A Phase I/II Study of Escalating Doses of Thalidomide (Thal) in Conjunction with Bortezomib (Vel) and High Dose Melphalan (Mel) As A Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) in Patients with Advanced Multiple Myeloma (MM).

Abstract 3104

Thalidomide is an active agent in the treatment of MM and shows additive and/or synergistic effects when combined with various chemotherapeutics in pre-clinical and clinical models. We conducted a phase I/II study of Thal in combination with Vel and high dose Mel with PBSCT in patients (pts) with either disease progression or less than complete response after a prior PBSCT. Inclusion criteria included a diagnosis of MM and the availability of adequate PBSC. Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, uncontrolled CNS metastases, known cardiac amyloid deposition, severe organ dysfunction, Karnofsky score <70%, or severe sensory neuropathy. Conditioning for PBSCT consisted of Vel 1.6 mg/m2 IVP on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1. Thal was administered in a planned dose escalation steps of 600, 800 and 1000 mg (in cohorts of 3 pts) daily for 5 days. Dexamethasone (Dex) 10–20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE ver 3. No dose limiting toxicities (≥ grade IV non-hematological SAE) occurred in the phase I portion of this study allowing full dose escalation with 9 pts enrolled. All pts experienced somnolence, more prominent at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with improvement in sedation. In the phase II portion of the study, an additional 19 pts were treated with Thal 1000 mg daily. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after PBSCT and were not attributed to Thal. All transplant-related SAEs resolved by day +28 after transplantation. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8–14 days), ANC >1000/uL 10 days (range 9–14 days), and plt >20,000 12 days (range 9–25 days).

28 pts (median age, 56) were enrolled in the phase I and phase II portions of the study. 18 pts were treated for disease progression after prior autologous transplant (median lines of prior therapy =2; range, 1–5); only 22% of pts achieved ≥PR to the most recent therapy prior to PBSCT. 7 pts were enrolled after achieving <CR after prior PBSCT. Restaging evaluation was completed at 1, 2, and 3 months and every 3 months thereafter using the modified IMWG criteria. At three months after PBSCT (compared to immediate pre-transplant) the overall response rate ≥PR was 44% (1 CR, 4 VGPR, and 6 PR). An additional 10 pt achieved SD and 4 pts experienced disease progression. 4 subjects subsequently underwent allogeneic transplant and are not evaluable for long term response. The median event-free (EFS) was 7 months. The median overall survival (OS) has not yet been reached. The estimated EFS and OS probabilities at 2 years are 5% and 60%, respectably.

Our results indicate that high-dose Thal can be safely added up to 1000 mg daily for 5 days to dose-intense Mel and Vel with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study.