SIRIUS Trial Heralds a New Era of Promise in Treating Resistant Myeloma


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The advent of daratumumab as an approved agent for the treatment of multiple myeloma provides a very exciting platform both now and for the future and heralds a new era of promise in the treatment of multiple myeloma.
— Jacob P. Laubach, MD, MPP (left), and Paul G. Richardson, MD

Multiple myeloma cells uniformly overexpress CD38.1 Daratumumab (Darzalex), a CD38-targeting human IgG1 kappa monoclonal antibody, has been evaluated in a series of phase I/II trials involving patients with relapsed or relapsed and refractory myeloma who have received at least two or more prior lines of therapy and has consistently shown promising activity in this setting.2,3 After a large and comprehensive phase I/II trial (GEN-501) established 16 mg/kg administered once weekly for eight doses, twice monthly for eight doses, and monthly for up to 24 months as an appropriate therapeutic regimen, the multicenter, single-arm phase II SIRIUS study—reviewed in this issue of The ASCO Post—confirmed that daratumumab at 16 mg/kg/wk for 8 weeks in cycles 1 and 2 and then every 2 weeks for 16 weeks in cycles 3 to 6 and every 4 weeks thereafter was indeed active in a refractory patient population.2,3

Heavily Pretreated Population

Specifically, in SIRIUS, previous proteasome inhibition consisted of bortezomib (Velcade) in almost all patients, carfilzomib (Kyprolis) in half, and lenalidomide (Revlimid) exposure in almost all patients, with pomalidomide in two-thirds and thalidomide (Thalomid) in almost half. All patients were exposed to dexamethasone as well. Noteworthy in the SIRIUS results was that almost all of the patients were refractory to both proteasome inhibition and immunomodulation, with approximately 80% refractory to alkylating chemotherapy and 80% also refractory to the combination of bortezomib and lenalidomide. Moreover, 40% were refractory to each of bortezomib, lenalidomide, and carfilzomib; over half to bortezomib, lenalidomide, and pomalidomide (Pomalyst); and one-third to bortezomib, lenalidomide, carfilzomib, and pomalidomide (a so-called quad-refractory group, constituting an exquisite area of unmet medical need).

Therefore, this population consisted of a group of patients with an urgent requirement for effective therapy, with a guarded prognosis and an expected median progression-free survival of 5 months and an overall survival of 9 months based upon prior studies of patients in whom both proteasome inhibition and immunomodulatory drugs had failed.4 Remarkably, partial response or better was seen in approximately one-third of patients, including a very good partial response or better in 12%. In this group of relapsed and refractory patients, an additional half of the patients experienced at least stable disease or minimal response. Median time to response was also rapid at 1 month, with an encouraging median duration of response of 7.4 months.3

Comparison With GEN-501 Study

An important aspect of the SIRIUS trial was the determination that 16-mg/kg dosing was superior to 8-mg/kg dosing on a similar schedule. This was carried out in a prospective randomized fashion, which was further supported by the GEN-501 study, in which a sequential approach with 8 mg/kg vs 16 mg/kg was pursued and showed a similar difference in efficacy in favor of the higher dose.2,3

Moreover, in both studies, the drug was generally well tolerated, with most common side effects in the SIRIUS study including fatigue, anemia, nausea, and thrombocytopenia. Infusion-related reactions occurred in over 40% of patients, with one-third occurring during first infusion, including a small number of grade 3 reactions. Treatment was discontinued in 5% of patients due to adverse events, with none considered related to treatment.3

Again, this is commensurate with what was reported in the GEN-501 trial, with the majority of adverse events observed being mild to moderate.2 Similarly, the most common side effects included fatigue, with other adverse events of interest such as neutropenia and thrombocytopenia also being noted. The most frequent serious adverse events were infection-related events, which are common and well recognized in this population, for whom immunocompromise is profound. Interestingly, allergic rhinitis was seen in the phase I population, which was less of an issue in the SIRIUS trial, where a more aggressive and consistent approach to premedication was followed.2,3

Encouragingly, in the GEN-501 study, which enrolled 104 patients (and thus was comparable to the 106 patients enrolled in SIRIUS), the overall response rate in the large cohort who received 16 mg/kg was 36%, including complete responses and very good partial responses in a similar proportion to that seen in SIRIUS.2 Therefore, data from these studies were highly supportive of each other and provided a strong basis for the recent U.S. Food and Drug Administration (FDA) approval of daratumumab in this setting. Daratumumab was previously granted Breakthrough Status by the FDA in 2013 and was the first monoclonal antibody to be approved for the treatment of multiple myeloma in 2015.

Mechanism of Action of First-in-Class Antibodies

Excitingly, this was then rapidly followed by the approval of elotuzumab (Empliciti) for relapsed or relapsed and refractory multiple myeloma in combination with lenalidomide and dexamethasone.5 Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocyte activation molecule F7 (SLAMF7) and is mechanistically distinct from daratumumab while also being a first-in-class humanized immunoglobulin G1 immunostimulatory monoclonal antibody in and of itself.6-8

In contrast, CD38 is a 45-kD type II transmembrane glycoprotein that is associated with cell-surface receptors in lipid rafts; it regulates cytoplasmic CA2+ flux and mediates signal transduction in both lymphoid and myeloid cells.9,10 CD38 is also expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues of nonhematopoietic origin, which makes it a highly provocative target in the treatment of myeloma.

Mechanistically, daratumumab binds to the unique CD38 epitope, and preclinical studies have shown that it induces target-cell killing of CD38-expressing tumor cells by means of a multiplicity of mechanisms, including complement-mediated and antibody-dependent cell-mediated cytotoxic effects as well as antibody-dependent cellular phagocytosis, apoptosis, and inhibition of the enzymatic activity of CD38, which may be a vital mechanism.11 Taken together, this may explain its potent activity as monotherapy, compared with the other antibodies such as elotuzumab, where combinations are essential to their activity.12

Recent data have suggested daratumumab’s combination with lenalidomide, bortezomib, and pomalidomide is an especially active strategy, with synergy demonstrated. In aggregate, the advent of daratumumab as an approved agent for the treatment of multiple myeloma provides a very exciting platform both now and for the future and heralds a new era of promise in the treatment of multiple myeloma. ■

Disclosure: Dr. Laubach is a consultant for Takeda and Novartis and has received research support from Takeda, Novartis, Onyx, and Celgene.

References

1. Lin P, Owens R, Tricot G, Wilson CS: Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 121:482-488, 2004.

2. Lokhorst HM, Plesner T, Laubach JP, et al: Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 373:1207-1219, 2015.

3. Lonial S, Weiss BM, Usmani SZ, et al: Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet 387:1551-1560, 2016.

4. 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 26:149-157, 2012.

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

6. 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 112:1329-1337, 2008.

7. Collins SM, Bakan CE, Swartzel GD, et al: Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: Evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother 62:1841-1849, 2013.

8. Guo H, Cruz-Munoz ME, Wu N, et al: Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol 35:41-51, 2015.

9. Konopleva M, Estrov Z, Zhao S, et al: Ligation of cell surface CD38 protein with agonistic monoclonal antibody induces a cell growth signal in myeloid leukemia cells. J Immunol 161:4702-4708, 1998.

10. Deaglio S, Vaisitti T, Billington R, et al: CD38/CD19: A lipid raft-dependent signaling complex in human B cells. Blood 109:5390-5398, 2007.

11. 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 186:1840-1848, 2011.

12. Richardson PG, Jagannath S, Moreau P, et al: Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2:e516-e527, 2015.


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