A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of MM cells, with lower expression on natural killer (NK) cells and little to no expression on normal tissues. The mechanism of action of Elo is primarily NK cell-mediated antibody-dependent cellular cytotoxicity against MM cells. In the Phase 1 portion of this 1703 study, Elo escalated from 5 to 20 mg/kg intravenously (IV) plus Ld resulted in an 82% objective response rate (ORR) in pts with R/R MM (Lonial, J Clin Oncol 2012). Historically, lenalidomide plus high dose dexamethasone provided a 61% ORR and a median 11.1 months (mos) progression free survival (PFS) in a similar pt population (Dimopoulos, Weber, N Engl J Med 2007). At the time of previous presentation (Moreau, ASCO 2012), median PFS in the Phase 2 portion the 1703 study of Elo + Ld was not reached (NR) with 10 mg/kg after a median follow-up of 17.2 mo and was 18.6 mo with 20 mg/kg.

Pts with R/R MM previously treated with 1–3 prior therapies were randomized to Elo 10 or 20 mg/kg IV (days 1, 8, 15, 22 every 28 days in cycles 1–2 and days 1, 15 in cycles ≥3) plus lenalidomide 25 mg (PO) (days 1–21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on Elo dosing days. All pts received a premedication regimen of methylprednisolone or dexamethasone, diphenhydramine, ranitidine, and acetaminophen prior to elo dosing to minimize infusion reactions. Treatment continued until disease progression, unacceptable toxicity, or death. Pts were monitored for PFS until 60 days post-treatment follow-up. The primary objective was efficacy (ORR ≥partial response) according to the International Myeloma Working Group criteria.

73 pts were treated (10 mg/kg, n=36; 20 mg/kg, n=37). Median age was 63 (range, 39–82) years, 55% received ≥2 prior therapies, 60% prior bortezomib, and 62% prior thalidomide. Median (range) duration of treatment was 20.5 (3.0–31.0) and 16.0 (1.0–32.0) cycles with 10 and 20 mg/kg, respectively. At the data cutoff (July 10 2012), 27 pts (10 mg/kg, n=15; 20 mg/kg, n=12) were ongoing and 46 pts discontinued (disease progression, n=26; adverse events, n=11; investigator/pt decision, n=9). ORR was 84% overall; 92% with 10 mg/kg (chosen as the Phase 3 dose) and 76% with 20 mg/kg (see Table). Overall median time to objective response was 1 month (range, 0.7–19.2). After a median follow-up of 18.1 mos, median PFS in the 10 mg/kg cohort was 26.9 mos (95% confidence interval [CI]: 14.9–NR); however, 15 pts are still ongoing with a median follow-up of 23.9 mos, and the PFS data will likely mature further with longer follow up. Median PFS in the 20 mg/kg cohort was 18.6 mos (95% CI: 12.9–NR). In subgroup analyses combining 10 and 20 mg/kg cohorts, ORRs for pts with 1 (n=33) or ≥2 prior therapies (n=40) were 91% and 78%, respectively, and overall median PFS were 25.0 (95% CI: 15.7–NR) and 21.3 mos (95% CI: 14.0–NR), respectively. Pts with prior thalidomide (n=45) had an ORR of 82% and median PFS of 26.9 mos (95% CI: 14.9–NR). Fifty-six (78%) pts experienced ≥1 treatment emergent grade ≥3 event. Most common were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%), anemia (12%), leukopenia (10%), hyperglycemia (10%), pneumonia (7%), diarrhea (7%), fatigue (7%), and hypokalemia (6%). Two deaths occurred on study (multiple adverse events [n=1; pneumonia, multiple organ failure and sepsis]; disease progression [n=1]). Investigator-designated (any grade) infusion reactions were reported in 12% of pts; 1 pt had a grade 3 event (rash). There were 4 cases of second primary malignancies (prostate; bladder; myelodysplastic syndrome; nasal squamous cell); all were deemed unrelated to Elo.

In pts with R/R MM, Elo + Ld was generally well tolerated. Elo at 10mg/kg (the phase 3 dose) + Ld resulted in a high ORR and an encouraging median PFS of 26.9 mos after 18.1 mos of median follow-up. Phase 3 trials of Elo 10 mg/kg ± Ld are ongoing in newly diagnosed MM (ELOQUENT-1; CA204-006; NCT01335399) and R/R MM (ELOQUENT-2; CA204-004; NCT01239797).

Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Elotuzumab is not currently approved for any indication. Jagannath:Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Facon:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:Celgene: Honoraria, Research Funding. Reece:Johnson & Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Deng:Abbott Biotherapeutics Corp: Employment. Kroog:BMS: Employment. Singhal:Abbott Biotherapeutics: Employment, Equity Ownership. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy.