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

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 < 20%. Preclinical studies have demonstrated Len resistance is mediated via the wnt-β-catenin pathway which is modulated by Thal. The minimal overlapping side effect profile and differing mechanism of action of Len and Thal and preclinical data provided the rationale for the combination of Len/Thal/D in an attempt to improve RR and overcome lenalidomide resistance. The aim of this study was to determine the tolerability, maximum tolerated dose (MTD) and evaluate preliminary activity.

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.

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.

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.

Shah:Celgene: Consultancy, Membership on an entity's 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.