Immunotherapy Immediately Following Transplantation for Multiple Myeloma: Early Recovery of Aggressive Cytotoxic Cells and Improved Immune Recovery.

Autologous peripheral blood stem cell transplantation (APBSCT) is effective for the treatment of multiple myeloma (MM), however the majority of patients relapse. Recent evidence shows an improved outcome if absolute lymphocyte count is increased immediatedly following APBSCT in patients with hematologic malignancy. We designed a phase II trial evaluating a dose escalation of SQ IL-2 and standard dose GM-CSF post-transplant for myeloma patients. Patients (n=18) received melphalan 200mg/m² with GM-CSF 250mg/m²/day beginning on day 5. IL-2 began on the day of transplant and continued 5 days per week for 4 weeks. Peripheral blood samples were obtained at baseline (pre-transplant) and every week for 4 weeks post-transplant and evaluated using flow cytometry for cell subsets using antibodies directed against CD3, CD4, CD8, CD25 and CD56. Control patients (n=11) consisted of MM patients who received melphalan 200mg/m² with either G-CSF or GM-CSF without IL-2. IL-2 at a dose of 1 X 10⁶IU/m²/d was not tolerated in 2 of 6 patients due to grade 4 fatique and diarrhea (n=1) and grade 4 supraventricular arrhythmia (n=1). A dose of 6 X 10⁵ IU/m²/d was well tolerated by 12 patients. Level 3 or greater toxicities included nausea (n=5), diarrhea (n=3), anorexia (n=11), mucositis (n=9). Engraftment of neutrophils occurred on day 12 and platelets on day 18. The LOS was 21 days in IL-2 treated cohort and 18 days in control group. Absolute lymphocyte counts on days 10–15 were increased an average of 152% in the IL-2 cohort (range 25–390%) over the control group. At day 21, there was a marked increase in the number of CD3+CD8+ cytotoxic T cells (43 %, +/− 7.5%) , CD56 +NK cells ( 78.3 %, +/− 9.1), and CD8+CD56+ NKT cells (36.8 %, +/− 9.8%) compared to patients’ baseline levels. Cytotoxicity of Day #21 PBMNC in the IL-2 cohort was strikingly increased at 28.1% (18.5 – 29.2%) compared to 5.5 % (3.59 – 6.52%) at baseline when tested against a human myeloma cell line (RPMI 8226) using chromium release assays (E: T ratio = 100:1). These results demonstrate a tolerable regimen of immediate post-transplant immunotherapy with marked increase in the number and function of early cytotoxic effector cells. The enhanced immune recovery may translate into an improved outcome.