Leopard: A Phase II Study Of Post Autologous Stem Cell Transplantation (ASCT) Maintenance Lenalidomide and Prednisolone For Myeloma (MM), Incorporating Minimal Residual Disease (MRD) Assessments

Despite improved outcomes achieved with high dose melphalan conditioned ASCT for MM patients, relapse is inevitable. Consolidation/maintenance therapy with novel agents following ASCT can prolong progression free (PFS) and overall survival (OS) as well as further improve depth of response, the latter being associated with superior survival. More sensitive techniques are now available to monitor minimal residual disease (MRD).

To document disease response changes in MM patients receiving maintenance lenalidomide and alternate-day prednisolone (RAP) after a single ASCT. To sequentially quantify MRD in those patients achieving an immunofixation negative (IF-) complete response (CR) utilizing freeLite chain (FLC), hevyLite chain (HLC, in patients with intact IgG or IgA immunoglobulin) and multiparameter flow cytometry (MFC). To assess PFS/OS and safety/tolerability.

Phase II, open label, single arm, multi-center study. Newly diagnosed patients with MM were commenced on RAP (lenalidomide 10mg/continuous daily increasing to 15mg after 8 weeks and alternate day prednisolone 50mg) 6-8 weeks after a single MEL200 ASCT as part of first-line therapy. RAP was continued until unacceptable toxicity or relapse/progression. Serum for FLC/HLC was collected every 2 months. Patients achieving an IF- CR had serial BMATs for MFC. This is an interim analysis of the first 30 of a total of 60 patients recruited to the study.

This analysis included 30 patients (M 17, F 13), median age 61 years (range 46-71), ISS stage I: 11, II/III: 19. 27 patients had diagnostic cytogenetics +/- FISH performed - 10 had poor risk features (t(4;14), t(14;16), del17p, del13 and/or +1q). After a median 549 days (range 385-768), 16 patients remain on therapy. Median PFS was 470 days (range 64-768), median OS was 514 days (range 247-768). Discontinuation was due to relapse/progressive disease in 8, AEs in 5 and poor compliance in 1. 4 patients have died; 3 due to MM and 1 due to therapy related AML [tAML].

The best achieved overall response rate (ORR) was 100%, with 19 IF- CR (63%) (13 stringent CR [sCR]), 10 VGPR (33%) and 1 PR (3%). 16 patients demonstrated an enhanced response while on RAP, including conversion to CR (n=3) or sCR (n=10) (6/10 were MFC negative [MFC-]). Median time to achieving best response was 111 days (range 28-287). 18 patients who achieved IF- CR had MFC studies and 11 were MFC-: of these 11, 5 had normal (FLC-) and 6 abnormal (FLC+) FLC ratios. Five of the 18 were MFC+, 4 of whom were FLC- and have not relapsed. Two of the 18 fluctuated between MFC+ and MFC-. Seven IF- CR patients had HLC analysis; 5/7 patients were MFC- in all samples, 3 of which also had normal HLC ratios (HLC-) and were FLC-. 2/7 patients were MFC+/HLC-.

10 patients relapsed/progressed after a median of 229 days (64-621), 5 from IF- CR (3 sCR). 5/8 with diagnostic cytogenetics had poor risk features, all with +1q in addition to other abnormalities. 3/19 remaining patients with cytogenetics who did not progress have +1q, suggesting a trend (p=0.07) to worse PFS in those with 1q+. In those who relapsed from IF- CR: 2 converted from MFC- to MFC+ prior to relapse/HLC-, 1 was FLC+ and 1 converted to FLC+ at relapse; 2 were MFC-/FLC- converting to FLC+ at relapse; 1 was MFC+/FLC+).

All grade haematologic AEs comprised thrombocytopenia 7/30 (23%) (grade 3/4: 4), neutropenia 2/30 (grade 3: 1) and anaemia 3/30(grade 3: 1). All grade non-haematologic adverse events regardless of relatedness to study treatment (>10%) were: infections (URTI: 53%, LRTI: 23%, VZV reactivation: 23%, UTI: 13%), diarrhoea (37%), fatigue (27%), muscle cramps (23%), insomnia (23%), mouth ulcers (13%), peripheral oedema (13%). There was 1 second primary malignancy (SPM) - tAML. This occurred 461 days after commencing RAP. AEs leading to discontinuation were thrombocytopenia (3 patients), central retinal vein thrombosis and tAML.

11 patients tolerated lenalidomide dosing as per protocol, 6 were not increased from 10 to 15mg, 8 required dose modification for AEs (6 to 10mg; 2 to 5mg) and 5 were discontinued due to AEs.

RAP maintenance improved depth of response post-ASCT with some achieving best response > 8 months after initiation. ORR was 100%, with high rates of CR (20%) and sCR (43%). Correlation between MFC and serological testing appears poor. Many patients who relapsed had poor-risk cytogenetics (+1q), suggesting that these patients may benefit less from RAP maintenance.

Off Label Use: Lenalidomide not approved for maintenance therapy post ASCT in Australia. Spencer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.