Antitumour Activity of Bortezomib-Pegylated Liposomal Doxorubicine Association: Results of an Ongoing Study in Multiple Myeloma Patients.

Background: There are evidences supporting the existence of a synergism between the proteasome inhibitor bortezomib and anthracyclines. In addition, in vivo data show enhancement of the antitumor activity of pegylated liposomal doxorubicine (Peg LD) when used in combination with bortezomib. Patients and therapy. Based on these findings we are using this combination as salvage therapy in active multiple myeloma in an ongoing study. So far, 18 patients MM patients (7 F and 11 M, median age 62 years, range 45–71) with resistant or relapsing disease after high or conventional dose chemotherapy have been enrolled. Patient distribution according to disease status and previous therapy is as follow:

1. 3 and 7 patients with disease resistant to (including PR cases) or relapsing after high dose chemotherapy with PBSC support, respectively;

2. 4 and 4 patients with disease resistant to or relapsing disease after conventional dose chemotherapy, respectively.

Bortezomib 1,3mg/m² is given as a bolus IV injection on days 1,4,8 and 11 for eight three-week cycles (induction therapy), then administered on days 1,8,15 and 22 for three five-week cycles as maintainance therapy. PegLD is given at a dose of 40mg/m² every 3 weeks. In the first cohort, including four patients, Peg LD is employed after the completion of the 8^th cycle of bortezomib, during the maintenance phase therapy. In the remaining fourtheen cases, Peg LD is combined with bortezomib starting from the 4^th induction cycle. Sequential drug administration was chosen in order to evaluate if the antitumor activity exerted by combination therapy is superior to that achieved with bortezomib employed as single agent.

Results. In the first cohort, including 4 patients (3 with resistant disease to high dose chemotherapy and 1 with relapsing disease after two different combinations of conventional dose chemotherapy), bortezomib resulted in three objective responses (2 nCR, 1 PR) and one disease stabilization. However, the addition of PegLD did not induce in any significant improvement of response in 3/4 cases who have completed the planned treatment. In the second cohort, including 6 patients with resistant to high (2 pts) or conventional (4 pts) dose therapy and 8 with relapsing disease, myeloma progression has been documented in two istances after the second cycle of bortezomib. One patient died of uncontrolled disease, while another, responding to VP-16 salvage therapy, is at present time alive and in good PR. Of the remaining 12 patients, 9 have reached a PR and 3 a nCR after the first 3 cycles of bortezomib. In the 7 patients who at present time have received at least three cycle of bortezomib-PegLD combination, a conversion of 2 PRs in CRs and a further reduction of serum concentration of paraprotein in a third patient were documented. Overall, bortezomib or PegLD-bortezomib combination, has been well tolerated. Grade 1–2 thrombocytopenia was the most common hematological toxicity. All patients have complained mild to moderate asthenia and grade 1–2 paresthesias.

Conclusion. It is not possible to achieve any firm conclusion regarding the effect of bortezomib-PegLD combination on the control of resistant-relapsing MM, mainly because of the small sample size of treated patients. However, our findings suggest that this combination therapy may exert in some cases a significant antitumor activity.