Discussion
diarrhoea, renal impairment, MM, bone pain, musculoskeletal pains, tumour
RENAL IMPAIRMENT, EVENT, DISEASE, ADVERSE EFFECTS, TUMOUR, MYELOMA, PERIPHERAL NEUROPATHY
This study investigated the potential to repurpose NMP as an immunologically active epigenetic fragment in the setting of RR–MM. NMP was generally well tolerated at starting doses up to 400 mg/day and intra-patient dose escalation culminated in a ceiling daily exposure of 1 g/day without definition of the MTD. The single observed DLT of diarrhoea, which was observed at the 200 mg/day dose level and did not recur with rechallenge at the same dose, may not have been NMP related. Moreover, many of the commonly reported low grade AEs (e.g. musculoskeletal pains, renal impairment and peripheral neuropathy) are frequent manifestations of underlying myeloma confounding causality assessments. An association between NMP exposure and bone pain was observed which may indicate a treatment-related event. Prior reports of augmented bone morphogenic protein signalling [NMP disposition in humans has mainly been studied from a toxicology and toxicokinetic perspective, to minimise adverse effects from inhalation in industrial settings [Although no patient demonstrated an IMWG-defined objective treatment response, potential disease stabilising activity was noted with four patients remaining on study more than 100 days and one subject demonstrating disease control for up to 20 cycles. Correlation of PK data with preclinical studies indicates that any anti-myeloma activity is not readily explained by the direct effects of NMP-mediated BET-bromodomain inhibition on tumour cells. We therefore posited that disease control could be immune mediated, noting that NMP may modulate immune function at micromolar concentrations achieved in these patients [