Bortezomib (Velcade®) is effective in MM as single agent. A strong rationale supports the association of bortezomib with anthracyclines. Bortezomib may increase the activity of anthracyclines by inhibiting maturation of P-gp, suppressing DNA repair and inducing phosphorylation and cleavage of Bcl-2. Anthracyclines down-regulate the bortezomib anti-apoptotic effect. In vitro studies demonstrated that liposome encapsulated doxorubicin can overcome MDR-1 overexpression. It has a longer half-life, lower cardiac toxicity and comparable efficacy. Thus, we added non-pegylate liposomal doxorubicin (Myocet®) to the low dose VTD regimen (

Ciolli et al. Leukemia & Lymphoma 2006;47(1): 171–173
). Aims of the study were to evaluate the feasibility of treatment and stem cells harvest and transplantation, to compare ORR and TTP in respect to LD-VTD. The study was performed in accordance with the Declaration of Helsinki. Eligibility criteria: pts primary refractory (PR) or relapsed and refractory (R/R), with a LVEF more than 45% and a measurable disease. Therapy: bortezomib 1.0 mg/m2 i.v. bolus days 1, 4, 8 and 11 of a 28-d cycle, Myocet 50 mg/m2 i.v over 60 minutes on day 4 (1 hour after bortezomib), oral dexamethasone 24 mg on the day of and the day following each bortezomib dose. Thalidomide 100 mg/d if non controindicated. All toxicities were defined according to NCI criteria. Response was evaluated after each cycle. Pts with progressive disease (PD) were removed from the study, the others continued until best response for a maximum of 4 cycles. Time to response was from the date of the first administration of bortezomib to the first evidence of response. From June 2005, 28 pts, median age 68 years, entered the study: 5 stage IIA, 20 IIIA and 3 IIIB. 16 (57%) were the PR pts and 12(43%) those R/R. 8(29%) had a β2microglobulin >4 mg/L, 7 a PS >2 and 8 a pre-existing peripheral neuropathy (PN) grade 2. Median time from diagnosis was 4 years and a median of 4 (range 2–6) were the prior therapy lines. All pts had previously received thalidomide plus dexamethasone; 8 had previously received bortezomib. 13 (46%) did not receive thalidomide due to a pre-existing neurological toxicity. Haematological toxicity was registered 14–17 days from the start of therapy and lasted for a maximum of 4 days: grade 2 neutropenia in 3 pts, grade 4 thrombocytopenia in 5. A patient had a grade 4 gastric haemorrhage. 3 pts had pneumonia, 2 HZ infection and 1 a DVT. Other adverse advents of grade >1 were fatigue (50%), nausea (60%), diarrhoea (15%), alopecia (10%). None progression of PN was observed. No patient experienced clinical evidence of cardiac toxicity. At July 31th 2006,. all pts were valuable for response: 3 PD, 4 SD, 21 responders: 8 CR, 2 nCR, 7 PR,4 MR (ORR 75%). Median time to best response was 1 month (range 1– 2). 3 pts successfully harvested the PBSC and 1 was transplanted. After a median follow-up of 9 months, median TTP and OS had not been reached, 23 pts were alive and 5 (2 PD and 3 responders) had died. Myocet did not add toxicity to LD-VTD. PBSC has been successfully performed in eligible pts. More pts and an adequate follow-up are needed to draw any definitive conclusion about TTP and OS, however, this regimen appears feasible and effective with an increased ORR compared to our previous LD-VTD experience (75% vs 53%).

Topics:
bortezomib, dexamethasone, doxorubicin, liposomes, multiple myeloma, thalidomide, brachial plexus neuritis, toxic effect, anthracycline antibiotics, cardiotoxicity

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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