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also participate in chaperone-mediated autophagy [155-157] . Heat-shock proteins (HSPs) therefore help alleviate
[158]
proteotoxic stress to prevent apoptosis in MM . Consistent with this, HSP70 and/or HSP90 inhibition
induces UPR and apoptosis in MM [159-161] . In preclinical studies, combination of HSP90 inhibitors KW-2478,
Retaspimycin, and 17-AAG with bortezomib demonstrated synergistic cytotoxicity [162-164] . Another HSP90
inhibitor, NVP-HSP990, displayed potent, in vitro anti-myeloma activity and synergism with melphalan,
HDAC inhibitors, and PI3K/mTOR inhibitors [165,166] . Other HSP90 inhibitors such as PU-H71, SNX5422,
and NVP-AUY922 have also shown promising pre-clinical results in MM [158,167-169] . Apart from HSP90,
HSP70 has recently emerged as a promising therapeutic target in MM and a number of HSP70 inhibitors
(e.g., PET-16, Ver-155008, MAL3-101) have shown good pre-clinical anti-myeloma activity [160,161,170,171] .

Interestingly, treatment of MM cells with HSP90 inhibitors (e.g., 17-AAG, NVP-AUY922), bortezomib, or
dexamethasone results in compensatory upregulation of HSP70 which confers a degree of drug-resistance
and protects MM cells from apoptosis [172,173] . HSP70 is a molecular chaperone of HSP90. Consequently,
inhibition of HSP70 leads to the downregulation of HSP90 while inhibition of HSP90 results in
upregulation of HSP70 [160,171,174] . It has been shown however, that simultaneous inhibition of both HSP70 and
HSP90 leads to greater MM cytotoxicity compared to inhibiting HSP90 alone [160,171,174] . To this end, there has
been increasing interest in developing inhibitors against heat shock factor 1 (HSF), the “master regulator”
[158]
of the heat shock response that controls the expression of both HSP90 and HSP70 . In preclinical studies,
several novel HSF1 inhibitors (e.g., CCT251236, KRIBB11) were found to induce MM cell death that was
associated with the induction of the UPR .
[175]
Autophagy modulators currently in clinical trials
Several clinical trials have highlighted the potential role of autophagy modulators in the treatment of MM.
For the purpose of consistency while discussing these trials, overall response rate (ORR) is defined as a
partial response (PR) or better, and clinical benefit rate (CBR) is defined as stable disease (SD) or better.

Hydroxychloroquine/Chloroquine
Hydroxychloroquine (HCQ)/Chloroquine (CQ) have been clinically studied for their potential role in
inhibiting autophagy. Although the exact mechanism of HCQ/CQ has not been elucidated, it is thought to
[176]
function by alkalinizing intracellular compartments which disrupts the autophagic proteolytic process .
HCQ/CQ have been extensively studied in myeloma to potentiate the effects of other anti-myeloma drugs,
particularly PI.

A phase I clinical trial assessed the efficacy of HCQ in combination with bortezomib in patients
[177]
with relapsed or refractory MM . Patients were given a 2-week run in with HCQ alone, followed by
combination therapy with bortezomib. The combination of HCQ and bortezomib was well tolerated, with
no adverse events meeting the criteria of a dose-limiting toxicity. Of the 22 patients assessed at the end of
the study, 13.6% had a very good partial response (VGPR), 13.6% had minimal response (MR), and 45.5%
had stable disease (SD). Interestingly, all of the patients who had a VGPR were bortezomib-naïve. Twenty-
seven percent of patients in the study had progressive disease (PD). Of these, two thirds were bortezomib-
refractory. This study also found a therapy-associated increase in autophagic vesicles in BM plasma cells.
However, due to the small sample size, the authors were unable to correlate number of autophagic vesicles
with clinical response.

A smaller phase II trial looked at CQ in combination with bortezomib and cyclophosphamide in
refractory MM . Of the 11 patients enrolled, 8 completed at least 2 cycles and were assessed for clinical
[178]
response. The most common side effects included fatigue, constipation, myalgia, anorexia, anemia and
thrombocytopenia, but was generally well tolerated. 37.5% of patients achieved a PR with a median
duration of response of 4 months. One patient (12.5%) had SD, and 50% of patients experienced PD, with