Subcutaneous Injection Of Bortezomib, Combined With Doxorubicin and Dexamethasone (sPAD) Is Effective and Safety Induction Therapy For Untreated Multiple Myeloma Patients

Bortezomib is the first generation proteasome inhibitor which is used as induction therapy for multiple myeloma (MM) patients. Recently, triplet therapies including bortezomib are recommended by several committees. Among various triplet therapies, PAD (bortezomib, doxorubicin, and dexamethasone), which was reported in the analysis of randomized phase III HOVON-65/ GMMG-HD4 trial, is an effective therapy. Complete response (CR), including near CR, was superior after PAD induction to VAD induction (15% vs. 31%; P < .001) (Sonneveld P et al.). However, peripheral neuropathy (PN) was observed in 37% of PAD induction arm (grade 3 or 4 Peripheral neuropathy (PN) was 24%). Recently, some investigators reported that subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile (Moreau P et al.). PN was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Therefore, we performed a phase 2 PAD study using subcutaneous bortezomib (sPAD) in Japanese MM patients.

Eligible patients were aged 20 years and older from whom was obtained written informed consent. Between July 2011 and April 2013, 30 symptomatic MM patients were enrolled in this trial. They received bortezomib (1.3 mg/m² on days 1, 4, 8, and 11) by subcutaneous injection, oral dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12), and intravenous doxorubicin (20 mg/m² on days 1 and 4), every 21 days as their induction regimen. Subcutaneous injections were administrated with reduced-concentration to 2.0mg/ml (3mg bortezomib reconstituted with 1.5ml normal saline). In addition, we studied a pharmacokinetics of bortezomib. Plasma samples were collected in cycle 1 on day 11. Bortezomib plasma concentrations were measured with a validated liquid chromatography. We compared this sPAD therapy with intravenous injection bortezomib dexamethasone (BD) therapy (N=40), as a historical control. Statistical analyses were done with Stata /MP (version 12.1).

Patient's characteristics at inclusion did not differ between two groups. Overall response rate (VGPR or CR) of sPAD therapy was superior to BD therapy (77% vs. 30%; p<0.001). The CR rate was 2.5% in patients who were treated with BD and 30% in patients who were treated with sPAD (p=0.001). The median progression free survival (PFS) was 6 months for the BD therapy and 22 months for the sPAD therapy. Patients who were treated with sPAD had a significantly better PFS (p<0.001). Median overall survival (OS) was not reached at 24 months in sPAD therapy and 23 months for BD therapy. Patients who were treated with sPAD had a significantly better OS (p=0.0251). Grade 3 or worse PN (5% vs. 28%; p=0.040) was significantly less common with sPAD than BD. Subcutaneous administration was locally well tolerated. Eight patients enrolled in the pharmacokinetic study. Table 1 shows bortezomib concentration profile after subcutaneous administration on day 11, cycle 1. Mean maximum plasma concentration of bortezomib (C_max) was lower than previously reported level (C_max = 12.27 ng/mL (7.41-19.40)). However, mean bortezomib systemic exposure (AUC_last) was similar to previous report (AUC_last = 156.8 ngxh/mL (85.0-240.0)).

sPAD therapy is promising induction therapy for untreated MM patients because of efficacy and safety. Furthermore, reduced bortezomib-concentration subcutaneous administration may help to reduce PN. Further study might be warranted.

Table 1

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No relevant conflicts of interest to declare.