Relapsed or Refractory Multiple Myeloma: Prospective Study with Bortezomib, Non-Pegylated Liposomal Doxorubicin and Dexamethason (PAD Regimen)

Combining bortezomib with pegylated liposomal doxorubicin for the treatment of Multiple Myeloma (MM) may reciprocally increase their efficacy in vitro and appears to offer higher overall response rates in vivo. With the aim to verify the synergistic interaction towards myeloma cells we planned a prospective study with bortezomib, non-pegylated liposomal doxorubicin and dexamethason in patients with relapsed/refractory multiple myeloma (R/R MM). In this setting of patients, showing a poor outcome because of multi-drug resistance, low-performance status and toxicity to previous chemotherapy, bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to doxorubicin and overcome drug-resistance. Thus, to improve outcome minimizing therapy-related toxicity, bortezomib was added to non-pegylated liposomal doxorubicin and dexamethason (PAD regimen).

From November 2005 and January 2012, 50 patients with R/R MM (relapsed n= 37 and refractory n= 13) referred to the our Institution received PAD regimen. Male/Female ratio: 27/23; Median age: 61 years (range 34–79); median time from diagnosis: 32 months (range 4–121); median of previous therapy lines: n= 3 (range 1–5); patients previously underwent to autologous and allogeneic hemopoietic stem cell transplantation (auto- and allo-HSCT): 22 and 5, respectively. Planned treatment: bortezomib 1, 3 mg/mq iv days 1, 4, 8, 11; non-pegylated liposomal doxorubicin 30 mg/mq on day 1 and dexamethason 40 mg days 1–4 of a 28-day cycle up to 6 cycles.

Forty patients (80%) received the planned treatment schedule whereas 10 patients did not complete it because of toxicity (1 patients) and resistant or progressive disease (9 patients). Median time to best response was 3 months (range 2–6). The overall response rate was 74% with 10 CR (20%), 15 vGPR (30%) and 12 PR (24%). Fifteen of the responder patients underwent HSCT (auto-HSCT: 9; allo-HSCT: 6). The previous use of anthracyclines (35 patients) and bortezomib (3 patients) did not seem influence the response. Median duration of response was 24 months (range 6–57 months). After a median follow-up of 58 months, 14 (28%) patients were alive and, of these, 7 (14%) in Continue CR. The safety profile was manageable: the hematologic grade 3/4 toxicity (neutropenia, thrombocytopenia and anemia) was 28%; non-hematologic grade 3/4 toxicity (sensory or motor neuropathy, infections, fever, fatigue, diarrhea) was 36%. Despite heavy previous treatments, including anthracycline-based, no significant cardiac toxicity was observed.

According to our study, the PAD regimen appears feasible and effective in both elderly and heavily pre-treated R/R MM patients. In fact a significant improved clinical outcome in our cohort of patients was observed.

No relevant conflicts of interest to declare.