Introduction
Multiple myeloma (MM) is a malignant neoplasm characterized by the clonal proliferation of plasma cells in the bone marrow that produce monoclonal protein (M protein) (1,2). Although MM remains an incurable malignancy, the survival rates have improved markedly (2). The first notable improvement came following the introduction of autologous stem cell transplantation (3,4). In addition, the use of drugs with antiangiogenic, antiproliferative and immunomodulatory effects, including thalidomide (5) and lenalidomide (6,7), and proteasome inhibitors, including bortezomib (8,9), were introduced (10). These agents have been combined with melphalan, resulting in high response rates in patients with MM (11–14).
Melphalan is a cytotoxic agent used extensively in the treatment of MM (15,16). For decades, the combination of melphalan with prednisolone provided the standard of care for elderly patients with MM. Previously, a bortezomib plus oral melphalan and prednisolone (VMP) regimen was demonstrated to exert synergistic anticancer effects (17,18), and thus this has become the current standard regimen for patients with MM (11).
The oral bioavailability of melphalan is known to be widely variable (19–21). For example, Sviland et al (22) demonstrated that pretreatment of the patients with the histamine 2 (H2) receptor blocker, cimetidine, reduced the oral bioavailability of mephalan by ~35%. This reduction is thought to stem from the poor absorption of melphalan (19), since its solubility is known to decrease under alkaline pH conditions (23,24). However, this pharmacokinetic interaction has not been conclusively demonstrated to be associated with any reduced clinical efficacy. Furthermore, there is no mention of any drug interactions between oral melphalan and gastric antisecretory drugs in the medical package insert in Japan.
The aim of the present study was to assess whether the clinical efficacy and toxicity of melphalan were influenced by the concomitant use of gastric antisecretory drugs in patients with MM receiving VMP therapy. The clinical significance of the interaction between melphalan and gastric antisecretory drugs was also discussed.
Discussion
Limitations to the present study included its retrospective small sample size and a lack of plasma melphalan concentrations. However, the results in the present study are sufficient to call attention to the interaction between melphalan and gastric antisecretory drugs.
In the present study, three of the ten patients received gastric antisecretory drugs in addition to VMP therapy. Of the three patients in the concomitant group, two patients received rabeprazole sodium and one received famotidine. With the exception of the use of gastric antisecretory drugs, the control and the concomitant groups were comparable in terms of the characteristics of the patients (Table I) and the doses of chemotherapeutic agents in the VMP regimen (Table II). However, the decrease in the level of the M protein in treatment cycles 2 and 3 was significantly greater in the control group (Fig. 1), indicating a more favorable clinical response in that cohort. In addition, all the patients in the control group were graded as having a PR to the drug therapy, compared with the SD identified in the concomitant group (Table III). Taken together, these findings suggested that the clinical efficacy of the VMP regimen against MM decreases on co-administration of the gastric antisecretory drugs. As for bortezomib, the pharmacokinetics, efficacy and safety of bortezomib were not affected by co-administration of either the proton-pump inhibitor, omeprazole (27), or the H2 receptor blocker, lafutidine (28).
The hallmark adverse events of melphalan are known to be hematological and GI toxicities. The present study disclosed no significant difference in the analyses of hematological toxicity between the control and concomitant groups (Fig. 2 and Table IV), in stark contrast with the clinical efficacy findings reported in the present study. These results are in agreement with previous reports, which cited no significant differences in hematological toxicity among patients receiving oral melphalan following cimetidine pretreatment (22). Therefore, in spite of the decreased bioavailability of melphalan in the concomitant group, the plasma concentrations were likely to have remained within a range in which myelosuppression would be predicted to occur. The observed differences in GI toxicity (Table IV) may be partly explained by the poorer solubility of melphalan tablets with increasing gastric pH.
Taken together, these results suggested that the interaction of the VMP regimen with gastric antisecretory drugs resulted in a marked decrease in the clinical efficacy of melphalan. As such, oral melphalan should not be co-administered with gastric antisecretory drugs, and this drug interaction should prominently feature in the medical package insert.
The mechanism of the interaction between melphalan and gastric antisecretory drugs remains to be fully elucidated. For example, melphalan was reported to be unstable at alkaline pH, and the dissolution of melphalan tablets occurred more slowly at an increased gastric pH (23). Furthermore, Sviland et al (22) reported a 35.5% decrease in the oral bioavailability of melphalan in patients pretreated with cimetidine. Therefore, drugs that induce a potent and long-lasting inhibition of gastric acid secretion [a pharmacological hallmark of rabeprazole sodium (29,30) and famotidine] would predispose a patient towards this interaction. Food intake was also reported to decrease the absorption rate of oral melphalan (31,32). It is notable that melphalan was administered before the meal in the present study.
Taken together, the results in the present study suggest that this drug interaction may arise from the poor solubility of the melphalan tablets, brought about by an increase in gastric pH caused by the concomitant use of gastric antisecretory drugs, thereby resulting in a diminished clinical efficacy of melphalan.
In conclusion, the interaction between oral melphalan and gastric antisecretory drugs may result in a marked decrease in its clinical efficacy in the treatment of MM. This drug interaction possibly results from a reduction in the absorption of melphalan caused by an increase in gastric pH. Due to the aforementioned limitations of the current study, further research is necessary to obtain definitive evidence for these conclusions.