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Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

The aim of the present study was to clarify whether gastric antisecretory drugs affect the clinical efficacy and toxicity of orally administered melphalan in patients with multiple myeloma. A total of 10 patients receiving bortezomib plus oral melphalan and prednisolone (VMP) therapy between December 2011 and November 2014 were analyzed retrospectively. The patients were divided into a control group (seven patients) and a concomitant group (three patients, who were also administered with gastric antisecretory drugs). The gastric antisecretory drugs included rabeprazole sodium (two patients) and famotidine (one patient). No significant differences between the groups were observed in either the characteristics of the patients or the VMP regimen. The levels of monoclonal protein (M protein) in the control group tended to decrease (with a VMP cycle-dependency), although they were primarily stable in the concomitant group. During the second and third VMP cycles, the levels of M protein were markedly lower in the control group compared with the concomitant group. All the patients in the control group achieved a partial response, whereas those in the concomitant group exhibited stable disease. Hematological toxicity levels were revealed to be comparable between the two groups, whereas gastrointestinal toxicity was more prevalent in the control group. In conclusion, the results of the present study suggested that the clinical efficacy of melphalan may be reduced by the co-administration of gastric antisecretory drugs. This interaction may result in decreased toxicity and clinical efficacy of melphalan.

Lenalidomide (Len), an immunomodulatory drug, has significant clinical activity in patients with relapsed and refractory multiple myeloma (MM), and it is usually administered at a dose of 25 mg daily. For Len to exert its therapeutic effects with minimum adverse effects, it is important to determine the most suitable dosage on the basis of the physiques and body surface area (BSA) of patients. We investigated the relationship between pharmacokinetic variability of this drug and its toxicity and therapeutic efficacy. The institutional review boards and ethics committees at both participating centers approved the study protocol and all patients provided written informed consent. Thirteen Japanese patients with relapsed and refractory MM were enrolled in this study. They were treated with Len at 10-25 mg for 21 days every 4 weeks. The dose of Len administered to patients with renal dysfunction was reduced according to consensus statements on the optimal use of Len. Dexamethasone at 8-40 mg weekly was added to each drug cycle. Peripheral blood was collected three hours after Len administration in the first cycle and the plasma concentration of Len was evaluated using high performance liquid chromatography. Response and progression were assessed according to the International Myeloma Working Group criteria and the severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The median values of age (years) and estimated creatinine clearance (eCLcr, mL/min) of the 13 enrolled patients (male to female ratio=5:8) were 69 and 66.3, respectively. The number of patients in stages I, II, and III or the unknown stage of the International Staging System were 8, 1, 2, and 2, respectively. The number of the patients who achieved the best responses during three cycles of treatment were one (7.7%) in complete response, four (30.8%) in partial response, and eight (61.5%) in stable disease. The percentage of hematological adverse events (Grade 3/4) was 38.5% and no non-hematological events (Grade 3/4) were observed. The Len concentration ranged from 172.5 ng/mL to 555.6 ng/mL with a median concentration of 341.8 ng/mL. eCLcr values did not correlate with Len concentrations, but significantly correlated with C/D ratios (p <0.005, Figure 1). We next evaluated the correlation between Len concentration and the severity of adverse events. The percentage of patients with any Grade 1/2 adverse event and the percentage of those with Grade 3/4 adverse events were 61.5% (8/13) and 38.5% (5/13), respectively. A Receiver Operating Characteristic curve analysis of Len concentrations was used to determine an optimal cutoff value with the Youden index. The percentage of severely of any Grade 3/4 adverse event for patients with ≥ 320 ng/mL Len was 62.5% (5/8), and that of patients with <320 ng/mL was zero (0/5). The Fisher's exact test demonstrated that the severity of adverse effects significantly correlated with the Len concentration (Table 1, p <0.05). However, there was no correlation between Len concentrations and best responses. These findings indicate that it is possible to avoid severe adverse events without reducing therapeutic efficacy by monitoring Len concentrations. In conclusion, this pilot study suggests that it is important to determine the Len dosage on the basis of its plasma concentration. This issue should be clarified further in a large-scale study. Disclosures Kado: Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Kitazawa:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Fuchida:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Okano:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Hatsuse:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Murakami:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Ueda:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Kokufu:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment. Shimazaki:Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center: Employment.