Studies evaluating functional high risk
| Reference . | Study population, N . | ER or FHR definition . | ER, N (%) . | First-line treatment, N (%) . | Median OS (early vs late relapse) . | Factors influencing ER . | ||
|---|---|---|---|---|---|---|---|---|
| Baseline factors . | Treatment related . | Impact of response . | ||||||
| Jimenez-Zepeda et al 201540 | Princess Margaret Cancer Center, N = 184 | ER: progressive disease within 12 months from transplant | 27 (14) | In overall population: • PI based: 119 (64.7) • IMiD based: 65 (35.3) • ASCT: 184 (100) | 20 mo vs 93 mo (P = . 001) | Favoring • Thalidomide induction regimens (P = .04) | Patients with ER showed a lower ≥ VGPR rate that those with non-ER | |
| Kumar et al 201823 | Center for International Blood and Marrow Transplant Research database, N = 3256 | ER: progressive disease within 24 months from transplant | 1239 (38) | In overall population: • Bort based: 748 (22) • Len based: 342 (10) • Len-Bort based: 545 (17) • ASCT: 3256 (100) | 44.7 mo vs 113.7 mo (P < .001) | Favoring: • DS/ISS III (P = .02) Protective: • Chemo sensitivity (P = .007) | Protective: • Transplant after 2008 (P = .02) • Post-ASCT maintenance with novel agent (P = .02) | |
| Spencer et al 201921 | Australian and New Zealand Myeloma and Related Diseases Registry, N = 1320 | FHR: ER + SOR ER: progressive disease within 12 months of commencing 1st line of therapy SOR: best response to 1st line minimal response or stable disease | FHR: 270 (20.4) ER: 118 (8.9) SOE: 152 (11.5) | N/A | ER, 20.2 mo vs 60.7 mo (P < .001) SOR, 57.8 mo vs 59.3 mo | ER, favoring: • Higher ISS (P < .001); • Higher R-ISS (P < .001); • Inferior ECOG (P = .007); • Hypercalcemia (P = .002); • Renal insufficiency (P < .001); • Anemia (P < .001) SOR, favoring: • Age >70 y (P = .01) | SOR, favoring: • Bort based (P = .001) | SOR (MR or SD) in early vs late relapse: 25% vs 11% (P < .001) |
| Kastritis et al 202024 | Department of Clinical Therapeutics, Athens (Greece), N = 297 | ER: progressive disease within 12 months from transplant | 43 (14.5) | In overall population: • Bort based: 139 (47) • Len based: 248 (6) • Bort + IMiD: 26 (9) ASCT: 297 (100) | mOS 18 mo (early relapse) vs 5-years OS 71% (late relapse) | Favoring: • LDH ≥ ULN (P = .018) • Hypercalcemia (P = .034) | Protective: • Consolidation therapy (P < .001) • Maintenance (P < .048) | Response rates and depth of response to induction therapy were not significantly different among those with early vs later relapse |
| Corre et al 202033 | Retrospective study, N = 2627 patients | ER: progressive disease within 18 months from initial therapy or within 12 months from transplant | 496 (18.9) | In overall population: • PI based: 1129 (43) • PI + IMiD: 1485 (57) ASCT: 2627 (100) | HR 4.40 (P < .0001) | Favoring: • ISS II/III (P < .001) • High-risk cytogenetics, including del(17p) or t(4;14) or gain 1q or del(1q32) (P < .001) Protective: • Trisomy 5 (P = .0024) | • Poor response to treatment (<VGPR) (P < .001) | |
| D'Agostino et al 202035 | CoMMpass data set, N = 926 | ER: progressive disease within 18 months from diagnosis | 191 (20.6) | In overall population • Bort based: 83 (9) • Len based: 63 (7) • Bort + Len based: 319 (34) • Carf based: 215 (23) ASCT: 440 (53) | 32.8 mo vs 54 mo (ISS III) vs 65 mo (cytogenetics high risk) | Favoring: • TP53 mutation (P < .001) • High LDH (P = .006) • L-chain translocation (P = .033) • IGLL5 mutation (P = .007) | Favoring: • Refractoriness to PIs (P < .001) or IMiDs + PIs (P < .001) Protective: • Carfilzomib-based induction (P = .01) | • Lower ORR (P < .001; • Poor response to treatment (<VGPR) (P < .001) |
| Bygrave et al 202122 | NCRI Myeloma XI, N = 1349 | ER: progressive disease within 12 months from transplant | 174 (12.9) | CTd vs CRd as induction treatment If ≤ VGPR prior ASCT: VTd ASCT = 1349 (100) | 26 mo vs 91 mo (P < .001) | Favoring: • Anemia (P < .0001) • Low platelet count (P = .0001) • Heavy plasma cell infiltration (P < .0001) • Advanced ISS stage (P = .0029) • High-risk genetic (P < .0001) | Protective: Len-based maintenance (P = .0005) | |
| Soekojo et al 202236 | CoMMpass data set, N = 512 | FHR: primary refractory to induction therapy plus progressive disease within early relapse within 12 months of starting induction therapy without high-risk cytogenetics (ER) | FHR: 61 (11) | In FHR population: • PI based: 43 (36) • IMiD based: 18 (15) • PI + IMiD: 50 (42.7) ASCT = N/A | 27.6 mo (FHR) vs 44.7 mo (GHR) vs NR (SR) (P < .001) | Favoring: mutations affecting the IL- 6/Jak/STAT3 pathway, associated with aberrant mitosis and DNA damage response | ||
| Reference . | Study population, N . | ER or FHR definition . | ER, N (%) . | First-line treatment, N (%) . | Median OS (early vs late relapse) . | Factors influencing ER . | ||
|---|---|---|---|---|---|---|---|---|
| Baseline factors . | Treatment related . | Impact of response . | ||||||
| Jimenez-Zepeda et al 201540 | Princess Margaret Cancer Center, N = 184 | ER: progressive disease within 12 months from transplant | 27 (14) | In overall population: • PI based: 119 (64.7) • IMiD based: 65 (35.3) • ASCT: 184 (100) | 20 mo vs 93 mo (P = . 001) | Favoring • Thalidomide induction regimens (P = .04) | Patients with ER showed a lower ≥ VGPR rate that those with non-ER | |
| Kumar et al 201823 | Center for International Blood and Marrow Transplant Research database, N = 3256 | ER: progressive disease within 24 months from transplant | 1239 (38) | In overall population: • Bort based: 748 (22) • Len based: 342 (10) • Len-Bort based: 545 (17) • ASCT: 3256 (100) | 44.7 mo vs 113.7 mo (P < .001) | Favoring: • DS/ISS III (P = .02) Protective: • Chemo sensitivity (P = .007) | Protective: • Transplant after 2008 (P = .02) • Post-ASCT maintenance with novel agent (P = .02) | |
| Spencer et al 201921 | Australian and New Zealand Myeloma and Related Diseases Registry, N = 1320 | FHR: ER + SOR ER: progressive disease within 12 months of commencing 1st line of therapy SOR: best response to 1st line minimal response or stable disease | FHR: 270 (20.4) ER: 118 (8.9) SOE: 152 (11.5) | N/A | ER, 20.2 mo vs 60.7 mo (P < .001) SOR, 57.8 mo vs 59.3 mo | ER, favoring: • Higher ISS (P < .001); • Higher R-ISS (P < .001); • Inferior ECOG (P = .007); • Hypercalcemia (P = .002); • Renal insufficiency (P < .001); • Anemia (P < .001) SOR, favoring: • Age >70 y (P = .01) | SOR, favoring: • Bort based (P = .001) | SOR (MR or SD) in early vs late relapse: 25% vs 11% (P < .001) |
| Kastritis et al 202024 | Department of Clinical Therapeutics, Athens (Greece), N = 297 | ER: progressive disease within 12 months from transplant | 43 (14.5) | In overall population: • Bort based: 139 (47) • Len based: 248 (6) • Bort + IMiD: 26 (9) ASCT: 297 (100) | mOS 18 mo (early relapse) vs 5-years OS 71% (late relapse) | Favoring: • LDH ≥ ULN (P = .018) • Hypercalcemia (P = .034) | Protective: • Consolidation therapy (P < .001) • Maintenance (P < .048) | Response rates and depth of response to induction therapy were not significantly different among those with early vs later relapse |
| Corre et al 202033 | Retrospective study, N = 2627 patients | ER: progressive disease within 18 months from initial therapy or within 12 months from transplant | 496 (18.9) | In overall population: • PI based: 1129 (43) • PI + IMiD: 1485 (57) ASCT: 2627 (100) | HR 4.40 (P < .0001) | Favoring: • ISS II/III (P < .001) • High-risk cytogenetics, including del(17p) or t(4;14) or gain 1q or del(1q32) (P < .001) Protective: • Trisomy 5 (P = .0024) | • Poor response to treatment (<VGPR) (P < .001) | |
| D'Agostino et al 202035 | CoMMpass data set, N = 926 | ER: progressive disease within 18 months from diagnosis | 191 (20.6) | In overall population • Bort based: 83 (9) • Len based: 63 (7) • Bort + Len based: 319 (34) • Carf based: 215 (23) ASCT: 440 (53) | 32.8 mo vs 54 mo (ISS III) vs 65 mo (cytogenetics high risk) | Favoring: • TP53 mutation (P < .001) • High LDH (P = .006) • L-chain translocation (P = .033) • IGLL5 mutation (P = .007) | Favoring: • Refractoriness to PIs (P < .001) or IMiDs + PIs (P < .001) Protective: • Carfilzomib-based induction (P = .01) | • Lower ORR (P < .001; • Poor response to treatment (<VGPR) (P < .001) |
| Bygrave et al 202122 | NCRI Myeloma XI, N = 1349 | ER: progressive disease within 12 months from transplant | 174 (12.9) | CTd vs CRd as induction treatment If ≤ VGPR prior ASCT: VTd ASCT = 1349 (100) | 26 mo vs 91 mo (P < .001) | Favoring: • Anemia (P < .0001) • Low platelet count (P = .0001) • Heavy plasma cell infiltration (P < .0001) • Advanced ISS stage (P = .0029) • High-risk genetic (P < .0001) | Protective: Len-based maintenance (P = .0005) | |
| Soekojo et al 202236 | CoMMpass data set, N = 512 | FHR: primary refractory to induction therapy plus progressive disease within early relapse within 12 months of starting induction therapy without high-risk cytogenetics (ER) | FHR: 61 (11) | In FHR population: • PI based: 43 (36) • IMiD based: 18 (15) • PI + IMiD: 50 (42.7) ASCT = N/A | 27.6 mo (FHR) vs 44.7 mo (GHR) vs NR (SR) (P < .001) | Favoring: mutations affecting the IL- 6/Jak/STAT3 pathway, associated with aberrant mitosis and DNA damage response | ||
Bort, bortezomib; Carf, carfilzomib; CTd, cyclophosphamide-thalidomide-dexamethasone; ER, early relapse; GHR, genomic high risk; IL-6, interleukin 6; Len, lenalidomide; mOS, median overall survival; MR, minimal response; N/A, not available; NCRI, National Cancer Research Institute; ORR, overall response rate; SOR, suboptimal response; SR, standard risk; STAT3, signal transducer and activator of transcription 3; ULN, upper limit of normal; VTd, bortezomib-thalidomide-dexamethasone.