Leopard: A Phase II Study of Maintenance Lenalidomide and Prednisolone Post Autologous Stem Cell Transplantation (ASCT) for Myeloma, Incorporating Minimal Residual Disease Assessments
Authors: Kalff Anna , Kennedy Nola , Walker Patricia A. , Khong Tiffany T. , Schwarer Anthony , Roberts Andrew W. , Campbell Philip , Filshie Robin , Smiley Angela , Gorniak Malgorzata , Black Marion , Jenkins Nicole , Raines Geoffrey , Spencer Andrew 
Published: October 2019

Abstract
Background
Despite improved outcomes achieved with high dose melphalan conditioned ASCT for Myeloma (MM) patients, relapse is inevitable. Maintenance therapy following ASCT improves the depth of response achieved by induction therapy and prolongs both progression free (PFS) and overall survival (OS). Achievement of stringent (s) complete response (CR) is predictive of improved outcome, as is minimal residual disease (MRD) negativity (-neg) assessed by sensitive techniques such as multiparameter flow cytometry (MFC) of bone marrow (BM).
Aim
To document disease response changes, PFS/OS in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after ASCT. To sequentially quantify MRD in patients achieving a complete response (CR) utilising freeLite chain (FLC) and MFC. To assess safety and tolerability.
Methods
Phase II, open label, single arm, multi-centre study. Newly diagnosed patients with MM commenced RAP maintenance (lenalidomide 10mg/continuous daily increasing to 15mg after 8/52 and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP continued until toxicity or relapse/progression. Serum for FLC was collected every 2/12, patients achieving CR had serial BM MFC. Statistical analysis: Prism v5.0a.
Results
60 patients (M=37, F=23), with a median age of 61 years (range 41-71) commenced RAP maintenance. ISS stage at diagnosis: I: 20, II/III: 37 (3 unknown). 51/60 patients had diagnostic cytogenetics ± FISH performed – 15 had poor risk features (t(4;14), t(14;16), del17p, del13, +1q21), 11/15 had +1q21.
After a median 23 months (range 12-36) following initiation of RAP, 33 patients remain on therapy. One patient has been lost to follow-up. Discontinuation was due to relapse/progressive disease (10), AEs (13), physician choice (2), poor compliance (1) and death (1). 15 patients have relapsed/progressed, 11 patients have died; 7 due to MM, 2 due to therapy related AML (tAML) and 2 other.
Both the median PFS and OS have not been reached. When looking at the association between survival and poor risk cytogenetics ± FISH, those with +1q21 had both inferior PFS and OS: median PFS was 646 days vs not reached (NR) for those without +1q21 (P=0.04), median OS was 701 days vs NR for those without +1q21(P=0.013).
34 patients improved their post ASCT response on RAP. Best response was CR in 36 (60% - 25 sCR), 21 VGPR (35%) and 2 PR (3%), achieved in a median of 77 days (range, 0-447). 30 of 36 patients in CR went on to have sequential MRD studies: 21/30 were multiply MRD-neg and 9/30 were multiply MRD-pos. There was no difference in PFS between MRD-pos and MRD-neg patients (p=0.3). Of the MRD-neg patients, 16/21 had predominantly normal FLC ratios (sCR), 4/21 MRD-neg patients relapsed, 3 had normal FLC ratios. Of the MRD-pos patients, 6/9 had normal FLC ratios (sCR), 3/9 MRD-pos relapsed. Correlation between MRD neg and sCR was poor (r2=0.05) and there was no difference in relapse rate between patients achieving MRD-neg versus those who achieved sCR.
All grade haematologic AEs comprised thrombocytopenia 15/60 (25%)(grade 3/4: 6 [10%]), neutropenia 10/60 (grade 3: 5), and anaemia 5/60 (%)(grade 3: 1). All grade non-haematologic AEs regardless of relatedness to study treatment (>10%) were: infections (URTI: 35%, LRTI: 25%, VZV reactivation: 13%), diarrhoea (38%), insomnia (32%), fatigue (26%), peripheral neuropathy (20%), cramps (18%), hyperglycemia (12%). There have been six second primary malignancies (SPMs) – 2 tAML (onset post C1D1: 15m, 21m), 1 adenocarcinoma of bowel (onset post C1D1: 30m) and 3 skin cancers (SCCs). AEs leading to discontinuation were myelosuppression (9), SPM (2), retinal vein thrombosis (1) and fatigue (1).
24 patients (40%) tolerated lenalidomide dosing as per protocol, 13 were not increased from 10mg/d to 15mg day, and 23 required dose modifications for AEs.
Conclusion
RAP maintenance improved depth of response post-ASCT (including conversion to deeper response categories > 14months), with high rates of CR/sCR (60%). Neither MFC or FLC demonstrated superiority over the other for prediction of outcome and correlation between the two was poor. Recapitulating earlier findings of an interim analysis, patients with +1q21 had inferior PFS/OS, suggesting that this group may benefit less from RAP maintenance. Only 21% of patients discontinued RAP due to toxicity, comparable to IFM 2005-02 and CALGB 100104 studies.

Disclosures
Off Label Use: Lenalidomide used as maintenance post-ASCT. Spencer:Takeda: Consultancy, Honoraria; janssen-Cilag: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding.