Treatment of Smoldering Multiple Myeloma: Ready for Prime Time?
Abstract
:1. Introduction
2. Evolving Definition of SMM
3. Prognostic Features and Risk Stratification Models for SMM
3.1. Risk Factors for Progression
3.2. Risk Stratification Models
3.3. Limitations and Other Considerations
4. Clinical Trials Investigating Early Intervention for SMM
4.1. Prevention
4.2. Treatment and Other Ongoing Studies
5. Unanswered Questions Regarding Early Intervention for SMM
5.1. Who Requires Early Intervention?
5.2. What Is the Optimal Intensity of Early Intervention?
5.3. What Is the Optimal Duration of Early Intervention?
6. Suggested Approaches to the Management of SMM
7. Conclusions
Funding
Conflicts of Interest
References
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Monoclonal Gammopathy of Undetermined Significance | Smoldering Multiple Myeloma | Multiple Myeloma |
---|---|---|
|
|
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Progression to multiple myeloma, solitary plasmacytoma, or AL amyloidosis: 1%/year | Progression to active multiple myeloma: 10%/year | |
End-organ damage (CRAB criteria) includes:
|
Model | Risk Stratification | Progression Rate | Median Time to Progression | |
---|---|---|---|---|
PETHEMA [21]
| High risk | 2 risk factors | 5 year, 72% | 23 months |
Intermediate risk | 1 risk factor | 5 year, 46% | 73 months | |
Low risk | No risk factors | 5 year, 4% | Not reached | |
Mayo 2008 [18]
| High risk | 3 risk factors | 2 year; 52%; 5 year, 76% | 1.9 years |
Intermediate risk | 2 risk factors | 2 year, 27%; 5 year, 51% | 5.1 years | |
Low risk | 1 risk factor | 2 year, 12%; 5 year, 25% | 10 years | |
Mayo 2018 (20/2/20) [31]
| High risk | ≥2 risk factors | 2 year, 47.4%; 5 year, 81.5% | 29.2 months |
Intermediate risk | 1 risk factor | 2 year, 26.3%; 5 year, 46.7% | 67.8 months | |
Low risk | No risk factors | 2 year, 9.7%; 5 year, 22.5% | 109.8 months |
Clinical Trial | Phase | N | Intervention | Endpoints | Results | Adverse Events (Grade 3–4) |
---|---|---|---|---|---|---|
QuiRedex (NCT00480363) [4,45] | III | 119 | Rd (n = 57) vs. observation (n = 62) Induction: R 25 mg PO D1-21 + dex 20 mg PO D1-4, 12–15; every 28 days × 9 cycles Maintenance: R 10 mg PO D1-21; every 28 days × 2 years | Primary: TTP to active MM Secondary: RR, OS, safety |
| Infection (6%), asthenia (6%), neutropenia (5%), rash (3%) |
E3A06 (NCT01169337) [44] | II/III | 182 | R (n = 92) vs. observation (n = 90) R 25 mg PO D1-21; every 28 days until progression | Primary: PFS Secondary: safety |
| Neutropenia (13.6%), infection (10.2%), skin rash (5.7%), dyspnea (5.7%), fatigue (6.8%), hypertension (9.1%), hypokalemia (3.4%) |
Clinical Trial | Phase | N | Intervention | Endpoints | Results | Adverse Events (Grade 3–4) |
---|---|---|---|---|---|---|
NCT01572480 [47] | II | 12 | KRd induction → R maintenance Induction: K 20/36 mg/m2 IV D1, 2, 8, 9, 15, 16 + R 25 mg PO D1-21 + dex 20/10 mg (cycles 1–4/5–8) D1, 2, 8, 9, 15, 16, 22, 23; every 28 days × 8 cycles Maintenance: R 25 mg PO D1-21; every 28 days × 2 years | Primary: RR Secondary: MRD negativity, safety |
| Lymphopenia (50%), neutropenia (17%), skin rash (33%), infection (8%), cardiac (8%) |
GEM-CESAR (NCT02415413) [48] | II | 90 | KRd induction → HDT-ASCT → KRd consolidation → Rd maintenance Induction: K 20/36 mg/m2 IV D1, 2, 8, 9, 15, 16 + R 25 mg PO D1-21 + dex 40 mg D1, 8, 15, 22; every 28 days × 6 cycles HDT-ASCT: Melphalan 200 mg/m2 → ASCT Consolidation: K 36 mg/m2 IV D1, 2, 8, 9, 15, 16 + R 25 mg PO D1-21 + dex 40 mg D1, 8, 15, 22; every 28 days × 2 cycles Maintenance: R 10 mg PO D1-21 + dex 20 mg D1, 8, 15, 22; every 28 days × 2 years | Primary: MRD negativity Secondary: RR, safety |
| Neutropenia (6%), thrombocytopenia (11%), infection (18%), skin rash (9%) |
NCT02279394 [49] | II | 50 | Elotuzumab-Rd induction → Elotuzumab-R maintenance Induction: Elotuzumab 10 mg/kg IV D1, 8, 15, 22 (cycles 1–2), D1, 15 (cycles 3–8) + R 25 mg PO D1-21 + dex 40 mg PO D1, 8, 15, 22 (cycles 1–2), D1, 8, 15 (cycles 3–8); every 28 days × 8 cycles Maintenance: Elotuzumab 20 mg/kg IV D1 + R 25 mg PO D1-21; every 28 days; cycles 9–24 | Primary: PFS Secondary: RR, safety, TTP, OS |
| Hypophosphatemia (34%), neutropenia (26%), lymphopenia (22%) |
NCT02916771 [50] | II | 62 (planned) | RId induction → RI maintenance Induction: R 25 mg PO D1-21 + I 4 mg PO D1, 8, 15 + dex 40 mg PO D1, 8, 15, 22; every 28 days × 9 cycles (cycles 1–9) Maintenance: R 15 mg PO D1-21 + I 4 mg PO D1, 8, 15; every 28 days × 15 cycles (cycles 10–24) | Primary: PFS Secondary: TTP, ORR, OS, safety |
| Hypertension (6.3%), hypophosphatemia (4.2%), rash (4.2%), thrombocytopenia (4.4%), neutropenia (4.4%), hyperglycemia (2.2%) |
CENTAURUS (NCT02316106) [51] | II | 123 | Daratumumab intense (n = 41) vs. intermediate (n = 41) vs. short dosing (n = 41) Daratumumab 16 mg/kg IV; every 8-week cycle (all schedule) Extended intense arm: Cycle 1: weekly Cycles 2–3: every 2 weeks Cycles 4–7: every 4 weeks Cycles 8–20: every 8 weeks Extended intermediate arm: Cycle 1: weekly Cycles 2–20: every 8 weeks Short dosing arm: Cycle 1: weekly × 8 doses | Primary: CR, PD/death rates Secondary: ORR, PFS, OS |
| Grades 3–4 TEAEs: 44%, 27%, 10% for intense, immediate, short dosing, respectively. The most common grade 3–4 TEAEs (observed in >1 patient in any arm): hypertension, hyperglycemia |
NCT02603887 [52] | I | 13 | Pembrolizumab Pembrolizumab 200 mg IV every 3 weeks × 8 cycles; with option to continue up to 24 cycles if continued benefit | Primary: ORR Secondary: clinical benefit rate (≥minor response), safety |
| Discontinuation due to irAEs: 3 patients (2 transaminitis; 1 tubulointerstitial nephritis) |
NCT01718899 [56] | I/IIa | 22 | PVX-410 vaccine ± R Low-dose cohort (n = 3): PVX-410 vaccine 0.4 mg SC; every 2 weeks × 6 doses Target-dose cohort (n = 9): PVX-410 vaccine 0.8 mg SC; every 2 weeks × 6 doses PVX-410 + R combination cohort (n = 10): PVX-410 vaccine 0.8 mg SC; every 2 weeks × 6 doses + R 25 mg PO D1-21; every 28 days × 3 cycles | Primary: AEs Secondary: immune response to vaccine |
|
Clinical Trial | Phase | N | Intervention | Endpoints | Results | Study Dates |
---|---|---|---|---|---|---|
HO147SMM (NCT03673826) | II | 120 (planned) | KRd vs. Rd → R maintenance KRd arm: K 20/36 mg/m2 IV D1, 2, 8, 9, 15, 16 + R 25 mg PO D1-21 + dex 20 mg (cycles 1–4), 10 mg (cycles 5–9) D1, 8, 15, 22; every 28 days × 9 cycles Rd arm: R 25 mg PO D1-21 + dex 20 mg (cycles 1–4), 10 mg (cycles 5–9) D1, 8, 15, 22; every 28 days × 9 cycles Maintenance: R 10 mg PO D1-21; every 28 days × 2 years | Primary: PFS Secondary: MRD negativity; OS, safety | On-going | Study start date: Nov 19, 2018 Estimated primary completion date: Oct 2025 Estimated study completion date: Oct 2025 |
ASCENT (NCT03289299) | II | 83 (planned) | Dara-KRd induction → Dara-KRd consolidation → Dara-R maintenance Induction: Dara 16 mg/kg IV D1, 8, 15, 22 (cycles 1–2); D1, 15 (cycles 3–6) + K 20/36 mg/m2 IV D1, 2, 8, 9, 15, 16 + R 25 mg PO D1-21 + dex 40 mg D1, 8, 15, 22; every 28 days × 6 cycles Consolidation: Dara 16 mg/kg IV D1 (cycles 7–12) + K 36 mg/m2 IV D1, 2, 8, 9, 15, 16 + R 25 mg PO D1-21 + dex 20 mg D1, 8, 15, 22; every 28 days × 6 cycles Maintenance: Dara 16 mg/kg IV D1 (every odd cycle for cycles 13–24) + R 10 mg PO D1-21; every 28 days × 12 cycles | Primary: sCR Secondary: MRD negativity; OS, PFS, safety | On-going | Study start date: May 25, 2018 Estimated primary completion date: Jun 1, 2022 Estimated study completion date: Jun 1, 2026 |
NCT03937635 | III | 288 (planned) | Dara-Rd (treatment approach) vs. Rd (prevention approach) Dara-Rd arm: Dara 16 mg/kg IV D1, 8, 15, 22 (cycles 1–2); D1, 15 (cycles 3–6); D1 (cycles 7–24) + R 25 mg PO D1-21 + dex 40 mg D1, 8, 15, 22 (cycles 1–12); every 28 days up to 24 cycles Rd arm: R 25 mg PO D1-21 + dex 40 mg D1, 8, 15, 22 (cycles 1–12); every 28 days up to 24 cycles | Primary: OS, FACT-G score Secondary: PFS, best response, safety | On-going | Study start date: Apr 30, 2019 Estimated primary completion date: Nov 30, 2023 Estimated study completion date: Nov 30, 2028 |
AQUILA (NCT03301220) | III | 390 (planned) | Daratumumab SC vs. observation Daratumumab 1800 mg SC D1, 8, 15, 22 (cycles 1-2); D1, 15 (cycles 3–6); D1 (cycles 7–39) every 28 days up to 3 years | Primary: PFS Secondary: TTP, ORR, OS, safety | On-going | Study start date: Nov 7, 2017 Estimated primary completion date: Dec 16, 2021 Estimated study completion date: Dec 22, 2025 |
NCT02960555 | II | 61 (planned) | Isatuximab Isatuximab IV D1, 8, 15, 22 (cycle 1); D1, 15 (cycles 2–6); D1 (subsequent cycles); every 28 days up to 30 cycles | Primary: RR Secondary: PFS, OS | On-going | Study start date: Feb 8, 2017 Estimated primary completion date: Feb 1, 2022 Estimated study completion date: Feb 1, 2022 |
NCT02886065 | Ib | 20 (planned) | PVX-410 vaccine + citarinostat ± R PVX-410 + citarinostat + R arm: PVX-410 vaccine 0.8 mg SC biweekly × 6 doses + citarionostat 180 mg PO D1-21 × 3 cycles + R 25 mg PO D1-21 × 3 cycles; every 28 days PVX-410 + citarinostat arm: PVX-410 vaccine 0.8 mg SC biweekly × 6 doses + citarionostat 180 mg PO D1-21 × 3 cycles; every 28 days | Primary: safety | On-going | Study start date: Nov 2016 Estimated primary completion date: May 2021 Estimated study completion date: May 2021 |
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Kim, E.B.; Yee, A.J.; Raje, N. Treatment of Smoldering Multiple Myeloma: Ready for Prime Time? Cancers 2020, 12, 1223. https://doi.org/10.3390/cancers12051223
Kim EB, Yee AJ, Raje N. Treatment of Smoldering Multiple Myeloma: Ready for Prime Time? Cancers. 2020; 12(5):1223. https://doi.org/10.3390/cancers12051223
Chicago/Turabian StyleKim, E. Bridget, Andrew J. Yee, and Noopur Raje. 2020. "Treatment of Smoldering Multiple Myeloma: Ready for Prime Time?" Cancers 12, no. 5: 1223. https://doi.org/10.3390/cancers12051223