The Hematologist

November-December 2015, Volume 12, Issue 6

Monoclonal Antibodies in the Treatment of Multiple Myeloma with a Focus on Elotuzumab and Daratumumab

Andrew J. Yee, MD Instructor in Medicine, Harvard Medical School, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center
Boston, Massachusetts
Noopur Raje, MD Associate Professor of Medicine at Harvard Medical School; Director of the Multiple Myeloma Center at Massachusetts General Hospital
Massachusetts General Hospital, Boston, Massachusetts

Published on: October 19, 2015

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

Lokhorst HM, Plesner T, Laubach JP, et al. Targeting cd38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-1219.

Monoclonal antibodies designed against cell surface proteins such as CD20 (rituximab) or HER2 (trastuzumab), cytokines such as VEGF (bevacizumab), and now immune checkpoints such as PD1 (e.g., pembrolizumab) have transformed oncology care and are routinely used across nearly all tumor types. Although treatment options for multiple myeloma (MM) over the last decade have converted the disease into a chronic condition for many patients, it is only now that the potential of monoclonal antibodies in the treatment of MM is being recognized.

Recent publication of important data using two monoclonal antibodies, elotuzomab and daratumomab, in relapsed refractory MM show improving outcomes, and these agents may be paradigm-shifting additions to MM treatment.1-3 Elotuzumab is a humanized recombinant monoclonal IgG1 antibody targeting signaling lymphocyte activation molecule (SLAMF7), also known as CS1 (CD2-subset-1). SLAMF7 is a cell surface glycoprotein that is highly expressed on both normal and MM plasma cells, and to a lower extent, on lymphocytes such as natural killer (NK) cells; it is absent in other tissues and hematopoietic stem cells.4,5 Expression of SLAMF7 is nearly universal in MM, irrespective of cytogenetic abnormalities and degree of disease progression. Elotuzumab is proposed to have several modes of action: antibody-dependent cellular cytotoxicity of MM cells involving natural killer NK cells and enhancement of NK cell activity against MM cells by binding to NK cell SLAMF7.6

As a single agent, elotuzumab does not show significant clinical activity.7 However, when it is combined with lenalidomide and dexamethasone, a phase I/II trial in relapsed or refractory MM showed an overall response rate of 84 percent with a median progression-free survival of 29 months.8 More recently, a phase III study, ELOQUENT-2, compared the combination of elotuzumab, lenalidomide, and dexamethasone to lenalidomide and dexamethasone in patients with relapsed disease.9 Patients with one to three prior lines of therapy were eligible to participate. Of note, the trial limited enrollment of patients with prior lenalidomide treatment to 10 percent, and these patients had to demonstrate at least a partial response to lenalidomide. Elotuzumab 10 mg/kg was given weekly for the first two cycles and then every other week. Lenalidomide and dexamethasone were given according to a conventional 28-day schedule. This trial enrolled 646 patients with a median of two prior lines of therapy. A significant proportion had high-risk cytogenetics (32% with del[17p] and 9% with t[4;14]). The elotuzumab-containing arm had superior progression-free survival (19.4 months vs. 14.9 months in the control group; p<0.001), and the overall response rate was also higher (79% vs. 66%; p<0.001). Adverse effects were similar between both arms, except for infusion reactions with elotuzumab (10% [grade 1-2]). Taken together, ELOQUENT-2 is the first study to show the benefit of adding a monoclonal antibody to conventional treatment in MM.

Daratumumab is a human IgG1κ monoclonal antibody that targets CD38, a transmembrane glycoprotein found at low levels on lymphoid and myeloid cells, and is involved with calcium flux and signal transduction. Conversely, in MM, CD38 is highly expressed,10 and the idea of targeting CD38 was proposed more than 20 years ago.11 Daratumumab was identified in preclinical studies as having uniquely potent activity against MM through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.12 Recently it was evaluated in a phase I/II study where it demonstrated striking effectiveness as a single agent in heavily pretreated patients.1 In a cohort of 42 patients receiving 16 mg/kg, 64 percent of patients were refractory to both bortezomib and lenalidomide, 17 percent were refractory to carfilzomib, and 36 percent were refractory to pomalidomide. The overall response rate in this group was 36 percent, including two patients who had a complete response and two patients with a very good partial response. Furthermore, responses were durable, and 65 percent of patients who had a response were free of progression at one year. The most common adverse events were infusion-related reactions (grade 1-2, in 71% of the cohort). These observations were corroborated at the annual meeting of the American Society of Clinical Oncology in 2015 by the SIRIUS study, in a similar refractory MM population.13 The SIRIUS study was a phase II trial of daratumumab as a single agent in patients who had three or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, and it showed an overall response of 29 percent. These findings establish daratumumab as the first monoclonal antibody to have single-agent activity, particularly in a challenging patient population with refractory disease.

The two trials presented here with elotuzumab and daratumumab are the first to show promising activity for monoclonal antibody therapy in MM, with only infusion reactions as a minimal and manageable toxicity. Another anti-CD38 monoclonal antibody, SAR650984 (isatuximab), is undergoing clinical development.14 Other targets have been considered in MM, including the transmembrane protein CD138 (with indatuximab ravtansine [BT062]) and the cytokine IL-6 (with siltuximab). Given the encouraging efficacy and tolerability of elotuzumab and daratumumab, combinations are ongoing with immunomodulatory drugs and proteasome inhibitors, both in the relapsed setting and for patients with newly diagnosed disease. Their tolerability also raises the possibility of long-term use as maintenance therapy. Overall, elotuzumab and daratumumab (and future monoclonal antibodies), with their unique mechanism of action, are poised to transform the treatment of MM and may bring patients closer to the hope of a cure.

References

  1. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-1219.
  2. 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;30:1953-1959.
  3. Raje N, Longo DL. Monoclonal antibodies in multiple myeloma come of age. N Engl J Med. 2015;373:1264-1266.
  4. 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;14:2775-2784.
  5. 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;112:1329-1337.
  6. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62:1841-1849.
  7. 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;120:552-559.
  8. Richardson PG, Jagannath S, Moreau P, et al. Final results for the 1703 phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. 56th ASH Ann Meet. 2014;124:302.
  9. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-631.
  10. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple meyloma. Am J Clin Pathol. 2004;121:482-488.
  11. Goldmacher VS, Bourret LA, Levine BA, et al. Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple myeloma. Blood. 1994;84:3017-3025.
  12. de Weers M, Tai YT, van der Veers MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840-1848.
  13. Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius) . J Clin Oncol. 2015;33:LBA8512.
  14. Martin TG, Baz R, Benson DM, et al. A phase Ib dose escalation trial of SAR650984 (anti-CD-38 Mab) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. 56th ASH Ann Meet. 2014;653:83.

Conflict of Interests

Dr. Raje and Dr. Yee indicated no relevant conflicts of interest. back to top