In Vivo Purging Followed by AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) in PATIENTS with MULTIPLE MYELOMA (MM): Preliminary RESULTS of a Pilot STUDY

In the past decade, thalidomide, bortezomib, and lenalidomide have emerged as highly active agents in the treatment of MM. However, the optimal schedule and association of these drugs is still under investigation. Thalidomide has shown to be highly thrombogenic in induction therapy, especially in patients with high tumor burden, while Bortezomib (BOR) is not; moreover BOR does not affect peripheral blood stem cell (PBSC) collection and it has also been used in combination with Melphalan (MEL) before ASCT. Both in vitro laboratory data and preliminary phase II trials suggest synergistic effects when BOR is combined with Cyclophosphamide (CY); this drug is effective in treatment of MM and is not stem cell toxic. We started a pilot study in high risk MM patients, fit for ASCT, combining BOR, CY and dexamethasone (DEX) as induction and mobilizing therapy (CY-BOR), followed by supplemented BOR-ASCT, to determine: 1-feasibility and Response Rate (RR): percentage of complete remission (CR) and near CR (nCR) at day + 90 after ASCT; 2- clearance of Minimal Residual Disease (MRD) both in PBSC harvest and in bone marrow at day +90 after SCT; the percentage of plasma cells (PC) in PBSC harvested has been assessed by flow cytometry (FC), by using CD38, CD45, CD56, CD138, CD19, kappa and lambda staining. Patients receive three 3-weeks treatment cycles with BOR 1.3 milligrams/squared-meter/dose on days 1,4,8,11, in combination with DEX 40 milligrams/day i.v. on days 1,4,8,11 and CY i.v. 300 milligrams/squared-meter/dose on days 1,8,15. After the third course, patients achieving at least PR, undergo PBSC mobilization with BOR 1.3 milligrams/squared-meter/dose on days 1,4,8,11 in combination with DEX 40 milligrams/day i.v. on days 1,4,8,11 and CY i.v. 3000 milligrams/squared-meter/dose on day 8; Granulocyte-Colony Stimulating Factor (5 micrograms/kilogram) is given starting on day 9. Patients who successfully mobilize an adequate PBSC amount are planned to receive conditioning regimen, combining high-dose MEL(on day -1) with BOR (1.3 milligrams/squared-meter/dose on days -8 and -4). At present 10 patients (6 female and 4 male; median age: 71) have been enrolled and 8 are evaluable for response before PBSC harvest; 4 patients have been mobilized: in all of them we were able to collect a sufficient PBSC amount (median 11.1; range 3–11.2 CD34+ cells/kilograms) and to perform ASCT. Conditioning was well tolerated and was followed by quick engraftment: the median time to neutrophils>500/mcl was 9 days and 12 days for unsupported platelets count>20,000/mcl, without major extrahematological toxicity. With a minimum follow-up of 90 days after ASCT, 3 evaluable patients are alive, two in VGPR and one in CR; with a median follow up of 108 days (range 95–201) all 10 patients are alive and 100% of the evaluable patients achieved at least PR after only 2–3 courses of CY-BOR (table 1). The hematological toxicity was negligible and we did not observe neither thromboembolic events nor grade 3–4 neurotoxicity. Only one patient experienced a transient increase of liver enzymes during the first two courses of therapy. The study of MRD by flow cytometry in PBSC harvest of two evaluable patients shows complete clearance of plasmacells; in the others the MRD study is still ongoing and complete data will be further presented. This preliminary experience shows that this schedule is well tolerated and very effective also in elderly patients, allowing to collect a clonal plasmacells free harvest. Whether this will translate in an “in vivo” MRD clearance after ASCT, it should be confirmed by a longer follow up and by a PCR monitoring with patients specific probes (which is still ongoing).

Table 1: Baseline characteristics of patients and outcome Legenda: ISS: International Staging System; NE: not evaluable; A&W: alive and well; VGPR: very good partial remission