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Drug resistance in multiple myeloma
P Sonneveld1, H M Lokhorst, P Vossebeld
1Department of Hematology, University Hospital Rotterdam, Dijkzigt, The Netherlands. sonneveld@haed.azr.nl
Abstract:
The development of multidrug resistance (MDR) is a major obstacle to improving treatment outcomes in multiple myeloma. Recent studies have indicated that several specific mechanisms of MDR may be involved in clinically refractory multiple myeloma patients, such as expression of P-glycoprotein (P-gp), expression of the lung-resistance protein (LRP) and suppression of apoptosis via expression of Bcl-2. The emergence of these mechanisms of MDR in multiple myeloma is enhanced by exposure to chemotherapeutic agents. Recently, clinical reversal of MDR by noncytotoxic P-gp modulators such as verapamil, cyclosporin A (CsA), and PSC 833 was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR via modulation of P-gp is possible and that coadministration of these MDR modulators with chemotherapeutic agents alters the plasma pharmacokinetics of chemotherapeutic agents. Phase II and III clinical trials investigating the efficacy of these and other agents in the reversal of MDR in hematologic malignancies are ongoing.
Insights
Multidrug resistance (MDR) hinders multiple myeloma treatment. Noncytotoxic modulators show promise in reversing MDR by targeting P-glycoprotein (P-gp), potentially improving patient outcomes.
Area of Science:
- Oncology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a significant challenge in multiple myeloma treatment.
- Key MDR mechanisms include P-glycoprotein (P-gp) and lung-resistance protein (LRP) expression, and Bcl-2 mediated apoptosis suppression.
- Chemotherapy exposure can exacerbate MDR emergence in multiple myeloma.
Purpose of the Study:
- To investigate the clinical efficacy of noncytotoxic modulators in reversing MDR in multiple myeloma.
- To evaluate P-gp modulators like verapamil, cyclosporin A (CsA), and PSC 833 for MDR reversal.
Main Methods:
- Phase I/II clinical trials were conducted to assess MDR reversal agents.
- Co-administration of MDR modulators with chemotherapeutic agents was studied.
Main Results:
- Preliminary results suggest that P-gp modulation can reverse MDR in clinical settings.
- Coadministration of MDR modulators with chemotherapy impacts drug pharmacokinetics.
Conclusions:
- Noncytotoxic P-gp modulators offer a potential strategy for overcoming MDR in multiple myeloma.
- Further Phase II and III trials are ongoing to confirm efficacy in hematologic malignancies.