ReviewOptimal Management of Histone Deacetylase Inhibitor-Related Adverse Events in Patients With Multiple Myeloma: A Focus on Panobinostat
Introduction
Multiple myeloma (MM) is a neoplasm characterized by uncontrolled proliferation of abnormal plasma cells in the bone marrow and, typically, the overproduction of monoclonal proteins.1 It accounts for approximately 2% of all new cancer cases and 18% of new cases of hematologic malignancies.2 Although MM is incurable, recent advances in the treatment of MM have extended survival such that, for substantial periods of time, it can be a manageable chronic disease in many.3 Thus, patients live with the burden of the disease and any cumulative toxicities of treatment. Improvements in quality of life are needed to match improvements in survival. A number of new treatments have been approved for MM; however, for a time, new agents will inevitably be unfamiliar to clinicians, who will need to gain experience and understand how to use them optimally within the challenges of a real-world setting.
Multiple myeloma-related complications and adverse events (AEs) due to treatments are typically managed with dose reductions/interruptions, anti-infectives, transfusion, anticoagulation, growth factors, bisphosphonates, and pain control. However, if patients experience lack of response or intolerable AEs, involvement is required from other specialists, such as those in palliative medicine, pain management, radiotherapy, orthopedics, and psychology. A multidisciplinary approach is vital to the overall management of patients with MM because of the multisystem nature of the disease and the wide range of treatment-related toxicities that can occur.
In this review the difference between AEs resulting from treatment for MM and symptoms that are a result of the disease itself is discussed. Histone deacetylase inhibitor (HDACi) treatment-related AEs, the contribution of the disease to these symptoms, and strategies for their management are also discussed. Certain regimens for dose reduction/interruption and supportive care are suggested; however, these regimens should be taken as guidelines and might not be appropriate for all patients and individual circumstances.
Section snippets
Disease-Related Symptoms Versus Treatment-Related AEs
Multiple myeloma might be associated with hypercalcemia, renal impairment, anemia, bone disease, and/or infection.4, 5, 6 Treatment aims are to control the disease burden, prolong survival, and maintain or improve quality of life. Classes of drugs currently approved for the treatment of MM include proteasome inhibitors (PIs; bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, and pomalidomide), HDACi drugs (panobinostat), and monoclonal antibodies
Emerging Panobinostat Combination Therapies
Because of the improved efficacy seen with the additional use of panobinostat with bortezomib and dexamethasone for patients with relapsed or relapsed and refractory MM who have received ≥ 2 previous regimens, including bortezomib and an IMiD, several trials are under way to test novel panobinostat combinations that might produce superior efficacy and/or mitigate some of the toxicity observed with the regimen. Combinations currently under investigation include panobinostat with
Clinical Development of Histone Deacetylase 6-Specific Inhibitors
Histone deacetylase 6 (HDAC6)-specific inhibitors have been designed in an effort to retain efficacy and synergy with PIs via HDAC6-dependent inhibition of protein degradation. HDAC6 is a critical component of the aggresome protein degradation pathway and regulation of heat shock protein 90 chaperone function.42 It is hypothesized that specific inhibition of HDAC6 could provide efficacy similar to pan-deactetylase inhibition but reduce toxic effects driven by off-target functions.
Ricolinostat
Conclusion
The routine use of PIs and IMiDs has significantly improved survival in patients with MM. Further developments such as HDACi drugs and monoclonal antibodies will likely further improve survival. However, improved survival also means that patients will be exposed to more lines of treatment and live with disease-related symptoms and treatment-related AEs for longer periods of time. Therefore, it is important to prevent and effectively manage MM symptoms and treatment-related AEs to maintain
Disclosure
R.P. has received honoraria from Novartis Pharmaceuticals Corporation. J.D.C. has stated no conflicts of interest.
Acknowledgments
Editorial assistance was provided by Michael Demars, PhD (ArticulateScience LLC), and was funded by Novartis Pharmaceuticals Corporation.
R.P. is supported by the National Insitute for Health Research University College London Hospitals Biomedical Research Centre.
References (46)
- et al.
Improved survival in multiple myeloma and the impact of novel therapies
Blood
(2008) - et al.
Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial
Lancet Oncol
(2014) - et al.
Treatment of multiple myeloma: a comprehensive review
Clin Lymphoma Myeloma
(2009) - et al.
Deciphering the molecular and biological processes that mediate histone deacetylase inhibitor-induced thrombocytopenia
Blood
(2011) - et al.
Panobinostat (LBH589)-induced acetylation of tubulin impairs megakaryocyte maturation and platelet formation
Exp Hematol
(2012) - et al.
PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma
Blood
(2013) - et al.
Review of 1027 patients with newly diagnosed multiple myeloma
Mayo Clin Proc
(2003) - et al.
EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update
Eur J Cancer
(2007) - et al.
American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer
Blood
(2010) - et al.
Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials
Lancet
(2009)
Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment
Ann Oncol
Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial
Lancet Haematol
Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma
Blood
Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial
Lancet Oncol
Selective HDAC6 inhibitor ACY-241, an oral tablet, combined with pomalidomide and dexamethasone: safety and efficacy of escalation and expansion cohorts in patients with relapsed or relapsed-and-refractory multiple myeloma (ACE-MM-200 study)
Blood
Multiple myeloma
N Engl J Med
Cancer statistics, 2016
CA Cancer J Clin
Plasma cell neoplasms
Multiple myeloma: charging toward a bright future
CA Cancer J Clin
International uniform response criteria for multiple myeloma
Leukemia
Treatment-related symptom management in patients with multiple myeloma: a review
Support Care Cancer
Farydak (panobinostat) [prescribing information]
Effects of bone marrow infiltration by multiple myeloma on erythropoiesis
Blood
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