Prospective, Multicenter Study Of The Mtor Inhibitor Everolimus (RAD001) As Primary Therapy In Waldenstrom’s Macroglobulinemia

Introduction Everolimus (RAD001) is an inhibitor of MTORC1 and exhibits activity in WM patients with relapsed/refractory disease (JCO 2010; 28:1408-14). We therefore initiated this multicenter, prospective study to delineate the efficacy and tolerability of Everolimus as primary therapy in WM. Patients and Methods Patients with symptomatic WM, with adequate organ function, who were not previously treated, and who did not have symptomatic hyperviscosity were eligible. Intended therapy consisted of 10 mg of oral Everolimus daily, with sequential dose de-escalation to 7.5 mg daily, 5 mg daily, and 5 mg every other day permitted for toxicity. Patients were treated until progression or unacceptable toxicity. Patients were encouraged to use an oral dexamethasone solution to swish and spit up to 4 times daily for prevention of oral ulcerations. Study participants were assessed monthly for the first three months, and thereafter every 3 months which included a physical examination, complete blood counts, chemistries, and serum IgM monitoring. Bone marrow (BM) biopsies and aspirations were performed at baseline, at months 6 and 12, and as required for response assessment. Patients who received at least one cycle of therapy were evaluable for response. Results 33 patients were enrolled on this prospective, multicenter study and are evaluable for response. Median baseline characteristics for all patients: Age 62 (range 41-80 years); Hematocrit 31.3% (range 24.5-44.2%); Hemoglobin 10.8 (range 7.8-15.7 g/dL); serum IgM 4,440 (range 959-10,256 mg/dL), with 23 (69.7%) patients demonstrating an IgM level ≥3,000 mg/dL; serum M-protein 2.60 g/dL (range 0.31-5.31 g/dL), B2M 3 mg/L (1.6-6.7 mg/L). The median baseline BM disease burden was 70% (range 7.5-95%), and 21 patients (63.6%) demonstrated adenopathy or splenomegaly by CT scans at baseline. At best response, median serum IgM levels declined from 4,440 to 1,360 (p<0.0001), and serum M-protein decreased from 2.60 to 0.93 g/dL (p<0.0001). The median time to best serum IgM response was 6 months (range 6-36 months). Median hematocrit and hemoglobin levels increased from 31.3% to 34.5% (p=0.0112) and 10.8 to 11.8 g/dL (p= 0.009), respectively. Twenty-two patients were evaluable for response by both BM biopsy and IgM level determination at 6 months, at which time BM disease burden remained unchanged with a median of 65% involvement (range 10-95%; p=0.3595). The best overall response rate utilizing consensus criteria was 72.2% (2 Very Good Partial Responses, 18 Partial Responses, 4 Minor Responses, and 9 Stable Disease), and the major response rate (PR or better) was 60.6%. However, discordance between serum IgM levels upon which consensus criteria for response are based, and BM disease response were common and complicated response assessment. At 6 month assessments, 10 of 22 (45.5%) patients for whom both serum IgM and BM assessments were performed, discordance between serum IgM and BM disease involvement were observed. Among these patients, 2 had no change, and 8 had increased bone marrow disease involvement despite decreases in serum IgM levels. Grade ≥2 hematologic and non-hematologic toxicities possibly, probably or definitively associated with Everolimus included anemia (n=13, 39.4%), thrombocytopenia (n=4, 12%), neutropenia (n=6, 18.2%), hyperglycemia (n=3, 9.1%), oral ulcerations (n=9, 27.3%), pneumonitis (n=5, 15%), fatigue (n=5, 15.2%), rash (n=9, 27.3%), cellulitis (n=2, 6%), nausea (n=1, 3%), and diarrhea (n=1, 3%). With a median follow-up of 9 months (range 1-45 months), 6 patients remain on study. Reasons for study discontinuation included non-response or disease progression (n=17), unacceptable toxicity (n=6, including 5 for pneumonitis and 1 for neutropenia), noncompliance (n=2), and loss of follow-up (n=2). Conclusions Everolimus is active in the primary therapy of WM, with rapid reductions observed in serum IgM levels in most patients. Serum IgM discordance to underlying BM disease burden is common, and serial BM assessments are important for response monitoring in WM patients receiving Everolimus.) Disclosures: No relevant conflicts of interest to declare.