Although we have previously demonstrated the anti-myeloma (MM) effects of the novel proteasome inhibitor (PI) CEP-18770 alone and the ability of this PI to enhance the anti-MM effects of melphalan as well as another PI bortezomib (Sanchez et al. Br J Haematol, 148(4):569-581 ), this novel PI has not been evaluated in combination with immunomodulatory agents (IMiDs) or glucocorticosteroids. Bortezomib has been shown to demonstrate synergistic anti-MM effects with both of these classes of drugs which have led to the successful use of these combinations to treat patients with MM. Thus, we conducted these studies to ascertain the anti-MM effects of CEP-18770 in combination with the glucocorticosteroid dexamethasone (DEX) and/or IMiD lenalidomide (LEN) in vivo using our human SCID (severe combined immunodeficient)-hu MM, LAGk-1B (bortezomib-resistant tumor).
Each naïve SCID mouse received a 20 – 40 mm3 MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were randomized into treatment groups. CEP-18770 (4 mg; Cephalon, Inc., Frazer, PA, USA) stock solution was dissolved in propylene glycol (800 μ l) and added to 5% mannitol to generate a final stock solution of 1 mg/ml, diluted (5% mannitol). Mice were injected with 3 mg/kg twice weekly (T, Th) via intravenous (i.v.) injection. LEN stock solutions were prepared daily from pills and diluted in 5% carboxymethylcellulose. Mice were treated with 30 mg/kg of this IMiD daily via oral gavage. DEX was obtained as a 4 mg/ml stock solution, diluted (0.9% sodium chloride). Mice were treated with 1.25 mg/kg daily of this glucocorticosteroid via intraperitoneal (i.p.) injection. Tumor size was measured using standard calipers on a weekly basis (n=9–10 mice/group).
At day 28 post-tumor implantation, mice receiving CEP-18770 plus daily DEX markedly inhibited tumor volume growth (P=0.0007), compared to mice receiving vehicle, whereas CEP-18770 alone did not show a significant effect, but by day 35 both CEP-18770 administered alone and in combination with DEX significantly inhibited tumor volume growth (P < 0.0001) compared to mice receiving vehicle. Notably, DEX alone had no anti-MM activity at any time point throughout study duration. Overall, mice survived the DEX, CEP-18770, and CEP + DEX treatment regimens well with 9/10, 10/10, and 10/10 mice alive, respectively, at study termination (day 35). Similarly, at day 28 post-tumor implantation, mice receiving CEP-18770 plus daily LEN showed markedly smaller tumors compared to mice receiving vehicle (P=0.0004), whereas CEP-18770 alone did not show an effect. However, by day 35, both CEP-18770 administered alone (P < 0.0001) and the combination of CEP-18770 + LEN (P < 0.0001) significantly inhibited tumor volume growth compared to mice receiving vehicle alone. LEN alone showed no anti-MM activity at any time point throughout the study. Overall, mice survived the CEP-18770, LEN, and CEP + LEN treatment regimens well with 10/10, 10/10, and 9/10 mice alive, respectively, at study termination (day 35). The anti-MM effects of the triplicate combination of CEP-18770 + DEX + LEN in LAGk-1B-bearing mice was also evaluated. At day 28 and day 35, the triplicate combination also produced markedly smaller tumor volumes (P=0.0001) compared to vehicle-treated mice. However, this was not significantly different from single agent CEP-18770 or the combination of this PI with DEX or LEN. Overall, mice survived the triplicate combination regimen well with 9/10 mice alive at study termination (day 35).
These in vivo studies using our bortezomib-resistant LAGk-1B SCID-hu model show that CEP-18770 administered alone, in combination with DEX or LEN, or in triplicate combination with both DEX and LEN, resulted in statistically significant tumor volume growth inhibition when compared to vehicle-treated mice. Although initial anti-MM effects were more marked with the combination therapies, with longer follow-up single agent CEP-18770 produced similar anti-tumor effects as the CEP-18770-containing doublet and triplicate combinations. Furthermore, the toxicity profile was favorable and similar between CEP-18770 monotherapy, combined with either DEX or LEN, and the triplicate combination regimen. These results provide further support for the development of the novel PI CEP-18770 for the treatment of MM.
Berenson:Cephalon, Inc.: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.