Lenalidomide Is Safe and Active in Waldenstrom Macroglobulinemia (WM)
Authors: Leleu Xavier , Legouill Steven , Louni Chanaz , Lionel Karlin , Banos Anne , Arnulf Bertrand , Petillon Marie Odile , Tournilhac Olivier , Morel Pierre , Leblond Veronique 
Published: October 2019

Abstract
Background. Lenalidomide has proved safe and effective in multiple myeloma (MM), particularly in elderly patients. Furthermore, it has been showed that lenalidomide enhanced rituximab-mediated antibody-dependent cell-mediated cytotoxicity. Unexpectedly, lenalidomide (25 mg/d on days 21/28) along with rituximab (375 mg/m²/wk) produced clinically significant acute anemia in patients with WM, most of them received 25mg/day with no improvement when the dose was reduced (Treon et al. CCR, 2009). No cause was attributable to the occurrence of this adverse event. Thus, we sought to perform a study with incremental concentrations of single agent lenalidomide to determine the maximum tolerated dose (MTD) of lenalidomide in WM, and possibly unravel the cause of anemia upon treatment with lenalidomide.
Methods. RV-WM-0426 is a multicenter phase I/II dose escalation open label study of lenalidomide in relapse/refractory WM. Lenalidomide was given oral daily 21 / 28 days per cycles for 1 year, at escalated dose of 15 to 20 then 25mg across cohorts of 3 to 6 patients each during the phase 1 part, then followed by 9 patients to recruit in the phase 2 part at the maximum tolerated dose (MTD). The primary endpoint was the MTD, secondary endpoint included response rate (International WM Workshop) and response duration, safety, measurements of free light chain assays, and PFS and OS.
Results. 17 patients were enrolled in the study, the median age was 69 (range 48-81), with 7 patients older than 75, 70% were male. 53% had adverse IPSS 3. The median hemoglobin level was 11.2 (95%CI 9.9-12.5), median M spike level 26.5 (95%CI 23-40), 23% had clearance creatinin below 60ml/min. The median number of prior lines was 1 (range 1-8), all patients but 2 exposed to alkylating agents, 30% to nucleoside analogues, 47% to the monoclonal antibody mabthera, none of the patients have had a transplantation. The median time from diagnosis to study entry was 3 years (range 2-15). At the highest dose tested, 20 mg, 2 patients had dose-limiting toxicity, septic syndrome during grade 4 neutropenia and severe fatigue, respectively. The MTD was thus established at the 15 mg/day 21 days out of 28. 7/17 (41%) patients completed one year of single agent lenalidomide at 15mg day 21/28.
Single agent lenalidomide in WM provided an overall response (minimal response (MR) and better) on an intent-to-treat basis at 15mg/day of 36%, and an extra 2 patients had a prolonged stable disease (SD). A flare effect (transient initial increase of the M spike) was observed in 5 patients. With a median follow-up of 36 months, 14 have progressed with a median time to progression of 16 months (95%CI 5.5-26), with 35% of patients with a PFS greater than 24 months. One patient died with a 5-year overall survival (OS) of 91%.
The most common adverse event (AE ≥ 10%) was fatigue of at least grade 2, reported in 50% of the patients. The incidence rate of grade 3 and greater hematological AE at 15mg was 14% for anemia, 43% for neutropenia, and no thrombopenia observed. 78% experienced a non hematological AE of at least grade 2, but only 2 patients had a grade 3 AE, nephrotic syndrome and cramps. No second primary malignancy (SPM) nor thromboembolic event were reported to date. Only 21% of patients had dose reduction with a median time of 7 months, and 35% had study drug interruption related to an AE with a median time of 4 months.
Conclusion. The MTD of lenalidomide is 15mg/day given on days 21/28 in relapse and refractory WM. Lenalidomide is active in the treatment of RRWM and the safety profile appeared manageable, essentially of grade 2 AEs. Future studies may look into combinations to lenalidomide and continuous therapeutic effect in WM at the determined MTD.

Disclosures
Leleu: Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.