A 2-Stage Phase II Study of Panobinostat Consolidation in Multiple Myeloma (MM) Patients with < CR Following Single High-Dose Chemotherapy (HDT) Conditioned Autologous Stem Cell Transplantation (ASCT) As Part of First Line Therapy
Authors: Kalff Anna , Mithraprabhu Sridurga , Khong Tiffany T. , Ramachandran Malarmathy , Reed Kate , Quach Hang , Walker Patricia A. , Bergin Krystal , Spencer Andrew 
Published: October 2019

Introduction

Panobinostat is a pan-deacetylase inhibitor with activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. Panobinostat increases acetylation of histones 2, 3 and 4 (H2, H3 and H4) and proteins involved in multiple oncogenic pathways, including the aggresome protein degradation pathway.

Panobinostat has not been systematically evaluated as a single agent in patients with MM, however activity was demonstrated in patients with advanced MM in phase I and II trials. This, coupled with preclinical data, favorable toxicity profile and oral formulation strongly support its evaluation in a post-ASCT consolidation context.

Aim

To determine rate of conversion to CR/VGPR, to evaluate safety, toxicity and to document PFS/OS in MM patients treated with panobinostat consolidation post-ASCT.

To identify a pharmacodynamic biomarker that can be utilised to select patients most likely to benefit from panobinostat by assessing changes in acetylation of lysine residues in H2A, H2B, H3 and H4.

Methods

Phase II, open label, single arm study. Newly diagnosed MM patients commenced panobinostat (45mg 3x per week, alternate weeks: 1 cycle = 4/52) 8-12 weeks (median 11) after a single MEL200 ASCT. Panobinostat continued until toxicity/relapse/progression. After 6 cycles (6C), patients were restaged and only continued if depth of response improved (conversion to CR/VGPR).

Acetylation studies: PBMCs were collected at 3 time points - POST-ASCT, end of cycle 3 (EOC3) and end of cycle 6 (EOC6). CD3+ lymphocytes were assessed for changes in histone and tubulin acetylation in lysine (K) residues (H2A K5, H2B K5, H3 K9, H3 K14, H3 K18, H3 K27, H3 K56, H4 K5, H4 K8, H4 K12, H4 K16 and tubulin) by flow cytometry using mean fluorescence intensity (MFI) of the geometric mean. The MFI from a sample was normalized to the respective POST-ASCT sample and expressed as a fold difference.

Results

24 patients (F=12, M=12), median age 58yrs (44-69), commenced panobinostat. Diagnosis ISS stage: I/II: 16, III: 8. 20/24 had diagnostic cytogenetics/FISH: 5 were poor risk (t(4;14), t(14;16), +1q21).

After a median of 24m following panobinostat initiation (6-43m), 6 patients remain on therapy. Discontinuation was due to failure to improve depth of response (8), progression (6), non-compliance (2) and toxicity (2). 11 patients progressed, 2 died. Estimated 2 year PFS 65% (median PFS 25m, median OS NR).

22/24 patients completed at least 6C of therapy. 12/24 improved depth of response: VGPRàCR: 4, PRàVGPR: 7, PRàCR: 1; 4 patients within 0-3C, 8 patients within 3-6C. Two patients (one each from 0-3C and 3-6C groups) demonstrated a further reduction in tumour burden with maximal response occurring after EOC11 and EOC29. Median time to maximal response after was 4.6m after commencing panobinostat (1.2-29m). One patient who discontinued after EOC6 (failed to improve depth of response) had a further reduction in paraprotein from 5g/L to trace at 6m post EOC6 (sustained for 5m).

All grade haematological toxicity: thrombocytopenia: 9/24 (grade 3/4 = 6), neutropenia: 7/24 (grade3 = 6), anaemia: 1/24. Principal non-haematological toxicities were GI [nausea: 22/24 (grade 3 = 3), diarrhoea: 22/24 (grade 3=4)], fatigue: 18/22 and infection: 15/22 (grade 3=9). Only 5/24 patients tolerated dosing as per protocol. The median tolerated dose was 25mg.

Changes in histone acetylation were assessed for 11 responders and 5 non-responders. Responders demonstrated increasing levels of acetylation at EOC3 and EOC6: At EOC3, this was most marked for H2B K5, H3 K9, H3 K14, H3 K56, H4 K8, H4 K12, H4 K16 at EOC3, while at EOC6, all histone acetylation lysine residues tested were significantly increased compared to POST-ASCT. In contrast, there were no differences in the levels of acetylation for either EOC3 or EOC6 compared to POST-ASCT for the non-responders. The differences in observed changes in histone acetylation seen at EO6 in responders compared to non-responders were significant.

Conclusion

Single agent panobinostat consolidation post-ASCT improves depth of response in a non-favourable group of patients, and in some patients, induces a further reduction in tumour burden beyond 12m post-ASCT

Assessment of histone acetylation changes represents a pharmacodynamic biomarker of clinical benefit, with a strong correlation between the levels of acetylation and response of the patient to panobinostat.

Disclosures

Quach: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.