Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914)

Abstract

Summary. Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD 1 cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2±3 were observed more often with VAD 1 cyclosporin A than with VAD only: nausea (30% versus 8%, P 0´015), mucositis (18% versus 5%, P 0´13), infection (45% versus 35%, P 0´50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (218´5%, 26´9%)]. The median progression-free survival (PFS) was 8´6 months (VAD 1 cyclosporin A) versus 5´8 months (VAD): [log rank P 0´16, hazard ratio 0´71, 95% CI (0´44, 1´15)], and median overall survival was 13 months versus 14´6 months [log rank P 0´89, hazard ratio 0´96, 95% CI (0´62, 1´72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgppositive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

“…Since the mid-1980s, various clinical trials with anticancer drugs in combination with P-gp modulators (calcium channel blockers-nifedipine or verapamil-or cyclosporin A) have been performed [139 -141]. Unfortunately, with only few exceptions [142][143][144][145][146], these studies did not show any survival benefit for the combination of an anticancer drug plus a P-gp inhibitor [147][148][149][150][151]. In addition, because the P-gp inhibitors used in those trials presented overlap in substrate specificity with CYP3A4 inhibitors, pharmacokinetic interactions occurred, resulting in greater toxicity.…”

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

“…Targeting secondary drug resistance by inhibitors of the multidrug resistance (MDR) efflux pumps has failed in the clinical setting. 4 In contrast, targeting CAM-DR seems to be a reasonable strategy to increase the efficacy of common antimyeloma drugs and to prevent the development of secondary drug resistance after primary treatment.…”

Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study

“…It has been well documented that P-glycoprotein (P-gp), the gene product of the multidrug resistance protein 1 gene (MDR1, ABCB1), has been a major component of the drug efflux pump that prevents intracellular accumulation of anthracycline drugs [13]. Although reversal of MDR has been reported with several agents, unfortunately, they were relatively nonspecific and had low potency and/or adverse toxicity [4,21,24,43,45]. Consequently, the development of alternative therapeutic strategies employing more efficient delivery systems is imperative to overcome MDR.…”