Primary hematopoietic malignancies are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We have previously shown that treatment with GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human multiple myeloma (CAG) and ovarian carcinoma (OVCAR3) cell lines in vitro and in vivo (AACR 2005 Annual Meeting). The CAG multiple myeloma cell line (telomere length 2.7 Kb) was transfected with a retroviral vector encoding a triple fusion gene for HSV-TK, firefly luciferase and green fluorescence protein, and whole animal bioluminescence imaging was undertaken in either a subcutaneous or disseminated NOD/SCID model with extensive spinal cord and bone marrow tumor infiltration. In a subcutaneous model with CAG, GRN163L was administered three times per week (tiw) at 36 mg/kg for 4 weeks alone or in combination with either a single dose of melphalan (5 mg/kg) or 9 doses of Velcade (0.25 mg/kg tiw). Tumor mass was reduced 56% with GRN163L alone (p<0.001), 60% with melphalan alone (p<0.001), 89% with the combination of GRN163L and melphalan (p<0.001). At the dose used, Velcade alone showed no efficacy, but the combination of GRN163L with Velcade reduced the tumor mass by 68% (p<0.001) compared to controls. Data on the treatment with a mismatch control oligonucleotide in addition to dose optimization of GRN163L in combination with Melphalan and Velcade in subcutaneous and disseminated myeloma models (CAG, MM.1S) will be presented. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005. These data support the development of GRN163L as an effective and safe agent for therapy of hematopoietic malignancies.