Phase I trial of vorinostat plus bortezomib (bort) in relapsed/refractory multiple myeloma (mm) patients (pts)

A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma

“…At the MTD of 100 mg twice daily for four consecutive days every week, ITF2357, alone or in combination with dexamethasone, is unlikely to play a significant therapeutic activity in advanced MM. Thus, similar to what is already ongoing for other HDACIs [12], further clinical investigation of ITF2357 in combination with other drugs commonly used in the treatment of advanced MM, such as thalidomide, bortezomib, lenalidomide, or melphalan is warranted.…”

“…Phase I-II clinical trials are underway or have been recently performed with SAHA in patients with advanced hematological malignancies, including MM [6][7][8][9][10][11][12][13]. Overall, these studies showed that SAHA was tolerable, although its toxicity profile was not negligible.…”

“…One class of HDACIs is the hydroxamate derivatives family of compounds whose prototype is suberoyl anilide hydroxamic acid (SAHA) [5], which is being tested clinically in several hematological malignancies and has obtained FDA approval for the treatment of cutaneous T-cell lymphoma [6][7][8][9][10][11][12][13][14][15]. Our group has recently reported that ITF2357, an orally effective member of the family of hydroxamate-derived HDACIs, is a potent inducer of apoptosis and death of MM cells in vitro [16].…”

Rational Combinations Using HDAC Inhibitors

“…Compared with DNMTi, only limited data are available combining proteosome inhibitors such as bortezomib and NPI-0052 with HDACi. Results to date indicate that these combinations are well tolerated and seem to be clinically effective in both solid tumors and multiple myeloma (76,77). Clinical trials using HDACi in combination with recombinant TRAIL or agonistic anti-TRAIL receptor antibodies such as mapatumumab (anti-TRAIL receptor 1) or lexatumumab, AMG655 and Apomab (anti-TRAIL receptor 2), or pro-survival Bcl-2 family inhibitors have not yet been reported.…”

Treatment Options for Relapsed and Refractory Multiple Myeloma

“…The combination of proteasome inhibition and HDAC 6 inhibition [accomplished using HDACis, tipifarnib (106), or the HDAC6 specific agent tubacin (107)] results in preclinical synergy, a concept which is now being evaluated clinically. Preliminary data from phase I studies combining the HDACi vorinostat with bortezomib showed significant responses, and among the patients who were defined as bortezomib resistant, the ORR was 30% (108,109). A trial from Prince and colleagues also evaluated the efficacy of the combination of the HDACi romidepsin (also known as depsipeptide) with bortezomib and reported encouraging responses (110).…”