A Phase I Clinical Study and In Vivo Findings with PT-112, a Novel Immunogenic Cell Death-Inducing Small Molecule, in Relapsed or Refractory Multiple Myeloma.

PURPOSE PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule under Phase 2 development in several cancer types. It inhibits ribosome biogenesis and causes organelle stresses, leading to selective ICD in cancer cells. The possibility of PT-112's pyrophosphate moiety driving high drug concentrations to bone sites of disease led to an interest in PT-112 use in multiple myeloma. Here, we present findings from Phase I and in vivo studies for PT-112 in relapsed or refractory multiple myeloma (RRMM). EXPERIMENTAL DESIGN PT-112 biodistribution was analyzed in mice via laser ablation inductively coupled plasma mass spectrometry. Activity of PT-112 was assessed in de novo and variant Vk*MYC multiple myeloma mouse models as monotherapy or combination therapies. M-spike levels and survival were measured. A Phase I dose escalation study of PT-112 monotherapy was conducted using 3+3 design in heavily pretreated RRMM patients with exhausted available therapies. RESULTS In vivo biodistribution imaging revealed high concentrations in bone, kidney, lung, skin, and liver. PT-112 was active in Vk*MYC multiple myeloma mouse models, alone and in combination. Phase I data showed that PT-112 monotherapy was safe and well-tolerated, establishing a recommended Phase 2 dose of 360 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Confirmed responses and other signals of activity were observed. CONCLUSIONS These results suggest a lack of cross-resistance with standard of care and support the translational value of the Vk*MYC model system. Further clinical investigation of PT-112 is warranted in multiple myeloma.