Clinical drug resistance linked to reversible phenotypic transition and epigenetic alteration in multiple myeloma

The development of proteasome inhibitors (PIs) for the treatment of multiple myeloma (MM) has dramatically increased treatment responses and improved survival. The first-in-class PI, bortezomib, was used in a twice-weekly intravenous as a sustained single or combinational regimen for relapsed and subsequently for newly diagnosed MM. The relatively rapid acquisition of drug resistance to PI treatment remains a crucial obstacle. Gradual familiarity with toxicity and optimizing dose schedules have formed the current use of PIs as key components in promoting response and eliminating resistance. Combination therapies and schedule adaptation to once-weekly use of PIs have meanwhile been shown to be both more tolerable and highly efficacious. Interestingly, patients may remain sensitive to PIs after relapse of initial therapy, implying that PI resistance is reversible and suggest a previously unrecognized drug resistance mechanism via epigenetic changes that may be intrinsic to PI treatment. Examination of differential expressive genes in (i) relapsed and reversed (rev) B cell maturation antigen (BCMA) positive cells of MM patients; (ii) MM cell line MM1.S and the corresponding tolerant and reversed cells, and (iii) xenograft MM mouse models treated with vehicle (ctrl), sustained low concentration of bortezomib (bort_low), intermittent high concentration of bortezomib (bort_high), combined bortezomib and SAHA (bort_SAHA), or mice in which bortezomib was withdraw after treatment (rev).