Table 1.

Therapies targeting protein handling pathways in multiple myeloma (MM).

Drug Class	Drug Name	Mechanism of Action	Study Design	Status
PI	Bortezomib	Proteasome inhibition; Apoptosis via caspase 8/9; UPR apoptotic response	Single use approval	FDA approved
	Carfilzomib	Irreversible proteasome inhibition	Single use approval; Combination treatment DEX and/or LEN	FDA approved
	Ixazomib	Oral Proteasome inhibitor	Combination treatment with LEN and DEX	FDA approved
	Oprozomib	Proteasome inhibition; Apoptosis via caspase 8/9	Single agent	Phase IB/II
	Marizomib	Pan-Proteasome inhibition; Apoptosis via caspase 8/9; UPR apoptotic response	Single agent	Phase I
UPR Modulators	MKC-3946	Inhibition of XBP1 splicing by IRE1α endoribonuclease domain inhibition	Combination treatment with bortezomib	Preclinical
	Nelfinavir	Activation of PERK apoptotic pathway; Upregulation of CHOP; Inhibition of AKT phosphorylation	Combination treatment with bortezomib	Preclinical
			Combination treatment with bortezomib in R/R and progressive MM	Phase I
HDACi	Panobinostat	Broad spectrum inhibitor of HDAC leading to aggresome disruption; Apoptosis via caspase 8/9; UPR apoptotic response	Combination treatment with bortezomib and DEX (where 2 or more treatment options have been used prior)	FDA approved
	ACY-1215 (Ricolinstat)	Selective inhibition of HDAC6 leading to aggresome disruption; Apoptosis via caspase 8/9; UPR apoptotic response	Combination treatment with bortezomib	Preclinical
			Combination treatment with carfilzomib	Preclinical
			Combination treatment with LEN and DEX	Phase IB
Autophagy Inhibitors	Hydroxy-chloroquine	Inhibition of autophagy by increased lysosomal pH	Combination treatment with bortezomib R/R MM	Phase 1
			Combination treatment with carfilzomib	Preclinical
	Bafilomycin A1	Inhibition of autophagy by prevention of autophagosome/lysosome fusion	Combination treatment with bortezomib	Preclinical
HSP Inhibitors	NVP-HSP990	HSP90 inhibitor; Disruption of AKT, JAK/STAT pathways	Single agent	Preclinical
	TAS-116	HSP90 inhibitor Induction of apoptosis Disruption of AKT & ERK	Single agent; Combination treatment with bortezomib	Preclinical
	Tanespimycin	HSP90 inhibitor Induction UPR	Combination treatment with bortezomib	Phase I/II