Pharmacokinetics/pharmacodynamics

Maximum elotuzumab serum concentration (Cmax) increased in a dose-proportional manner from 5 to 20 mg/kg. But nonlinear pharmacokinetics (area under the curve [AUC]) increased more than proportionally. The systemic clearance (CL) decreased and terminal phase half-life (T1/2λ) increased with increasing doses, indicating a saturation of target-mediated elimination. Saturation of CS1 receptor by elotuzumab on bone marrow plasma cells achieved 80% and 95% at doses of 10 and 20 mg/kg, respectively, without dose-limiting toxicity (DLT). Bortezomib addition did not affect CS1 receptor saturation. No clinically significant differences were found in the pharmacokinetics of elotuzumab based on age (37–88 years), gender, race, baseline lactate dehydrogenase, renal impairment, end-stage renal disease and mild hepatic impairment (the mean terminal half-life is 33 days).34,36


Continue Reading

SAFETY AND TOLERABILITY

In Phase 1 study, the MTD of IV elotuzumab in combination with oral lenalidomide and dexamethasone is identified, 28 patients were enrolled. Three doses of elotuzumab were given, three patients each for 5 and 10 mg/kg and 22 patients for 20 mg/kg. There was no DLT at 5, 10 and 20 mg/kg of elotuzumab in first cycle. Elotuzumab in combination with lenalidomide and low-dose dexamethasone was, generally, well tolerated. Based on the efficacy data, 10 mg/kg of elotuzumab by IV infusion is recommended to combine with lenalidomide and low-dose dexamethasone.34

In Phase 3 ELOQUENT-2 trail, patients were randomly assigned to receive elotuzumab plus lenalidomide/dexamethasone (elotuzumab group), or lenalidomide/dexamethasone alone (control group). The median duration of treatment was 17 and 12 months in the elotuzumab and control groups, respectively. Serious adverse reactions were reported in 65% of the elotuzumab group and 57% in the control group. The most common grade 3 or 4 hematological AEs included lymphocytopenia in 77% versus 49% and neutropenia in 34% versus 44%, in the elotuzumab and control groups, respectively. The treatment-related AEs in the elotuzumab arm versus the control arm were fatigue (47% vs 39%), pyrexia (37% vs 25%), peripheral edema (26% vs 22%), nasopharyngitis (25% vs 19%), diarrhea (47% vs 36%), constipation (36% vs 27%), musculoskeletal or connective-tissue disorders included muscle spasms (30% vs 26%), back pain (28% vs 28%); the other disorders included cough (31% vs 18%) and insomnia (23% vs 26%).38

FUTURE DIRECTIONS AND CONCLUSION

Although MM remains incurable, treatment options have improved for patients during the past decade. Myeloma is a genetically diverse disease and thus has provided challenges for the implementation of precision medicine and targeted therapy. A better understanding of biomarkers that predict response to specific therapeutic regimens is needed to improve patient care.42 Utilization of CS markers specific for plasma cells has gained interest for directing the treatment of MM since additional targets and therapeutic antibodies are emerging. For example, daratumumab binds to CD38 which is highly expressed on MM cells and was recently approved for patients with MM. CD38 is less abundant on normal lymphoid and myeloid cells. Daratumumab exerts anti-myeloma activity by multiple immune-mediated mechanisms including complement-dependent cytotoxicity, ADCC and apoptosis induction.43,44 It is feasible that combined targeting of CD38 and SLAMF7 may improve anti-myeloma activity as downregulation of both receptors may represent a rare event and thus decreased probability of escape from ADCC.

The combination of elotuzumab with other mABs treatment is also being clinically evaluated. The PD-1 immune checkpoint inhibitor nivolumab, has antitumor immune response in various tumors and approval by the FDA for nonsmall cell lung cancer, melanoma, head/neck cancer, Hodgkin’s lymphoma and renal cell carcinoma. In a Phase III multicenter trial, patients with RRMM are randomly assigned to evaluate the clinical benefit and safety for the combination therapy of N-Pd group (nivolumab, pomalidomide and dexamethasone, the investigational arm), Pd group (pomalidomide and dexamethasone, the control arm) and NE-Pd group (elotuzumab, nivolumab, pomalidomide and dexamethasone, the experimental arm). This study is, currently, recruiting participants. (ClinicalTrials.gov Identifier: NCT02726581).

In summary, elotuzumab has shown promising early clinical results and understanding how to best combine targeting SLAMF7 in combination with other immune strategies as well as standard of care agents may lead to improved patient outcomes for the treatment of MM.

Acknowledgment

This work was supported by National Institute Health (award number: 1RO1CA159727-01_LAH) and National Institute General Medicine (award number: U54GM104942).

Disclosure

The authors report no conflicts of interest in this work.


Wei-Chih Chen,1 Abraham S. Kanate,2,3 Michael Craig,2,3 William P. Petros,1,3 Lori A. Hazlehurst1–3

1Department of Pharmaceutical Sciences, School of Pharmacy, 2Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, 3West Virginia University Cancer Institute, Morgantown, WV, USA 


References

1. Fairfield H, Falank C, Avery L, Reagan MR. Multiple myeloma in the marrow: pathogenesis and treatments. Ann N Y Acad Sci. 2016;1364(1):32–51.

2. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12(5)335–348.

3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–249.

4. Shah N, Callander N, Ganguly S, et al. Hematopoietic stem cell transplantation for multiple myeloma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(7):1155–1166.

5. Anreddy N, Hazlehurst LA. Targeting intrinsic and extrinsic vulnerabilities for the treatment of multiple myeloma. J Cell Biochem. 2017;118(1):15–25.

6. Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 2015;125(20):3049–3058.

7. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–157.

8. Laubach JP, Moreau P, San-Miguel JF, Richardson PG. Panobinostat for the treatment of multiple myeloma. Clin Cancer Res. 2015;21(21):4767–4773.

9. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–287.

10. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840–1848.

11. Richardson PG, Moreau P, Laubach JP, Maglio ME, Lonial S, San-Miguel J. Deacetylase inhibitors as a novel modality in the treatment of multiple myeloma. Pharmacol Res. 2016;117:185–191.

12. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315(3):971–979.

13. Zhang L, Fok JH, Davies FE. Heat shock proteins in multiple myeloma. Oncotarget. 2014;5(5):1132–1148.

14. Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120(5):947–959.

15. Bianchi G, Richardson PG, Anderson KC. Promising therapies in multiple myeloma. Blood. 2015;26(3):300–310.

16. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–2784.

17. Hazlehurst LA, Argilagos RF, Emmons M, et al. Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells. Cancer Res. 2006;66(4):2338–2345.

18. Hazlehurst LA, Dalton WS. Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev. 2001;20(1–2):43–50.

19. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene. 2000;19(38):4319–4327.

20. Bouchon A, Cella M, Grierson HL, Cohen JI, Colonna M. Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J Immunol. 2001;167(10):5517–5521.

21. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329–1337.

22. Palumbo A, Sonneveld P. Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma. Expert Rev Hematol. 2015;8(4):481–491.

23. Palumbo A, Cavallo F. Lenalidomide in the treatment of plasma cell dyscrasia: state of the art and perspectives. Haematologica. 2013;98(5):660–661.

24. Lentzsch S, O’Sullivan A, Kennedy RC, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012;119(20):4608–4613.

25. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood. 2008;112(12):4445–4451.

26. Gandhi AK, Kang J, Capone L, et al. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets. 2010;10(2):155–167.

27. De Luisi A, Ferrucci A, Coluccia AM, et al. Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. Clin Cancer Res. 2011;17(7):1935–1946.

28. Gross CC, Brzostowski JA, Liu D, Long EO. Tethering of intercellular adhesion molecule on target cells is required for LFA-1-dependent NK cell adhesion and granule polarization. J Immunol. 2010;185(5):2918–2926.

29. Barber DF, Faure M, Long EO. LFA-1 contributes an early signal for NK cell cytotoxicity. J Immunol. 2004;173(6):3653–3659.

30. Balasa B, Yun R, Belmar NA, et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin- 2 and TNF- α pathways. Cancer Immunol Immunother. 2015;64(1):61–73.

31. Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 2011;(3):239–253.

32. Shi J, Tricot GJ, Garg TK, et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood. 2008;111(3):1309–1317.

33. van Rhee F, Szmania SM, Dillon M, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther. 2009;8(9):2616–2624.

34. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552–559.

35. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–1959.

36. Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2012;30(16):1960–1965.

37. Richardson PG, Jagannath S, Moreau P, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiplemyeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Hamatol. 2015;2(12)e516–e527.

38. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621–631.

39. Dimopoulos MA, Lonial S, White D, et al. Eloquent-2 update: a phase 3, randomized, open-label study of elotuzumab in combination with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma-3-year safety and efficacy follow-up. Blood. 2015;126(23):28.

40. Mateos MV, Granell M, Oriol A, et al. Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma. Br J Haematol. 2016;175(3):448–456.

41. Jakubowiak A, Offidani M, Pégourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127(23):2833–2840.

42. Wang Y, Sanchez L, Siegel DS, Wang ML. Elotuzumab for the treatment of multiple myeloma. J Hematol Oncol. 2016;9(1):55.

43. Costello C. An update on the role of daratumumab in the treatment of multiple myeloma. Ther Adv Hematol. 2017;8(1):28–37.

44. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood.

Source: Cancer Management and Research.
Originally published July 12, 2017.