Table 3.
Results from selected studies in relapsed/refractory MM evaluating combinations of lenalidomide with other novel agents (IMiDs and proteasome inhibitors)
| Study | Type of study | Regimen | Schedule | N | Prior treatment | Response | TTE | Key toxicities |
|---|---|---|---|---|---|---|---|---|
| Richardson et al51 | Phase I | RVD | MTD: Len 15 mg on days 1–14 of 21-day cycle Bort 1.0 mg/m2 on days 1, 4, 8, 11 of 21-day cycle Dex 20 or 40 mg on days 1, 2, 4, 5, 8, 9, 11, 12 in case of progression after two cycles |
38 | Median: 5 Thal: 87% Bort: 55% Len: 18% |
All evaluable patients ≥MR: 61% CR/nCR: 8% |
Median TTP: 7.7 months Median OS: 37 months |
% of patients Grade ≥ 3 neutropenia: 63% Grade ≥ 3 thrombocytopenia: 45% Grade ≥ 3 anemia: 18% Grade ≥ 3 peripheral neuropathy: 0% Grade ≥ 3 venous thromboembolism: 3% |
| Richardson et al52 | Phase II | RVD | Len 15 mg on days 1–14 of 21-day cycle Bort 1.0 mg/m2 on days 1, 4, 8, 11 of 21-day cycle Dex 20 or 40 mg (cycles 1–4) or 10 or 20 mg (cycles 5–8) on days 1, 2, 4, 5, 8, 9, 11, 12 After 8 cycles responding patients could receive maintenance: Len on days 1–14 of 21-day cycle Bort on days 1 and 8 Dex on days 1, 2, 8, 9 |
64 | Median: 2 Thal: 73% Bort: 53% Len: 6% |
All evaluable patients ≥MR: 78% ≥PR: 64% nCR/CR: 25% |
Median TTP: 9.5 months Median PFS: 9.5 months Median OS: 26 months |
% of patients Grade ≥ 3 neutropenia: 30% Grade ≥ 3 thrombocytopenia: 22% Grade ≥ 3 anemia: NA Grade ≥ 3 peripheral neuropathy: 3% Grade ≥ 3 venous thromboembolism: 0% |
| Dimopoulos et al53 | Phase II | RVD | Len 15 mg on days 1–14 of 21-day cycle Bort 1.0 mg/m2 on days 1, 4, 8, 11 of 21-day cycle Dex 40 mg on days 1–4 After 8 cycles patients without progression continued with: Len on days 1–21 of 28-day cycle Dex 40 mg on days 1–4 |
49 | Median: 2 Thal: 80% Bort: 88% Len: 0% |
All evaluable patients ≥PR: 63% VGPR: 14% CR: 6% |
Median PFS: 7 months Median OS: 16 months |
% of patients Grade ≥ 3 neutropenia: 26% Grade ≥ 3 thrombocytopenia: 14% Grade ≥ 3 anemia: 20% Grade ≥ 3 peripheral neuropathy: 14% Grade ≥ 3 venous thromboembolism: 4% |
| Palumbo et al57 | Phase II | RMPT | Len 10 mg days 1–21 of a 28-day cycle Mel 0.18 mg/kg po on days 1–4 Pred 2 mg/kg on days 1–4 Thal 50 mg or 100 mg on days 1–28 After 6 cycles maintenance with len 10 mg on days 1–21 of 28-day cycle |
44 | Median: 1 Thal: 23% Bort: 20% Len: 0% |
All evaluable patients ≥PR: 75% VGPR: 32% CR: 2% |
1-year PFS: 52% 1-year OS: 72% |
% of patients Grade ≥ 3 neutropenia: 63% Grade ≥ 3 thrombocytopenia: 34% Grade ≥ 3 anemia: 34% Grade ≥ 3 neurotoxicity: 0% Grade ≥ 3 venous thromboembolism: 0% |
| Shah et al58 | Phase I | RTD | MTD: Len 25 mg days 1–21 of 28-day cycle Thal 100 mg days 1–28 Dex 40 mg on days 1–4, 9–12, and 17–20 of cycles 1–2; thereafter 40 mg on days 1, 8, 15, 21 |
18 | Median: 3 Thal: NA Bort: NA Len: NA |
All evaluable patients ≥PR: 92% VGPR: 23% nCR: 15% |
Median PFS: NA Median OS: NA |
DLTs: steroid-induced toxicity; rash due to thalidomide plus atrial fibrillation; hypertensive crisis and volume overload due to dexamethasone |
| Berenson et al55 | Phase II | DVD-R | Len 10 mg on days 1–14 of a 28-day cycle Bort 1.0 mg/m2 on days 1, 4, 8, 11 Dex 40 mg on days 1, 4, 8, 11 PLD 4.0 mg/m2 on days 1, 4, 8, 11 |
18 | Median: 4 Thal: 50% Bort: 89% Len: 33% |
All evaluable patients ≥PR: 56% VGPR: 28% CR: 6% |
Median PFS: NA Median OS: NA |
% of patients Grade ≥ 3 neutropenia: 17% Grade ≥ 3 thrombocytopenia: 22% Grade ≥ 3 anemia: 11% Grade ≥ 3 neurotoxicity: 6% Grade ≥ 3 venous thromboembolism: NA |
| Niesvizky et al56 | Phase Ib | CRd | MTD not yet reached: Car 15–27 mg/m2 on days 1, 2, 8, 9, 15, 16 of a 28-day cycle Len 10–25 mg on days 1–21 Dex 40 mg on days 1, 8, 15, 22 of cycles 1–4; thereafter 40 mg on day 1 |
32 | Median: 2.5 Thal: 46% Bort: 77% Len: 54% |
All evaluable patients ≥PR: 55% VGPR: 20% CR: 10% |
Median PFS: NA Median OS: NA |
% of patients Grade ≥ 3 neutropenia: 8% Grade ≥ 3 thrombocytopenia: 15% Grade ≥ 3 anemia: 15% Grade ≥ 3 neurotoxicity: 0% Grade ≥ 3 venous thromboembolism: NA |
Abbreviations: MM, multiple myeloma; CR, complete response; nCR, near-complete response; VGPR; very good partial response; PR, partial response; NA, not available; TTE, time to events; TTP, time to progression; EFS, event-free survival; OS, overall survival; Len, lenalidomide; Bort, bortezomib; Thal, thalidomide; Dex, dexamethasone; Pred, prednisone; Doxo, doxorubicin; Cyclo, cyclophosphamide; Mel, melphalan; Car, carfilzomib; po, oral administration; RVD, lenalidomide, bortezomib, and dexamethasone; RMPT, lenalidomide, melphalan, prednisone, and thalidomide; RTD, lenalidomide, thalidomide, and dexamethasone; DVD-R, pegylated liposomal doxorubicin, bortezomib, dexamethasone, and lenalidomide; CRd, carfilzomib, lenalidomide, and dexamethasone; MTD, maximum tolerated dose.