Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study
Authors: Jakubowiak Andrzej J , Benson Don M , Bensinger William , Siegel David S , Zimmerman Todd M , Mohrbacher Ann , Richardson Paul G , Afar Daniel EH , Singhal Anil K , Anderson Kenneth C 
Published: October 2019

Abstract 3023

Background:

Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM.

Methods:

The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on days 1 and 11 in combination with bortezomib (1.3 mg/m2 IV) administered on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone 20 mg PO was added for patients with disease progression after cycle 2 or 3 on days 1, 2, 4, 5, 8, 9, 11, and 12 of subsequent cycles. Patients with stable disease or better after 4 cycles continued treatment until disease progression or unexpected toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses were assessed during each cycle using European Group for Bone Marrow Transplantation (EBMT) criteria.

Results:

The 28 enrolled patients had a median time since MM diagnosis of 3.5 years and had received a median of 2 prior therapies; 11 patients (39%) had received prior bortezomib, 4 (14%) were refractory to bortezomib, and 12 (43%) were refractory to their last therapy. Three patients each received the 2.5, 5, and 10 mg/kg doses of elotuzumab and 19 received 20 mg/kg. No DLTs were observed during cycle 1 and the MTD was not reached. After a median of 6 cycles of therapy (range, 1–25 cycles), 2 patients remain on therapy. Serious adverse events related to elotuzumab were 1 grade 3 chest pain and 1 grade 3 gastroenteritis. The most frequent grade 3/4 AEs were lymphopenia (25%), fatigue (14%), thrombocytopenia, neutropenia, hyperglycemia, peripheral neuropathy, and pneumonia (11%), and leukopenia and anemia (7%). Twenty-seven patients completed at least 2 cycles of therapy or progressed earlier and were therefore evaluable for response (Table). An objective response (≥ PR) was observed in 13/27 (48%) evaluable patients, including 7% CR and 41% PR. A clinical response (≥ MR) was seen in 17/27 (63%) evaluable patients. Notably, a partial response was seen in 2 (50%) of 4 patients refractory to prior bortezomib. The objective response rate (ORR) was 60% (6/10), 50% (6/12), and 20% (1/5) in patients who had received 1, 2, or 3 previous lines of therapy, respectively. Analysis of bone marrow plasma cells indicated that 10 and 20 mg/kg elotuzumab doses resulted in complete or near complete saturation of CS1 sites by elotuzumab. Median time to progression was 9.46 months in the overall population as well as in the bortezomib-naïve population.

Conclusions:

The combination of elotuzumab and bortezomib had a manageable safety profile. Key toxicities attributable to elotuzumab appeared to be related to infusion reactions. The combination showed promising efficacy with an ORR of 48% and a clinical response rate of 63%. Notably, activity was seen in bortezomib-refractory patients (ORR = 50%). The median time to progression was 9.46 months for both the overall and the bortezomib-naïve populations.

Disclosures:

Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson, Centocor Ortho Biotech: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor Ortho Biotech: Speakers Bureau. Off Label Use: Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study. Bensinger:Millennium Pharmaceuticals, Celgene Corp., Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Zimmerman:Millennium, Celgene: Speakers Bureau. Mohrbacher:Millennium: Speakers Bureau. Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Afar:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Millennium, Celgene, Novartis, Onyx, Merck, Bristol-Myers Squibb: Consultancy; Acetylon: Stock Options; Acetylon: Membership on an entity's Board of Directors or advisory committees.