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Repurposing of FDA-approved drugs for use in MM
Metformin, the oral biguanide drug used in the treatment of diabetes, has been shown to exert anti-MM
effects both in vitro and in vivo. The exact mechanism of metformin’s anti-tumour activity has not been
[132]
elucidated, but it is hypothesized to induce autophagy through the inhibition of STAT3 and BCL-2 . The
anti-retroviral drug nelfinavir has also shown anti-MM effects in vivo by triggering the UPR, and has been
studied extensively clinical trials for relapsed MM [190,191] . A new phase 1 clinical trial is assessing the safety
and efficacy of metformin, nelfinavir and bortezomib in with relapsed or refractory MM (NCT03829020).
This is only one example of the potential utility of drug repurposing strategies in cancer, rationally
designed based on theoretical synergistic mechanisms of activity.

CONCLUSION
Autophagy plays a crucial pro-survival role in MM. Increased protein synthesis and proteotoxic stress
are hallmarks of cancer, and MM is the prototypic cancer with impaired protein homeostasis based on its
staggering rate of immunoglobulin synthesis and baseline level of proteotoxicity. Importantly, autophagy
protects MM cells from excessive ER stress by limiting the secretion of immunoglobulins and providing an
alternative proteolytic pathway for the clearance of ubiquitinated proteins. Consistent with a therapeutic
role in targeting protein homeostasis, PI are highly effective anti-MM agents that are FDA approved for
the treatment of MM in all its stages. However, clinical resistance to PI is inevitable, leading to research
interest in targeting alternative pathways contributing to protein quality control such as autophagy, alone or
in combination with PI. As with other mechanisms of protein homeostasis, such as the UPR; while a basal
level of autophagy is cytoprotective and inhibiting autophagy to blunt non- proteasomal proteolysis has
also been shown to have therapeutic benefit, sustained autophagy as in the setting of persistent proteasome
inhibition, may result in autophagic cell death. This highlights the “Janus-faced” role of autophagy in MM.
Autophagy therefore represents an opportunity to therapeutically exploit MM’s unique “Achilles’ heel”: its
dependence on protein quality control. With a better understanding of the molecular sequalae of autophagy
inhibition/induction in MM, we are eagerly awaiting the development or repurposing of drugs to target
autophagy in an effort to overcome PI resistance and improve outcome for our patients with MM.

DECLARATIONS
Authors’ contributions
All authors contributed to the writing of this review article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.