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Phase II trial of single-agent panobinostat consolidation improves responses after sub-optimal transplant outcomes in
Sridurga Mithraprabhu1,2, Anna Kalff1,2, Kate H Gartlan3
1Myeloma Research Group, Australian Centre for Blood Diseases, Alfred Hospital-Monash University, Melbourne, Victoria, Australia.
Abstract:
Panobinostat is a pan-deacetylase inhibitor that modulates the expression of oncogenic and immune-mediating genes involved in tumour cell growth and survival. We evaluated panobinostat-induced post-transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three-times weekly (TIW) on alternate weeks of 28-day cycles commencing 8-12 weeks post-transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9-9·7) months of panobinostat. In responders, T-lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non-responders. The reduction in the proportion of CD127+ CD8+ T cells and CD4:CD8 ratio was significantly greater, after three and six cycles of panobinostat compared to pre-transplant, in non-responders when compared to responders. Whole marrow RNA-seq revealed widespread transcriptional changes only in responders with baseline differences in genes involved in ribosome biogenesis, oxidative phosphorylation and metabolic pathways. This study confirmed the efficacy of panobinostat as a single agent in multiple myeloma and established acetylation of lymphocyte histones, modulation of immune subsets and transcriptional changes as pharmacodynamic biomarkers of clinical benefit.
Insights
Panobinostat improved multiple myeloma depth of response in nearly half of patients post-transplant. Biomarkers like histone acetylation and immune cell changes correlated with clinical benefit.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Panobinostat is a pan-deacetylase inhibitor affecting genes in tumor growth.
- Multiple myeloma patients often fail to achieve complete response post-autologous transplantation.
- Evaluating post-transplant responses to panobinostat is crucial for treatment optimization.
Purpose of the Study:
- To evaluate panobinostat-induced responses in multiple myeloma patients post-transplant.
- To identify biomarkers correlating with treatment efficacy.
- To assess panobinostat's safety and tolerability in this patient population.
Main Methods:
- Patients received panobinostat 45 mg three-times weekly on alternate weeks.
- Response depth was assessed over 28-day cycles post-transplant.
- Pharmacodynamic biomarkers including histone acetylation, immune cell subsets, and RNA-seq were analyzed.
Main Results:
- 48% of patients improved their depth of response after a median of 4.3 months.
- Responders showed increased T-lymphocyte histone acetylation.
- Non-responders exhibited greater reduction in CD127+ CD8+ T cells and CD4:CD8 ratio.
- Responders displayed transcriptional changes in metabolic and ribosome biogenesis pathways.
Conclusions:
- Panobinostat demonstrated efficacy as a single agent in multiple myeloma post-transplant.
- Lymphocyte histone acetylation, immune subset modulation, and transcriptional changes are pharmacodynamic biomarkers of clinical benefit.
- Panobinostat offers a potential treatment option for patients with refractory multiple myeloma.
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