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Hydroxychloroquine + bortezomib is a combination therapy investigated for the treatment of relapsed or refractory multiple myeloma. This regimen pairs hydroxychloroquine, a small molecule autophagy inhibitor originally approved for malaria and autoimmune conditions, with bortezomib, a first-in-class proteasome inhibitor. The therapeutic rationale is based on the simultaneous blockade of the two primary cellular protein degradation systems: the ubiquitin-proteasome pathway (inhibited by bortezomib) and the lysosomal-autophagy pathway (inhibited by hydroxychloroquine). By preventing the degradation of misfolded or regulatory proteins through both routes, the combination induces significant proteotoxic stress and synergistic cytotoxicity in plasma cells. Clinical evaluation led by the Abramson Cancer Center at the University of Pennsylvania established the safety profile and a recommended Phase 2 dose for this combination.
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