Selected studies of bortezomib, thalidomide, and lenalidomide.
| Author N/n . | Regimen . | Response rate, % (CR + PR) . | Time-to-event data . | Key toxicities . |
|---|---|---|---|---|
| Abbreviations: CR, complete response; PR, partial response; Btz, bortezomid; nCR, near CR; TTP, time to progression; OS, overall survival; DOR, duration of response; PLD, pegylated liposomal doxorubicin; Thal, thalidomide; PFS, progression-free survival; EFS, event-free survival; Dex, dexamethasone; Len, lenalidomide; PD, progressive disease; NR, not reported; ALT, alanine transaminase; CNS, central nervous system; DVT/PE, deep venous thrombosis/pulmonary embolism | ||||
| Richardson1,2 333/315 | 8 3-wk cycles Btz 1.3 mg/m2 days 1, 4, 8, 11 3 5-wk cycles days 1, 8, 15, 22 | 43 CR/nCR: 15 | TTP: 6.2 mo OS: 29.8 mo DOR: 7.8 mo | Grade 3/4: thrombocytopenia 26/4%; neutropenia 12/2%; anemia 9/1%; peripheral neuropathy 7/1%; diarrhea 7/0%; fatigue 5/<1%; dyspnea 5/<1% |
| Orlowski3 322/310 | 8 3-wk cycles Btz 1.3 mg/m2 days 1, 4, 8, 11 PLD 30 mg/ m2 day 4 | 48 CR/nCR 14 | TTP: 9.3 mo DOR: 10.2 mo | Grade 3/4: neutropenia 30%; thrombocytopenia 22%; anemia 9%; diarrhea 7%; asthenia 6%; fatigue 5%; hand foot syndrome 5% |
| 324/303 | 3-wk cycles Btz 1.3 mg/m2 days 1, 4, 8, 11 | 43 CR/nCR 11 | TTP: 6.5 mo DOR: 7 mo | Grade 3/4: thrombocytopenia 15%; neutropenia 14%; anemia 9%; peripheral neuropathy 9%; neuralgia 5% |
| Chanan-Khan4 21 | 6 4-wk cycles Btz 1.3 mg/m2 days 1, 4, 15, 18 PLD 20 mg/m2 days 1, 15 Thal 200 mg daily | 56 CR: 22 | PFS: 10.9 mo OS: 15.7 mo | Grade 3/4: neutropenia 43/4%; thrombocytopenia 22/9%; anemia 22/0% |
| Zangari7 85/85 | 8 3-wk cycles Btz 1.0–1.3 mg/m2 days 1, 4, 8, 11 Thal 50–200 mg/day from cycle 2 Dex 20 mg day of/day after btz for suboptimal response after 3 cycles | 55 CR/nCR: 16 | EFS: 9 mo OS: 22 mo | Most common grade 3/4 toxicities were thrombocytopenia and neutropenia. Nonhematologic toxicities included neuropathy. |
| Richardson8 24/21 | 8 3-wk cycles Btz 1.0–1.3 mg/m2 days 1, 4, 8, 11 Len 5–20 mg days 1–14 Dex 20 mg day of/day after btz for PD | 52 CR/nCR: 10 | NR | Most common grade 3/4 toxicities were thrombocytopenia and neutropenia. Significant neuropathy did not occur and rates of DVT were low (<5%) |
| Kropff10 50/50 | Btz as above Dex 20 mg day of/day after btz Cyclophosphamide 50 mg daily | 82 CR/nCR: 12 | EFS: 12 mo OS: not reached | Dose-limiting grade 3/4: thrombocytopenia 0/19%; infection 25/0%; peripheral neuropathy 19/0%; herpes zoster 17/0%; fatigue 15/0%; cardiovascular 9/0%; diarrhea 8/0%; orthostatic hypotension 6/0% |
| Reece11 21/20 | 28-d cycles Btz 0.7–1.5 mg/m2 days 1, 8, 15, or days 1, 4, 8, 11 Cyclophosphamide 150/300 mg/m2 days 1, 8, 15, 22 Prednisone 100 mg every other day | 45 CR/nCR: 15 | NR | Grade 3/4 (cycles 2–8 only): hyperglycemia 29/0%; neutropenia 24/5%; hypophosphatemia 19/10%; thrombocytopenia 14/5% |
| Berenson12 35/34 | 8 4-wk cycles Btz 0.7–1.0 mg/m2 days 1, 4, 8, 11 Melphalan 0.025–0.25 mg/kg days 1–4 | 47 CR/nCR: 15 | PFS: 8 mo | Grade 3/4: neutropenia 34/6%; thrombocytopenia 37/3%; anemia 23/6%; hypocalcemia 6/0% |
| Palumbo13 30/30 | 6 5-wk cycles Btz 1–1.6 mg/m2 days 1, 4, 15, 22 Melphalan 6 mg/ m2 and prednisone 60 mg/m2 days 1–5 Thal 100 mg daily | 67 CR/nCR: 17 | NR | Grade 3/4: thrombocytopenia; febrile neutropenia; fatigue; anemia; pneumonia; vasculitis; infections; sensory neuropathy |
| Terpos14 44/41 | 4 4-wk cycles Btz 1.0 mg/m2 days 1, 4, 8, 11 Melphalan 0.15 mg/kg days 1–4 Dex 12 mg/m2 days 1–4, 17–20 Thal 100 mg/d | 66 CR/nCR: 37 | PFS: 9.6 mo | Grade ≥ 3: thrombocytopenia 20%; neutropenia 8%; anemia 7%; peripheral neuropathy 6% |
| Richardson15 30/25 | 3-wk cycles Btz 0.7–1.3 mg/m2 and KOS-953 100–275 mg/m2 days 1, 4, 8, 11 | 32 CR/nCR: 12 | NR | Dose-limiting: grade 3/4 hepatotoxicity; grade 3 pancreatitis. Other grade 3/4 events included thrombocytopenia and elevated ALT (manageable with ursodiol). |
| Barlogie16 169/169 | Thal 200–800 mg/day | 30 CR: 2 | 2-year EFS: 20% 2-year OS: 48% | Grade > 2: CNS 25%, gastrointestinal 16%, peripheral neuropathy 9% |
| Palumbo18 First relapse 62/62 | Thal 100 mg/d continuously Dex 40 mg days 1–4 of each month | 56 | PFS: 17 mo 3-year OS rate: 60% | Tingling and numbness 19%; constipation 18%; sedation 13% |
| Second relapse and beyond 58/58 | 46 | PFS: 11 m OS: 19 mo | ||
| Dimopoulos19 53/53 | 3 4-wk cycles Thal 400 mg/d and Dex 20 mg/d days 1–5, 14–18 Cyclophosphamide 150 mg/m2 every 12 hours days 1–5 | 60 CR/nCR: 5 | TTP: 8.2 mo OS: 17.5 mo | Grade 3/4: neutropenia 18/8% |
| Offidani20 50/50 | 6 4-wk cycles Thal 100 mg/d Liposomal doxorubicin 40 mg/m2 day 1 Dex 40 mg days 1–4, 9–12 | 76 CR/nCR: 32 | OS: not reached PFS: 22 mo EFS: 17 mo | Grade ≥ 3: neutropenia 16%; nonhematologic toxicities 12%; venous thromboembolic disease 12%; severe infection 16% |
| Weber23 171 | 4-wk cycles Len 25 mg days 1–21 Dex 40 mg days 1–4 and 9–12, 17–20 (cycles 1–4) | 59 CR: 13 | TTP: 11.1 mo OS: 29.6 mo | Grade ≥ 3: neutropenia 36%; DVT/PE 18%; thrombocytopenia 12%; anemia 12%; pneumonia > 10%; atrial fibrillation 6%; fatigue 6%; diarrhea 5% |
| Dimopoulos24 176 | As above | 59 CR/nCR: 17 | TTP: 11.3 mo OS: not reached | Grade ≥ 3: neutropenia 27%; thrombocytopenia 10%; anemia 6%; DVT 5% |
| Richardson25 67 (once daily) 35 (twice daily) | 4-wk cycles Len 30 mg once daily or 15 mg twice daily, days 1–21 Dex 40 mg for 4 d every 14 d for suboptimal response | 18 CR/nCR: 6 (Once daily) 14 CR/nCR: 0 (Twice daily) | DOR: 19 mo (once daily), 23 mo (twice daily) PFS: 4.6 mo (combined) OS: 27 mo (combined) | Grade 3/4 (once daily): neutropenia 49/12%; thrombocytopenia 15/16%; leukopenia 36/2%; lymphopenia 31/6%; anemia 15/2% Grade 3/4 (twice daily): neutropenia 57/11%; thrombocytopenia 26/17%; leukopenia 34/0%; lymphopenia 31/9%; anemia 11/3% |
| Author N/n . | Regimen . | Response rate, % (CR + PR) . | Time-to-event data . | Key toxicities . |
|---|---|---|---|---|
| Abbreviations: CR, complete response; PR, partial response; Btz, bortezomid; nCR, near CR; TTP, time to progression; OS, overall survival; DOR, duration of response; PLD, pegylated liposomal doxorubicin; Thal, thalidomide; PFS, progression-free survival; EFS, event-free survival; Dex, dexamethasone; Len, lenalidomide; PD, progressive disease; NR, not reported; ALT, alanine transaminase; CNS, central nervous system; DVT/PE, deep venous thrombosis/pulmonary embolism | ||||
| Richardson1,2 333/315 | 8 3-wk cycles Btz 1.3 mg/m2 days 1, 4, 8, 11 3 5-wk cycles days 1, 8, 15, 22 | 43 CR/nCR: 15 | TTP: 6.2 mo OS: 29.8 mo DOR: 7.8 mo | Grade 3/4: thrombocytopenia 26/4%; neutropenia 12/2%; anemia 9/1%; peripheral neuropathy 7/1%; diarrhea 7/0%; fatigue 5/<1%; dyspnea 5/<1% |
| Orlowski3 322/310 | 8 3-wk cycles Btz 1.3 mg/m2 days 1, 4, 8, 11 PLD 30 mg/ m2 day 4 | 48 CR/nCR 14 | TTP: 9.3 mo DOR: 10.2 mo | Grade 3/4: neutropenia 30%; thrombocytopenia 22%; anemia 9%; diarrhea 7%; asthenia 6%; fatigue 5%; hand foot syndrome 5% |
| 324/303 | 3-wk cycles Btz 1.3 mg/m2 days 1, 4, 8, 11 | 43 CR/nCR 11 | TTP: 6.5 mo DOR: 7 mo | Grade 3/4: thrombocytopenia 15%; neutropenia 14%; anemia 9%; peripheral neuropathy 9%; neuralgia 5% |
| Chanan-Khan4 21 | 6 4-wk cycles Btz 1.3 mg/m2 days 1, 4, 15, 18 PLD 20 mg/m2 days 1, 15 Thal 200 mg daily | 56 CR: 22 | PFS: 10.9 mo OS: 15.7 mo | Grade 3/4: neutropenia 43/4%; thrombocytopenia 22/9%; anemia 22/0% |
| Zangari7 85/85 | 8 3-wk cycles Btz 1.0–1.3 mg/m2 days 1, 4, 8, 11 Thal 50–200 mg/day from cycle 2 Dex 20 mg day of/day after btz for suboptimal response after 3 cycles | 55 CR/nCR: 16 | EFS: 9 mo OS: 22 mo | Most common grade 3/4 toxicities were thrombocytopenia and neutropenia. Nonhematologic toxicities included neuropathy. |
| Richardson8 24/21 | 8 3-wk cycles Btz 1.0–1.3 mg/m2 days 1, 4, 8, 11 Len 5–20 mg days 1–14 Dex 20 mg day of/day after btz for PD | 52 CR/nCR: 10 | NR | Most common grade 3/4 toxicities were thrombocytopenia and neutropenia. Significant neuropathy did not occur and rates of DVT were low (<5%) |
| Kropff10 50/50 | Btz as above Dex 20 mg day of/day after btz Cyclophosphamide 50 mg daily | 82 CR/nCR: 12 | EFS: 12 mo OS: not reached | Dose-limiting grade 3/4: thrombocytopenia 0/19%; infection 25/0%; peripheral neuropathy 19/0%; herpes zoster 17/0%; fatigue 15/0%; cardiovascular 9/0%; diarrhea 8/0%; orthostatic hypotension 6/0% |
| Reece11 21/20 | 28-d cycles Btz 0.7–1.5 mg/m2 days 1, 8, 15, or days 1, 4, 8, 11 Cyclophosphamide 150/300 mg/m2 days 1, 8, 15, 22 Prednisone 100 mg every other day | 45 CR/nCR: 15 | NR | Grade 3/4 (cycles 2–8 only): hyperglycemia 29/0%; neutropenia 24/5%; hypophosphatemia 19/10%; thrombocytopenia 14/5% |
| Berenson12 35/34 | 8 4-wk cycles Btz 0.7–1.0 mg/m2 days 1, 4, 8, 11 Melphalan 0.025–0.25 mg/kg days 1–4 | 47 CR/nCR: 15 | PFS: 8 mo | Grade 3/4: neutropenia 34/6%; thrombocytopenia 37/3%; anemia 23/6%; hypocalcemia 6/0% |
| Palumbo13 30/30 | 6 5-wk cycles Btz 1–1.6 mg/m2 days 1, 4, 15, 22 Melphalan 6 mg/ m2 and prednisone 60 mg/m2 days 1–5 Thal 100 mg daily | 67 CR/nCR: 17 | NR | Grade 3/4: thrombocytopenia; febrile neutropenia; fatigue; anemia; pneumonia; vasculitis; infections; sensory neuropathy |
| Terpos14 44/41 | 4 4-wk cycles Btz 1.0 mg/m2 days 1, 4, 8, 11 Melphalan 0.15 mg/kg days 1–4 Dex 12 mg/m2 days 1–4, 17–20 Thal 100 mg/d | 66 CR/nCR: 37 | PFS: 9.6 mo | Grade ≥ 3: thrombocytopenia 20%; neutropenia 8%; anemia 7%; peripheral neuropathy 6% |
| Richardson15 30/25 | 3-wk cycles Btz 0.7–1.3 mg/m2 and KOS-953 100–275 mg/m2 days 1, 4, 8, 11 | 32 CR/nCR: 12 | NR | Dose-limiting: grade 3/4 hepatotoxicity; grade 3 pancreatitis. Other grade 3/4 events included thrombocytopenia and elevated ALT (manageable with ursodiol). |
| Barlogie16 169/169 | Thal 200–800 mg/day | 30 CR: 2 | 2-year EFS: 20% 2-year OS: 48% | Grade > 2: CNS 25%, gastrointestinal 16%, peripheral neuropathy 9% |
| Palumbo18 First relapse 62/62 | Thal 100 mg/d continuously Dex 40 mg days 1–4 of each month | 56 | PFS: 17 mo 3-year OS rate: 60% | Tingling and numbness 19%; constipation 18%; sedation 13% |
| Second relapse and beyond 58/58 | 46 | PFS: 11 m OS: 19 mo | ||
| Dimopoulos19 53/53 | 3 4-wk cycles Thal 400 mg/d and Dex 20 mg/d days 1–5, 14–18 Cyclophosphamide 150 mg/m2 every 12 hours days 1–5 | 60 CR/nCR: 5 | TTP: 8.2 mo OS: 17.5 mo | Grade 3/4: neutropenia 18/8% |
| Offidani20 50/50 | 6 4-wk cycles Thal 100 mg/d Liposomal doxorubicin 40 mg/m2 day 1 Dex 40 mg days 1–4, 9–12 | 76 CR/nCR: 32 | OS: not reached PFS: 22 mo EFS: 17 mo | Grade ≥ 3: neutropenia 16%; nonhematologic toxicities 12%; venous thromboembolic disease 12%; severe infection 16% |
| Weber23 171 | 4-wk cycles Len 25 mg days 1–21 Dex 40 mg days 1–4 and 9–12, 17–20 (cycles 1–4) | 59 CR: 13 | TTP: 11.1 mo OS: 29.6 mo | Grade ≥ 3: neutropenia 36%; DVT/PE 18%; thrombocytopenia 12%; anemia 12%; pneumonia > 10%; atrial fibrillation 6%; fatigue 6%; diarrhea 5% |
| Dimopoulos24 176 | As above | 59 CR/nCR: 17 | TTP: 11.3 mo OS: not reached | Grade ≥ 3: neutropenia 27%; thrombocytopenia 10%; anemia 6%; DVT 5% |
| Richardson25 67 (once daily) 35 (twice daily) | 4-wk cycles Len 30 mg once daily or 15 mg twice daily, days 1–21 Dex 40 mg for 4 d every 14 d for suboptimal response | 18 CR/nCR: 6 (Once daily) 14 CR/nCR: 0 (Twice daily) | DOR: 19 mo (once daily), 23 mo (twice daily) PFS: 4.6 mo (combined) OS: 27 mo (combined) | Grade 3/4 (once daily): neutropenia 49/12%; thrombocytopenia 15/16%; leukopenia 36/2%; lymphopenia 31/6%; anemia 15/2% Grade 3/4 (twice daily): neutropenia 57/11%; thrombocytopenia 26/17%; leukopenia 34/0%; lymphopenia 31/9%; anemia 11/3% |