Efficacy and Tolerability of CEP-18770 in Combination with Dexamethasone and Lenalidomide Using a SCID-Hu Model of Multiple Myeloma (MM)

We previously demonstrated the anti-MM effects of the proteasome inhibitor (PI) CEP-18770 with lenalidomide (LEN) and/or dexamethasone (DEX) using the MM xenograft model LAGκ-1B. Bortezomib has been shown to demonstrate synergistic anti-MM effects with both of these classes of drugs which has led to the successful use of these combinations to treat patients with MM. Thus, we conducted the current study to ascertain the anti-MM effects of CEP-18770 in combination with DEX and/or LEN in vivo using a different human severe combined immunodeficient (SCID) -hu MM model (LAGκ-1A) than then one previously evaluated and mentioned above (LAGκ-1B). Methods: 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 based on human immunoglobulin G (IgG) levels. CEP-18770 (4 mg; Cephalon, Inc., Frazer, PA, USA) stock solution was dissolved in propylene glycol (800 μl) and added to 5% mannitol to generate a final stock solution of 1 mg/ml, diluted (5% mannitol). Mice were injected with 1 mg/kg twice weekly (T, Th) via intravenous (i.v.) injection. LEN stock solutions were prepared daily from pills and diluted in 5% carboxymethylcellulose. DEX was obtained as a 4 mg/ml stock solution, diluted (0.9% sodium chloride). Mice were treated daily with DEX at 1.25 mg/kg via intraperitoneal (i.p.) injection and 30 mg/kg of LEN via oral gavage. On a weekly basis, tumor size was measured using standard calipers (n = 9–10 mice/group) and human IgG levels with an ELISA (Bethyl Laboratories, Montgomery, TX). This study was conducted according to protocols approved by the Institutional Animal Care and Use Committee. Results: At day 35 post tumor implantation, mice receiving the doublets of CEP-18770 plus daily dexamethasone or lenalidomide and the triplicate regimen containing all three drugs markedly inhibited tumor volume growth compared to mice receiving vehicle. Notably, P -values could not be calculated because all mice receiving the doublet and triplicate combination regimens had undetectable tumor volumes (zero tumor volume measurements) and thus a t-test could not be calculated. These tumors remained undetectable beginning at day 35 and throughout the study until its termination (day 91). CEP-18770 or DEX administered alone also significantly inhibited tumor volume growth (P = 0.0005, P = 0.0205, respectively) at this same time point, when compared to mice receiving vehicle, whereas LEN alone did not. However, in contrast to the tumors which eventually grew in mice after single agent treatment with CEP-18770, DEX, or LEN and the doublet LEN + DEX group, tumors did not reappear among mice which received the CEP-18770 doublet or CEP-18770 triplicate combination regimens. Similar inhibitory effects were obtained for IgG levels as those observed for tumor volume growth inhibition. Mice receiving CEP-18770 doublets (CEP-18770 + DEX or LEN) or all three drugs together were sacrificed at day 91. Overall, 10/10 mice survived the CEP-18770 + DEX regimen, and 9/10 mice survived in both the CEP-18770 + LEN and CEP-18770 + DEX + LEN groups. Conclusions: These in vivo studies using our LAGk-1A 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 significant inhibition of tumor growth as determined by measuring tumor volume and IgG levels when compared to vehicle-treated and single agent treated mice. Although the initial anti-MM effects were similar between single agent CEP-18770 and the doublet and triplicate combination therapies, with longer follow-up the doublet and triplicate combination therapies proved to be superior. The toxicity profile was negligible and similar between CEP-18770 monotherapy, combined with either DEX or LEN, and the triplicate combination regimen. Pre and post-treatment body weight comparisons of these groups demonstrated that mice receiving the different treatments gained weight to a similar extent during study treatment. This study demonstrates that using a different MM model (LAGκ-1A), the PI CEP-18770 in combination with DEX and/or LEN results in significant tumor growth and IgG inhibition, and provides further support for the development of the novel agent for the treatment of MM.

Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding.