Subcutaneous and Intravenous Bortezomib in Multiple Myeloma Patients Has Similar Response Rates and Toxicity Profile with No Difference in the Incidence of Peripheral Neuropathy: Report of the Czech Myeloma Group

Background:Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. The results of an international randomized phase III trial confirmed that SC application of bortezomib is not inferior to intravenous (IV) route, with similar response rates and improved toxicity profile.

Our aim was to confirm the results on a larger cohort of patients treated with IV or SC bortezomib in 2-year period within the Czech Myeloma Group.

Patients and methods: We performed a retrospective analysis of 262 patients with MM treated with bortezomib based regimens during 2012-2013 in the Czech Republic. In total, there were 177 patients in the IV arm and 85 patients in the SC arm. Patients undergoing high-dosed chemotherapy followed by autologous stem cell transplantation (ASCT) were assessed separately (N = 99). There were 164 patients treated in the first line setting and 98 patients in relapse/progression of MM. The patients received up to eight 28-day cycles of bortezomib-based regimen with bortezomib dose 1.3mg/m². The regimens used were following: CVD (cyclophosphamide, bortezomib, dexamethasone) in 58.2%/60.0%, VD (bortezomib, dexamethasone) in 10.7%/9.4%, BDD (bortezomib, doxorubicin, dexamethasone) in 9.6%/14.2%, VMP (bortezomib, melphalan, prednisone) in 6.0%/9.0%, bortezomib monotherapy in 1.1%/1.2%, BBD (bortezomib, bendamustine, dexamethasone) in 1.1%/2.4%, BP (bortezomib, prednisone) in 0%/1.6%, and other in 13.6%/2.4%. In order to reduce neurological toxicities, most of the patients received bortezomib once weekly. In both IV and SC arms we assessed the demographics and baseline characteristics, response rates and toxicities.

For statistical estimation we used Mann-Whitney U test and Chi-square test at p < 0.05.

Results:There were mild differences in the age and gender between IV and SC arms (median age 71.3 vs 67.9 years, p = 0.024; M/F ratio 1.4:1 vs 0.6:1, p = 0.007), other variables were without significant difference, including laboratory parameters (M-protein, hemoglobin, thrombocyte count, serum calcium level, albumin, creatinine, beta-2-microglobulin, lactate dehydrogenase, CRP), line of chemotherapy (first line, second line, third line and fourth and higher line) and therapeutic regimen used. Patients received median of 6 cycles in the IV group and 5 cycles in the SC group. The rates of response were similar in both, IV and SC arms with overall response rate (ORR) 71.7% vs 70.7%, complete remissions (CR) including stringent complete remissions (sCR) in 13.9% vs 8.6%, very good partial remissions (VGPR) in 30.8% vs 34.5% and partial remissions (PR) in 27% vs 27.6%. Toxicities were present in most patients (up to 99%), prevailing grade 1-2 toxicities, the most frequent grade ≥3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN). PN of any grade was present in 48% patients in the IV arm and in 41% in the SC arm. PN grade ≥2 was present in 20% vs 18% and PN grade ≥3 was present in 6% vs 4% (p = 0.782).

Conclusions:Subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration.

Supported by the grants IGA MZ CR NT 14393, NT 12215-4/2011, NT 14400, NT12451-5, NT 12215-4, and the grant MSM0021622434.