Table 5:
Selected smoldering multiple myeloma treatment studies
| Studies/number of patients | Treatments | Risk stratification | MRD (yes/no)/Method and sensitivity | ORR* (CR/MRD negative) (%) | PFS/OS | Adverse events (≥ grade 3) |
|---|---|---|---|---|---|---|
| Myeloma-like regimen | ||||||
| 2015, Korde and 2017, Mailankody N=18 [38, 39] |
Initial Therapy: 28 day-cycle [C1-8]: Carfilzomib 20/36 mg/m 2 i.v. days 1,2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. days 1–21 + dex 20mg (C1 – 4) and 10 (C5 – 8) p.o. or i.v. days 1, 2, 8, 9, 15, 16 then Maintenance: 28 day-cycle [C1 – 24] Lenalidomide 25 mg days 1 – 21 for up to 2 years (n=18) |
Risk stratification by: MAYO 2008 (low/intermediate/high): 83/17% PETHEMA (low/intermediate/high): 11/89% |
Yes/MFC 10−5 | After initial treatment: 100(89/83) At 2 years after maintenance: 100(89/63) |
No progression to symptomatic MM 3-, 4-year PFS 94%, 70.6% 3-, 4- year OS: 100% |
- Lymphopenia 39% - Neutropenia 28% - anemia 22% - diarrhea 17% - lung infection 17% - Hypophosphatemia 11% - Thrombocytopenia 11% - 1 patient developed CHF after 6th cycle |
| GEM-CESAR [60] 2017, Mateos (ASH 2019) NCT02415413 Ongoing study N=90 |
Induction: 28 day-cycle [C1-6]: Carfilzomib 20/36 mg/m 2 i.v. days 1,2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. days 1–21 + dex 40 mg days 1, 8, 15, 22 ASCT Melphalan 200 mg/m2 Consolidation: KRD as induction for 2 cycles Maintenance: 28 day-cycle Lenalidomide 10 mg days 1 – 21 + Dex 20 mg days 1, 8, 15, 22 for 2 years (N=60) |
High-risk by MAYO 2008 or PETHEMA: MAYO 21% PETHEMA 52% Both 27% |
Yes/MFC | After induction (n=60): 95(40/28) After ASCT (n=55): 95(64/58) After consolidation (n=55): 100(78/65) After maintenance (n=40) 100 (85/68) |
At 30 months PFS 93% (5 patients have biological progression) | After induction: -Infection 10% -Neutropenia 3% -Thrombocytopenia 5% |
| 2019, Bustoros ASH 2019) [42] NCT02916771 Ongoing study |
Induction: 28 day-cycle [C1-9]: Ixazomib 4 mg p.o. days 1, 8, 15 + lenalidomide 25 mg p.o. days 1–21 + dex (40 mg p.o. days 1, 8, 15, 22 Maintenance: 28 day-cycle [C10-24]: Ixazomib 4 mg p.o. days 1, 8, 15 + lenalidomide 15 mg p.o. days 1–21 (n=45) |
IMF 2019 criteria: 53.4% are high-risk | Yes/cfDNA and CTCs | - At least 1 cycles of treatment: 91(31/ongoing) - At least 9 cycles: 97(42.4, ongoing) |
Ongoing | - Hypophosphatemia 4.2% - Hypertension 6.3% - neutropenia 4.4% - Thrombocytopenia 4.4% |
| 2018, Liu (ASH 2017) NCT02279394 N= 50 [43] Ongoing study |
Induction: 28 day-cycle [C1-2] Elotuzumab 10 mg/kg i.v. days 1, 8, 15, 22 + lenalidomide 25 mg p.o. days 1–21 + dex 40 mg p.o. days 1, 8, 15, 22 [C3-8]: Elotuzumab 10 mg/kg i.v. days 1, 15 + lenalidomide as 25 mg p.o. days 1–21 + dex 40 mg p.o. days 1, 8, 15 Maintenance: 28 day-cycle [C9-24] Elotuzumab 10 mg/kg i.v. days 1 + lenalidomide 25 mg p.o. days 1–21 (n=50) |
High-risk by MAYO 2008 or PETHEMA | No | 84(6/NA) | 3-year PFS 95% | - Hypophosphatemia 34% - neutropenia 26% - Lymphopenia 22% - 1 patient had DKA sepsis and death |
| 2019, Mailankody NCT02697383 Ongoing study |
Induction: 28 day-cycle [C1-12] Ixazomib + dexamethasone Maintenance: 28 day-cycle [C1-24] Ixazomib (n=14) |
High-risk by MAYO 2008 or PETHEMA: MAYO 2008: 14% PETHEMA: 79% Both: 7% |
NA | After induction: 64(0/NA) | On going | - Gastrointestinal event 21% - Lung infection 14% |
| Lenalidomide alone of with dexamethasone regimen | ||||||
| QuiReDex [4, 61] Lenalidomide/dex vs observation 2013, Mateos 2015, Mateos N=119 |
Induction: 28 day-cycle [C1 - 9] Lenalidomide 25 mg p.o. days 1–21 + dex 20mg p.o. days 1-4, 12-15 then Maintenance: 28 day-cycle [C1 - 24] Lenalidomide 10 mg days 1 – 21 (n=57) |
High-risk by MAYO 2008 or PETHEMA: MAYO 2008: 18% PETHEMA: 40% Both: 42% |
No | After induction: 79(14/NA) After maintenance: 90(26/NA) |
Median time to progression NR 3-year PFS 77% 3-, 5-year OS 94%, 88% |
- Infection 6% - Asthenia 6% - Neutropenia 5% - Skin rash 3% - Thrombocytopenia 2% - Anemia 2% - Diarrhea 2% |
| Observe (n=62) | MAYO 2008: 13% PETHEMA: 39% Both: 48% |
0 | Median time to progression 23 months, HR 0.18, p<0.001 3-year PFS 30%, p<0.001 3-year OS 80%, 71%, p= 0.03 |
None | ||
| 2019, Lonial | [C1 – progressive disease]: 28 day-cycle Lenalidomide 25 mg p.o. days 1–21 (n=90) | Risk by IMF 2019 (low/intermediate/high): 34/38/28% | No | 50 (0/NA) | 3-year PFS: 91% | - Neutropenia 14% - Infection 10% - Hypertension 9% - Skin 6% |
| Observe (n=92) | 29/37/34% | 0 | 3-year PFS: 66 HR 0.28, p=0.002% HR for high-risk patient 0.09, |
|||
| Immunotherapy | ||||||
| 2019, Brighton [54] Phase 2 RCT N=85 |
[C1-progressive disease]: Siltuximab 15 mg/kg i.v. in 2 hour q 4 week (n=43) |
NA but included UHR 23% | No | NA | 1-year PFS: 84.5% Median PFS: NR | -Infections (5 patients in siltuximab and 6 patients in placebo group) -renal and urinary disorders (1 patient in the siltuximab group and 3 pts in the placebo group) |
| Observation (n=42) | NA but included UHR 41% | NA | 1-year PFS: 74.4% Median PFS: 23.5 months HR 0.5, p=0.0597 |
|||
| 2019, Manasanch N= 13 [51] |
[C1-8] Pembrolizumab 200 mg i.v. in 30 minutes q 21 days | Intermediate to high risk by either PETHEMA, MAYO 2008 or SWOG criteria | Yes/NGS | 8(8/8) | 2/13 patients progress to symptomatic MM at 24 months of follow-up time | -Transaminitis (3 patients) |
| 2019, Manasanch (ASH 2019) N=24 [49] |
Isatuximab 20 mg/kg i.v. in 4 week cycle [C1]every 1 week; [C2-6] every other week; [C7-30] every 4 week (n=24) |
All patients are high-risk by PETHEMA criteria | Yes/MFC | Best response 63(5/5) | Ongoing | - Infusion reaction 8% - Headache 4% - Neutropenia 5% - Urinary tract infection 5% |
| CENTAURUS study [47] 2017, Craig C Hofmeister (ASH 2017) NCT02316106 N=93 Ongoing study |
Daratumumab. 16 mg/kg IV in 8-wk cycles Long intensity (n=41): [C1]every 1 week; [C2-3] every other week; [C4-7] every 4 week; [C8-20] every 8 week |
Intermediate or high-risk smoldering multiple myeloma | No | Interim at 6 months after enrollment last case: 56(2/NA) |
1-year PFS: 98% | - infusion related toxicity 2% - Hypertension 5% - Hyperglycemia 2% |
| Intermediate intensity (n=41): [C1]every 1 week and [C2-20] every 8 week |
51(0/NA) | 1-year PFS: 93% | ||||
| Short intensity (n=41): [C1]every 1 week |
15(0/NA) | 1-year PFS: 89% | ||||
| 2018, Jagannath N=31 [46] |
[C1] Elotuzumab 20 mg/kg i.v. days 1, 8 then [C2-progressive disease] Elotuzumab monthly q 4 week | MAYO 2008 (intermediate): 93% |
No | Comparable both group: 10%(NA/NA) |
Comparable both group: 2-year PFS 69% |
Total grade 3-4: 47% -Upper respiratory tract infection 7% |
| [C1] Elotuzumab 10 mg/kg i.v. days 1, 8, 15, 22 [C2-progressive disease] Elotuzumab monthly q 2 week | MAYO 2008 (intermediate): 94% |
Total grade 3-4: 38% -Fatigue 6% -Diarrhea 6% -Insomnia 6% |
||||
Abbreviation: C, cycle; cfDNA, cell-free DNA; CTC, circulartory tumor cells; MFC, multicolor flow cytometry; NA, not available; OS, overall survival; PFS, progression free survival
*
PFS in all studies is measured as time from study entry to progression to MM with CRAB criteria or death, except 2019 Lonial ECOG study and CENTAURUS with PFS there being time from study entry until death or progression to MM with SLiM-CRAB criteria. (SLiM-CRAB (S=sixty, Li=light chains, M=MRI, C=calcium [elevated], R=renal failure, A=anemia, B=bone lesions)