Siltuximab May Partially Overcome Dexamethasone-Resistance in Relapsed or Refractory Multiple Myeloma

SAN DIEGO, CA—Siltuximab in combination with dexamethasone may partially overcome dexamethasone resistance in some cases of multiple myeloma (MM) refractory to prior dexamethasone-containing therapy, reported Peter M. Voorhees, MD, from the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, and colleagues at the 53rd American Society of Hematology Annual Meeting and Exposition.

Resistance to glucocorticoids, an important component of MM therapy, is common. In preclinical models, interleukin-6 (IL-6) protects MM cells from glucocorticoid-induced apoptosis. In a Phase 2, open-label, non-randomized study, investigators sought to determine if siltuximab, an IL-6 inhibiting monoclonal antibody, would be effective in combination with high-dose dexamethasone in patients with relapsed and relapsed/refractory MM. The primary endpoint was overall response rate (ORR, complete response [CR]+partial response [PR]) using European Group for Blood and Marrow Transplantation (EBMT) criteria. Secondary endpoints included time to progression, progression-free survival (PFS), and overall survival (OS).

Eligible patients included those with measurable, secretory disease who had received ≥2 prior lines of therapy (one of which contained bortezomib) and progressed during or after their last line of treatment, CrCl≥20mL/min, platelets ≥500×109/L, and neutrophils ≥1×109/L. Siltuximab 6mg/kg IV was administered Days 1 and 15 of a 28-day cycle in combination with dexamethasone 40mg orally once daily Days 1–4, 9–12, and 17–20 for a max of four cycles; then dexamethasone Days 1–4 for subsequent cycles. The first 14 patients received siltuximab alone for Cycles 1–2; 10 patients had dexamethasone added for progressive disease post-Cycle 1 or suboptimal response post-Cycle 2. Siltuximab plus dexamethasone was administered subsequently to 39 patients as the first 14 patients did not achieve at least PR with siltuximab monotherapy.

A total of 49 patients received the combination of siltuximab plus dexamethasone. Patients were heavily pretreated, having received prior bortezomib (100%), steroids (100%), immunomodulators (90%), alkylating agents (90%), and autologous stem cell transplant (65%). Median disease duration was four years (range 0.7–13.2) and median number of prior lines of therapy was four (range 2–9). Eighty-six percent of patients had disease that was refractory to the last prior line. Thirty two (73%) of 44 patients who had received prior dexamethasone therapy were refractory to the last dexamethasone-containing regimen.

Median duration of on-study therapy was four cycles (99 days). Of the 49 patients, 47 were evaluable for response: ORR by EBMT criteria was 17% (0 CRs, 8 PRs); ORR + minimal response (MR) rate was 23% (n=11). Using International Melanoma Working Group criteria, the ORR + MR rate was 27.7% (9 PRs, 4 MRs). Of the 11 patients with at least MR by EBMT criteria, five patients were refractory to the last dexamethasone-containing regimen and seven experienced less than MR on a prior dexamethasone-containing regimen. The median duration of response was 5.9 months (181 days, 95% CI: 147–365). A long-lasting response of ≥9 months was observed in three patients. For all 49 patients, the median PFS was 3.7 months (114 days, 95% CI: 84–148) and median OS was 20.4 months (621 days, 95% CI: 347–984). The OS ranged from 14 days to 37.7 months (1147 days).

Twenty-five percent of patients discontinued treatment due to an AE. The most common adverse events occurring in ≥25% of patients were thrombocytopenia, fatigue, anemia, abnormal hepatic function, neutropenia, diarrhea, peripheral edema, dyspnea, and dizziness. Nearly three-quarters (74%) of patients experienced a Grade ≥3 adverse event; the most common non-hematologic Grade ≥3 AEs were fatigue (8%), abnormal hepatic function (8%), and pneumonia (6%). Grade 4 hematologic toxicities were thrombocytopenia (12%), neutropenia (4%) and anemia (2%). Twenty (41%) patients experienced ≥1 serious adverse event. The most frequently occurring were pneumonia (8%), thrombocytopenia (6%), septic shock, anemia, and hemolytic anemia (4% each). Five deaths occurred during the study: three due to progressive disease and two due to infection (nosocomial infection, septic shock).

Overall, the combination of siltuximab and dexamethasone was well tolerated. Dr. Voorhees stated that, “although the ORR was modest in this relapsed/refractory patient population, responses were seen in patients with MM refractory to prior dexamethasone-containing therapy, suggesting that siltuximab may be able to at least partially overcome dexamethasone resistance in some cases. Overall, these results provide a rationale for further studies of siltuximab in combination with dexamethasone-based MM therapy.”