Phase I Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma

Abstract 1948 Background: The combination of lenalidomide (Len) and dexamethasone(D) have demonstrated overall response rates (ORR) of 60% in relapsed/refractory multiple myeloma (RRMM). The three drug combination of Len/Thalidomide/D has not previously been evaluated in RRMM. The ORR with LenD with prior Thalidomide(Thal) is 40–50%, while the ORR with ThalD after prior Len is Methods: Patients(pts) with relapsed/refractory myeloma with ≥ 1 line of therapy were eligible with adequate hematology, cardiac, pulmonary, and renal function. Patient were eligible regardless of prior Imid exposure or Imid refractory disease, enrolled in 3 dose cohorts(C), C1: Len 15 mg/Thal 100 mg/Dex, C2:Len 25 mg/Thal 100 mg/Dex, and C3: Len 25 mg/Thal 200/Dex. Dexamethasone was dosed in pulse dose fashion cycles 1–2 and reduced to weekly Dex in cycles 3 and beyond. Pts were treated until disease progression or toxicity. All patients received anticoagulation with warfarin or low molecular weight heparin. Results: 18 patients with median 3 prior lines of therapy (range: 1–6) were enrolled, age 67 (range: 52–81), male/female: 13/5; 3 in cohort 1, 6 in cohort 2 and 9 in cohort 3. There were no dose limiting toxicity (DLT) in cohort 1 (0/3), 1/6 DLT in cohort 2 and 2/8 DLT in cohort 3 (1 pt was unevaluable for DLT due to disease progression within cycle 1 and removed prior to completing cycle 1). The DLT in cohort 2 was due to steroid induced toxicity, requiring reduction in dex dosing in cycle 1. The DLT in cohort 3 included one patient with G3 rash due to thalidomide and asymptomatic G2 atrial fibrillation (a. fib) and a second patient with G3 hypertensive crisis and volume overload due to dexamethasone. Other toxicity included a patient with new onset symptomatic a fib in Cohort 3 (during cycle 2, therefore not a DLT) with concurrent newly diagnosed cardiac amyloidosis, and non-neutropenic fever and pneumonia in patient in Cohort 2. Among the 8 patients in C3 who received > 1 cycle, 5 required dose reduction of Thal to 100 mg. No DVT/PE were observed with use of anticoagulation. No G3/4 peripheral neuropathy has been observed. 13 patients were evaluable for efficacy (6 unevaluable: 1 withdrew consent after cycle 1, 4 patients in cycle 2 currently and responses not repeated/confirmed). Among the 13 evaluable patients the ORR (> PR) was 92%, 2 nCr, 3 VGPR, 7 PR and 1 with PD in cycle1. Among the 13 evaluable, 6/13 patients had prior thal, 10/13 autologous stem cell transplant, 9/13 prior Len and 8 patients were lenalidomide refractory. Among the 8 patients with Len refractory disease (4 had prior thal), the ORR was 88%, with 1 VGPR, 6 PR, and 1 PD in cycle 1. 4 pts, all with Len refractory disease, have discontinued therapy due to progressive disease after cycle 1, 4, 4, 6 (after initial PR to therapy), the other 4 remain on trial on cycle 3, 5, 7 and 9. Conclusions: The maximum recommended dose is lenalidomide 25 mg/thalidomide 100 mg/dex due to the DLT observed and need for dose reductions in thalidomide. The combination is well tolerated with only 1 pt discontinued therapy due to toxicity (a fib) and 4 pts discontinued secondary to PD. The very high ORR of 92% was much higher than seen with two drug regimen of Len/Dex. The preserved superior activity in lenalidomide refractory disease, supports the modulation of lenalidomide resistance with thalidomide, however a phase 2 trial is open and additional pts at cohort 2 will be enrolled to further evaluate the activity of this combination. Disclosures: Shah: Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Wang: Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding.