Prolonged Use of Lenalidomide (≥12 Cycles) for Multiple Myeloma (MM) Is Frequently Affected by Dose-Limiting Thrombocytopenia but Is Associated with Improved Quality of Response and Survival.
Authors: Yeboah Elizabeth , Masih-Khan Esther , Massey Christine , Reece Donna E. , Trudel Suzanne , Kukreti Vishal , Anglin Peter , Chen Christine 
Published: October 2019

Abstract
Abstract 1866
Poster Board I-891

Introduction:
Lenalidomide is currently approved for use in relapsed/refractory MM based on two large phase III trials accruing >700 patients (pts)(Dimopoulos et al, 2007; Weber et al, 2007). Subsequently, an Extended Access Program (EAP) supplied lenalidomide to an additional 1438 pts, providing confirmatory safety data (Chen et al, 2009). In this EAP protocol, lenalidomide was initiated in combination with dexamethasone at the same dose/schedule as that of the randomized trials. For all pts on the EAP, the median duration on therapy was short at 15.4 weeks (range 0.1–49.1), as most pts stopped protocol due to commercial availability of lenalidomide in the US. At our Canadian site, due to delays in lenalidomide availability, we maintained pts on the EAP until progressive disease (PD) or excessive toxicity. Of 122 MM pts on the EAP at our institution, 44(36%) received prolonged lenalidomide (≥12 cycles). We hypothesized that prolonged lenalidomide would be associated with improved progression-free survival (PFS) and aimed to identify disease/treatment variables that affect duration on therapy.

Methods:
From Sept 2005-Dec 2008, 122 relapsed/refractory MM pts treated on the EAP protocol at Princess Margaret Hospital were reviewed; 44(36%) of whom received ≥12 cycles of lenalidomide (Group 1), 78(64%) of who received <12 cycles (Group 2). Patient eligibility was identical to the pivotal phase III studies. Lenalidomide was initiated at 25mg PO daily for 21days with dexamethasone 40mg PO days 1–4, 9–12, 17–20 every 28day cycle. Comparison of variables (demographics, baseline disease characteristics, treatment details, responses, survival) between the 2 groups was performed.

Results:
Survival: As expected, both PFS and overall survival (OS) were prolonged for Group 1 versus Group 2: median PFS 21.8 vs 2.9 mos (p<0.0001); median OS > 42.5 vs 8.0 mos (p<0.0001). Causes of death were similar between groups: disease progression (PD)(87%), toxicity(11.5%)(p=0.17). Demographics and disease characteristics: Median age (122 pts) was 62 yrs (range 54–67); 58% male; MM subtypes: IgG 58%, IgA 20%, light chain only 19%. Most pts had received prior transplant (81%) and thalidomide (70%), without difference between the 2 groups. Comparison of baseline labs between Groups 1 and 2 identified significant differences in hemoglobin (median 110 vs 104g/L, p=0.002), platelet count (median 196 vs 126/uL, p=0.0005), LDH (median 165 vs 234 U/L, p<0.0001), respectively. Treatment and toxicity: The median number of lenalidomide cycles received were 18(12–40) for Group 1; 4(1–10) for Group 2. Although the number of pts requiring dose reductions was similar between groups (32% Group 1, 25% Group 2, p=0.5), Group 1 pts did not require dose reductions until significantly later (median cycle 8.5 vs 2.5, p<0.0001). Cytopenias were the major cause of dose reductions in all pts (67.6%), most due to thrombocytopenia. The higher baseline platelet counts in Group 1 may reflect greater marrow reserve, delaying the onset of drug-related thrombocytopenia. Thrombocytopenia did not, however, lead to differences in increased drug discontinuation between groups: PD (70% vs 74%), toxicity (14% vs17%)(p=0.4). Responses: More pts who were able to stay on lenalidomide longer (Group 1) vs those who discontinued early (Group 2) achieved a response to therapy (95% vs 55%, p<0.0001). In addition, more pts in Group 1 were able to stay on therapy longer to achieve a VGPR/CR (43% vs 9.5%, p<0.0001). Time to best response was accordingly prolonged in Group 1 vs Group 2 (5.7 cycles vs 1.8 cycles, p<0.0001).

Conclusions:
1) Relapsed/refractory MM pts receiving lenalidomide therapy for longer than 12 cycles have improved PFS and OS over those with shorter exposures.
2) Longer duration on therapy may be necessary to achieve optimal rates of both overall response and quality of response.
3) Lower baseline platelet counts and dose-reductions for thrombocytopenia during therapy were more common in pts who discontinued therapy early and may contribute to earlier disease progression.
4) Approaches to allow prolongation of lenalidomide exposure in MM by minimizing early dose reductions for thrombocytopenia should be further evaluated. Such approaches may include lowered-dose lenalidomide combinations taking care to use platelet-sparing agents or supportive care with thrombopoeitin agonists.

Disclosures:
Reece: Celgene: Honoraria, Research Funding. Trudel:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding.