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an overall clinical benefit rate of 40%. These studies demonstrate that HCQ/CQ are well tolerated in
combinations with PI and may help potentiate the effects of existing myeloma therapies.

A recent study looked at dual autophagic inhibition via HCQ and rapamycin with cyclophosphamide and
dexamethasone in patients with relapsed or refractory MM based on their preclinical, synergistic anti-
tumor activity [179,180] . The quadruple therapy was generally well-tolerated with one case of hematologic dose
limiting toxicity (thrombocytopenia) occurring at a HCQ dose of 800 mg, which was then established as
the maximum tolerated dose. Of the 18 patients enrolled in the trial, 1 had a VGPR and 3 had a PR, for an
ORR of 22%. Seven patients had MR, and 5 had SD, for a CBR of 89%. Median duration of a response was
4.5 months, and median time to best response was 1.9 months. Two patients had immediate progression
of disease. Unfortunately, correlative studies were unable to predict the depth of treatment response based
on the number of autophagic vesicles in BM-derived MM cells. The promising results of this study warrant
further investigation of dual autophagy modulation in MM.

HDAC6 inhibitors
HDAC inhibitors represent an important new group of anti-cancer drugs. There are 18 different isoforms
of HDACs in human cells that are subdivided into 4 classes based on subcellular localization and non-
[181]
cell-based enzymatic activity . Clinical studies with pan-HDAC inhibitors vorinostat and panobinostat
outlined a narrow therapeutic window due to frequent and often severe hematologic and non-hematologic
(particularly gastrointestinal/GI) toxicities, eliciting clinical interest in isoform-specific HDAC
[182]
inhibition .

Ricolinostat is an oral, selective HDAC6 inhibitor that has been extensively studied in MM. A phase 1b
multicenter trial of escalating doses of ricolinostat with lenalidomide and dexamethasone in patients with
[182]
relapsed or refractory MM showed 55% ORR . In lenalidomide-naïve and lenalidomide-sensitive patients,
the ORR was 69%, compared to 25% in lenalidomide-refractory patients. In patients that responded, the
median time to response was 7 weeks with a median duration of response of 24 months. Treatment with
ricolinostat was overall well tolerated with 2 patients experiencing a dose-limiting toxicity at the highest
tested dose which included syncope and myalgia.

Similarly promising results emerged from a phase 1/2 clinical trial assessing the safety and efficacy of
ricolinostat with bortezomib and dexamethasone in patients with MM relapsed or refractory to PI,
[183]
immunomodulatory drugs, or stem cell transplant . In this study, 15 patients were recruited for dose
escalation monotherapy with ricolinostat, and 57 patients were given combination therapy. Monotherapy
with ricolinostat was well tolerated with no dose-limiting toxicities up to 360 mg Q.D. Patients on
combination therapy did not have any dose-limiting toxicities during escalation studies. Most common
side effects associated with combination therapy were gastrointestinal toxicities, cytopenia, and fatigue.
Of the patients treated with monotherapy, 6 patients (6/15, 40%) had stable disease with a median response
duration of response of 11 weeks. Patients on combination therapy had an ORR of 29%, and a clinical
response rate of 39%. Interestingly, patients on combination therapy who were previously refractory to
bortezomib had an ORR of 14%. The response seen in patients with bortezomib-refractory MM suggests
that HDAC6 inhibitors can overcome resistance to PI.

Taken together, these results demonstrate a promising role for HDAC6 inhibitors in the treatment of
relapsed and/or refractory MM. There are currently ongoing trials assessing the role of HDAC6 inhibitors
in combination with anti-myeloma treatments such as pomalidomide and dexamethasone (NCT01997840,
NCT02189343).