BORTEZOMIB-BENDAMUSTINE-DEXAMETHASONE (BBD) IN PATIENTS WITH RELAPSED/REFRACTORY MYELOMA AND DIFFERENT RISK PROFILES NAMELY, CYTOGENETICS, PREVIOUS EXPOSURE TO BORTEZOMIB OR TO LENALIDOMIDE

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Background. To evaluate the efficacy of Bortezomib-Bendamustine-Dexamethasone in relapsed/refractory myeloma in relation to FISH defined cytogenetics, and pre-exposure to Lenalidomide- and Bortezomib-based treatments. Outcome of treatment in patients of relapsed/refractory myeloma depends on the efficacy of the rescue regimen, on patient and tumour characteristics and on previous treatments. Bendamustine, an alkylating drug with purine like activities may exert synergistic activity in combination with bortezomib and may render patients previously exposed to bortezomib sensitive to anew treatment with the proteasome inhibitor. Methods. 71 patients with relapsed/refractory MM have been enrolled. Median age: 65 years, range 40-86 years, male/female: 32/39, ISS stageII/III: 22, 29, and 20 patients, respectively. ECOG status II: 37, 31, and 3 respectively. Previous treatment lines: 1-2: 44, 3-4: 22, and ≥ 5: 5, respectively. Full data documentation for response (>1 cycle) is available for 65 patients. Treatment regimen: Bendamustine 70 mg/m2 day 1+4, Bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, Dexamethasone 20 mg on days 1, 4, 8 and 11, repeated every 4 weeks. Treatment was scheduled for 8 cycles, but should be discontinued in case of no response after 4 cycles at latest. Survival curves were calculated using SPSS software (version 17); comparisons were made using the log rank test. All survival data are provided for the intent-to-treat population. Results. At the time of analysis the median follow up is 7,1 months. 6 of the 71 patients enrolled had less than 1 cycle, while in the entire group the median number of cycles is 4. Overall response rate (CR-PR) was 58.5% and 75.4%, respectively when MR was included (CR-MR) in the patients who completed ≥ 1 cycle. Eleven patients (16.9%) had CR/nCR, 10 (15.4%) VGPR, 17 (26.2%) PR, and 11 (16.9%) MR, respectively. Overall response rate (CR-PR) in patients previously exposed to bortezomib was 56% (CR-MR: 73%) and was 47% (CRMR: 68%) in those pre-treated with lenalidomide-based regimens.Median progression- free survival (PFS) was 13 months, while for overall survival (OS) the median has not been reached as yet (figure 1a). Interestingly, no difference in PFS (p=0.733) and in OS (p=0.377) was found between patients with and without FISH defined adverse cytogenetics (t(4; 14), del17p, ampl 1q21). In patients pre-exposed to bortezomib, no difference in PFS (p=0.219) and in OS (p=0.378) was noted in comparison to bortezomib-naive patients. In contrast, pre-treatment with lenalidomide was found to be significantly associated with shortened PFS (p=0.0001), while for OS (figure 1B) no difference was noted (p=0.074).Toxicities: Grade 3/4 anaemia was found in 13%, leucopenia in 14%, thrombopenia in 36%, infections in 15% (plus 3% G5) and PNP in 5% of patients. Summary. In conclusion, the BBD regimen showed significant activity in relapsed/refractory myeloma. PFS and OS were similar in patients with and without adverse cytogenetics as well as in those pre-exposed to bortezomib or bortezomib naive. Lenalidomide pre-treatment, however was associated with significantly shorter PFS. The regimen was well tolerated with mainly haematological side effects and only 5% grade 3/4 PNP.

Haematologica, 2012; 97(s1):  347