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Updated: Sep 11, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
A Phase I Clinical Study and In Vivo Findings with PT-112, a Novel Immunogenic Cell Death-Inducing Small Molecule, in
Taxiarchis Kourelis1, Sikander Ailawadhi2, Dan T Vogl3
1Department of Hematology, Mayo Clinic Rochester, Rochester, Minnesota.
Purpose:
R,R-1,2 cyclohexanediamine-pyrophosphato-platinum(II) (PT-112) is a novel immunogenic cell death-inducing small molecule under phase II development in several cancer types. It inhibits ribosome biogenesis and causes organelle stresses, leading to selective immunogenic cell death in cancer cells. The possibility of PT-112's pyrophosphate moiety driving high drug concentrations to bone sites of disease has led to an interest in PT-112's use in multiple myeloma. In this study, we present findings from phase I and in vivo studies for PT-112 in relapsed or refractory multiple myeloma.
Experimental Design:
PT-112 biodistribution was analyzed in mice via laser ablation inductively coupled plasma mass spectrometry. The activity of PT-112 was assessed in de novo and transplantable Tg(Igkv3-5*-MYC)#Plbe (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 a 3 + 3 design in patients with heavily pretreated relapsed or refractory multiple myeloma with exhausted available therapies.
Results:
In vivo biodistribution imaging revealed high concentrations in the bone, kidney, lung, skin, and liver. PT-112 was active in Vk*MYC multiple myeloma mouse models, both alone and in combination. Phase I data showed that PT-112 monotherapy was safe and well-tolerated, establishing a recommended phase II 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 the 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.
Insights
PT-112, a novel immunogenic cell death inducer, shows promising safety and activity in relapsed or refractory multiple myeloma. Further clinical trials are recommended for this bone-targeting therapy.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- PT-112 is an investigational small molecule designed to induce immunogenic cell death (ICD) in cancer cells.
- Its pyrophosphate moiety suggests potential for high drug concentrations at bone sites, making it relevant for multiple myeloma.
- Relapsed or refractory multiple myeloma (RRMM) remains a significant unmet medical need.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary activity of PT-112 in patients with RRMM.
- To assess PT-112 biodistribution and efficacy in preclinical multiple myeloma models.
Main Methods:
- In vivo biodistribution studies using laser ablation inductively coupled plasma mass spectrometry in mice.
- Assessment of PT-112 activity in de novo and Vk*MYC multiple myeloma mouse models as monotherapy and combination therapy.
- A Phase I, 3+3 dose escalation study of PT-112 monotherapy in heavily pretreated RRMM patients.
Main Results:
- PT-112 demonstrated high drug concentrations in bone and other organs in vivo.
- The agent showed activity in preclinical multiple myeloma models, both alone and in combination.
- Phase I study established PT-112 as safe and well-tolerated, with a recommended Phase 2 dose of 360 mg/m2 and observed confirmed responses.
Conclusions:
- PT-112 exhibits a favorable safety profile and signals of clinical activity in RRMM.
- The preclinical Vk*MYC model shows translational value, suggesting potential lack of cross-resistance with standard therapies.
- Further clinical investigation of PT-112 in multiple myeloma is warranted.
