Phase II Trial of Oblimersen Sodium (G3139), Dexamethasone (Dex) and Thalidomide (Thal) in Relapsed Multiple Myeloma Patients (Pts).

Bcl-2 acts as an important regulator of the mitochondrial pathway of apoptosis and promotes resistance of MM cells to chemotherapy. The Bcl-2 antisense oligonucleotide G3139 specifically targets Bcl-2 and may enhance the anti-tumor efficacy of Dex and Thal. In this trial G3139 was administered at 5 mg to the first 3 Pts and then 7 mg/kg/d by IVCI for 7d of 21d cycle. On day 4, Pts started Dex 40 mg daily for 4 d and Thal 100-400 mg as tolerated. After 3 cycles, responding Pts continued G3139 on a 5-week cycle with Dex 20 mg x 4d and Thal at the tolerated daily dose for up to 1 yr with an optional second yr for responding Pts. Thirty-three Pts treated to date had the following characteristics: median age 60 yrs (range: 28- 76), 22 males; 16 Pts had complex karyotypes; 14 Pts had B2M > 2.5 g/dl; LDH >1.5 normal in 7 Pts; Cr >1.5 mg/dl in 6 Pts; platelets <100,000/ul in 4 Pts. Pts had received a median of 3 prior regimens (range 2-4) including auto-SCT. Seventeen Pts had received prior Thal for a median duration of 6.5 mos. (range 2–8); 11 had no response or progressed on Thal. G3139/Thal/Dex regimen was well tolerated. The median number of cycles per Pt was 8 (range: 1–16). Toxicities included reversible increase in Cr from a median of 1.2 (0.6–2.5) at baseline to 1.5 (range: 0.9–2) at cycle 6. G3139 dose was decreased (3–5 mg/kg/d) for Cr elevations in teh majority of Pts. Thrombocytopenia <100K occurred between cycle 1 and 2 (P= 0.008), and was reversible. Other toxicities (>grade 2) included fatigue, neutropenia, fever, electrolyte disturbance, muscle cramps, rash, hypotension, constipation and infections. Only 3 Pts maintained 400 mg/d of Thal, most Pts required dose reduction to 50–200 mg/d due neuropathy. Thirty Pts were evaluable for response; 24 Pts (80%) had documented responses, including 2 CR, 4 near-CR (+ immunofixation) and 12 PR; 6 had minimal response and 6 Pts had PD. The median duration of response is 13 mos. The estimated PFS is 12 mos and the median OS is 17.4 mo. The upper limits of the 95% confidence interval for PFS and OS have not been reached. At a median follow up of 1 yr (range 1.5–16.6 mo), 7 Pts had died and 26 are alive, of them 16 Pts continue on the study. Responding Pts had an early and significant increase in polyclonal IgM from a median baseline of 35.5 mg/dl (range: 8–75) to 94 (45–211) after cycle 3 (P=0.005), suggesting activation of the innate immune system. CD138+ cells were isolated from BM aspirates pre-treatment, and on d 4 or 7, and 28. Western blot analysis of Bcl-2 protein demonstrated demonstrated a decrease in Bcl-2 levels after normalization for protein loading by densitometry in 3 of 7 Pts with sufficient cells for analysis. The change of Bcl-2 protein levels did not correlate with response. Real time quantitative RT-PCR analysis was subsequently used to evaluate changes in Bcl-2 gene expression. Of 9 Pts evaluated, 6 demonstrated a significant decrease in Bcl-2 mRNA expression when normalized against GAPDH; 5 of them had a clinical response. In conclusion, G3139, Dex and Thal regimen is well tolerated in relapsed MM Pts. G3139 was associated with significant decrease in Bcl-2 gene expression in some Pts. G3139 appears to over-come resistance to Dex/Thal with impressive clinical responses in relapsed/refractory MM patients.