking the duration of maintenance treatment in multiple myeloma. N Engl J Med. 2026 Jul 16. doi: 10.1056/NEJMe2604761.