Studies evaluating MRD negativity in MM patients with HR cytogenetics
| . | Study . | Study design . | Population . | N (MRD data) . | HR definition . | MRD testing/sensitivity . | Proportion of MRD negativity . | Survival outcomes (MRD− vs MRD+) . |
|---|---|---|---|---|---|---|---|---|
| 1 | Perrot et al4 | Prospective (IFM 2009 trial) | NDMM | ITT population: 509 | t(4;14), t(14;16), deletion 17p | Next generation sequencing 1 × 10−6 | ITT population | ITT population and start of maintenance therapy: longer PFS in MRD− vs MRD+ both for HR and SR patients, although PFS in HR MRD− patients lower than that in SR MRD– patients |
| HR + SR | HR: 74 | All: 25% | End of maintenance therapy: longer PFS in MRD– vs MRD+ both for HR and SR; PFS benefit similar across HR and SR MRD– patients | |||||
| Evaluation at multiple time points | End of maintenance: 239 | HR: 31% | Hazard ratio for PFS in HR vs SR patients (adjusted for MRD status, treatment, ISS stage) | |||||
| HR: 27 | t(4;14): 40% | Start of maintenance: 1.69, 1.14-2.48, P = .008 | ||||||
| deletion 17p: 11% | End of maintenance: 1.08, 0.61-1.91, P = .785 | |||||||
| SR: 26% | ||||||||
| 2 | Lahuerta et al10 | Prospective (3 PETHEMA/GEM trials: GEM2000; GEM2005MENOS65; GEM2010MAS65) | NDMM | 609 | t(4;14) | Flow cytometry | 43% | PFS: |
| HR + SR | HR: 60 (of 370 with FISH data) | t(14;16), deletion 17p | 1 × 10−4 to 1 × 10−5 | HR: data not available | HR: 38 vs 14 mo, P < .001 | |||
| Evaluation 9 mo after enrollment (postinduction in non-ASCT group or post-ASCT) | Hazard ratio for PFS (adjusted for ISS stage and transplant) | |||||||
| HR: 0.30, 0.16-0.58, P < .001 | ||||||||
| SR: 0.44, 0.33-0.59, P < .001 | ||||||||
| OS: | ||||||||
| HR: 128 vs 26 mo, P < .001 | ||||||||
| Hazard ratio for OS (adjusted for ISS stage and transplant) | ||||||||
| HR: 0.21, 0.09-0.50, P < .001 | ||||||||
| SR: 0.40, 0.26-0.61, P < .001 | ||||||||
| 3 | Rawstron et al5 | Prospective (MRC IX trial) | NDMM | Post ASCT | t(4;14), t(14;16), t(14;20), deletion 17p, gain1q, del1p | Flow cytometry | All: 62.2% | PFS: |
| HR + SR | 397 | 1 × 10−4 | HR: 61.5% | HR: 15.7 vs 8.7 mo, P < .001 | ||||
| Day 100 post-ASCT assessment reported here | HR: 109 | SR: 59.8% | SR: 44.2 vs 33.7 mo, P = .014 | |||||
| Both HR cytogenetics and MRD status predictive of PFS and OS | ||||||||
| 4 | Li et al6 | Prospective (NCT02086942; NCT02248428) | NDMM | 123 | t(4;14), t(14;16), deletion 17p, gain1q | Flow cytometry | All: 25% | PFS: |
| HR + SR | HR: 72 | 1 × 10−4 | HR: 25% | HR: PFS: 45 vs 22 mo, P = .016 | ||||
| SR: PFS: NR vs 34 mo, P = .009 | ||||||||
| PFS in MRD– HR vs SR: 45 mo vs NR, P = .035 | ||||||||
| 4 y OS: | ||||||||
| HR: 100% vs 54%, P = −.012 | ||||||||
| SR: 87.5% vs 83.6%, P = .508 | ||||||||
| OS in MRD– HR vs SR: 100% vs 87.5%, P = .48 | ||||||||
| MRD status and HR cytogenetics: independent prognostic factors for PFS and OS in multivariate analysis | ||||||||
| 5 | Paiva et al12 | Prospective (PETHEMA/GEM 2000 and GEM2005) | NDMM (in CR) | 241 | t(4;14), t(14;16), deletion 17p | Flow cytometry | All: 64% | TTP: |
| HR + SR | HR: 16% | 1 × 10−4 to 1 × 10−5 | HR: not available | SR and MRD–: 83 mo, HR or MRD+ SR: 26 mo, HR and MRD+: 6 mo; P < .001 | ||||
| Day 100 post-ASCT | OS | |||||||
| HR and MRD–: NR, HR or MRD+ SR: 47 mo, HR and MRD+: 21 mo; P < .001 | ||||||||
| HR FISH and MRD+ were independent prognostic factors for unsustained CR (progression from CR within 1 y of ASCT) | ||||||||
| 6 | Paiva et al7 | Prospective (PETHEMA/GEM2010MAS65) | NDMM, older adults | 162 | (4;14), t(14;16), deletion 17p | Flow cytometry | HR: 27% | TTP: |
| HR + SR | HR: 26 (of 132 with FISH) | 1 × 10−4 to 1 × 10−5 | SR: 38% | HR: NR vs 12 mo | ||||
| All: 33% (22% of ITT population, N = 241) | SR: NR vs 15 mo | |||||||
| TTP HR MRD– vs SR MRD–: P = .70 | ||||||||
| TTP HR MRD+ vs SR MRD+: P = .02 | ||||||||
| MRD status and HR FISH: independent prognostic factors for TTP and OS | ||||||||
| 7 | Chakraborty et al9 | Retrospective | NDMM | HR: 185 | t(4;14), t(14;16), t(14;20), deletion 17p, gain1q | Flow cytometry | HR: 56% | PFS: |
| HR only | 1 × 10−4 | t(4;14): 60% | HR: 26 vs 17 mo, P < .001 | |||||
| Day 100 post-ASCT | Deletion 17p: 48% | t(4;14): 24 vs 12 mo, P = .002 | ||||||
| Deletion 17p: 22.5 vs 22 mo, P = .464 | ||||||||
| ≥2 HR abnormalities: 12 vs 14 mo, P = .293 | ||||||||
| OS: | ||||||||
| HR: NR vs 50 mo, P = .023 | ||||||||
| t(4;14): NR vs 31 mo, P = .039 | ||||||||
| Deletion 17p: 52 vs 50 mo, P = .774 | ||||||||
| ≥2 HR abnormalities: 36 vs 31 mo, P = .419 | ||||||||
| 8 | Hu et al8 | Retrospective | NDMM | 96 | t(4;14), t(14;16), deletion 17p, gain1q, del1p | Flow cytometry | All: 60% | PFS: |
| HR + SR | HR: 31 | 1 × 10−4 | HR: 42% | HR: NR vs 19 mo | ||||
| (matched) | HR vs SR MRD: 42% vs 69%, P = .014 | SR: 45.6 vs 24.1 mo | ||||||
| Day 100 post-ASCT | MRD status and HR FISH: independent prognostic factors for PFS | |||||||
| 9 | Goicoechea et al11 | Prospective (GEM2012MENOS65; abstract) | NDMM | 419 | t(4;14), deletion 17p, and t(14;16) | Flow cytometry | del17p: 24% | PFS: |
| HR + SR | HR: 90 (of 390 with FISH data) | 1 × 10−5 to 10−6 | t(4;14): 43% | HR: NR vs 25 mo | ||||
| t(14;16): 60% | del17p: NR vs 14 mo | |||||||
| SR: 50% | t(4;14): NR vs 28 mo | |||||||
| SR: NR vs 46 mo | ||||||||
| 10 | Kunacheewa et al13 | Retrospective (abstract) | NDMM | 136 | t(4;14), t(14;16), deletion 17p, gain1q (≥4 copies) and HR GEP signature | Flow cytometry | HR: 41% | PFS: |
| HR + SR | HR: 29 | 1 × 10−5 | SR: 54% | At median follow-up of 14 mo, median PFS was NR in HR or SR group; proportion of patients who relapsed or died in each group were | ||||
| End of initial therapy | HR: 40% vs 45%, | |||||||
| SR: 10% vs 20%, and | ||||||||
| PFS: HR vs SR; P = .004 | ||||||||
| 11 | Hahn et al14 | Prospective (PRIMeR, BMT CTN 0702; abstract) | NDMM | 445 | t(4;14), t(14;16), t(14;20), deletion 17p, deletion13, aneuploidy, β2-microglobulin > 5.5 mg/L | Flow cytometry | Post-ASCT | PFS: |
| HR + SR | HR: not known | 2.5 × 10−5 to 1 × 10−6 | All: 78% | MRD status and HR myeloma: independent prognostic factors for PFS in multivariate analysis | ||||
| Before transplant, post-ASCT before maintenance and 1 y post-ASCT | HR: not known | Hazard ratio for PFS (adjusting for MRD status and treatment arm) | ||||||
| 1 y post-ASCT: all: 84% | HR vs SR: 3.29, 2.09-5.18 | |||||||
| HR: not known |
| . | Study . | Study design . | Population . | N (MRD data) . | HR definition . | MRD testing/sensitivity . | Proportion of MRD negativity . | Survival outcomes (MRD− vs MRD+) . |
|---|---|---|---|---|---|---|---|---|
| 1 | Perrot et al4 | Prospective (IFM 2009 trial) | NDMM | ITT population: 509 | t(4;14), t(14;16), deletion 17p | Next generation sequencing 1 × 10−6 | ITT population | ITT population and start of maintenance therapy: longer PFS in MRD− vs MRD+ both for HR and SR patients, although PFS in HR MRD− patients lower than that in SR MRD– patients |
| HR + SR | HR: 74 | All: 25% | End of maintenance therapy: longer PFS in MRD– vs MRD+ both for HR and SR; PFS benefit similar across HR and SR MRD– patients | |||||
| Evaluation at multiple time points | End of maintenance: 239 | HR: 31% | Hazard ratio for PFS in HR vs SR patients (adjusted for MRD status, treatment, ISS stage) | |||||
| HR: 27 | t(4;14): 40% | Start of maintenance: 1.69, 1.14-2.48, P = .008 | ||||||
| deletion 17p: 11% | End of maintenance: 1.08, 0.61-1.91, P = .785 | |||||||
| SR: 26% | ||||||||
| 2 | Lahuerta et al10 | Prospective (3 PETHEMA/GEM trials: GEM2000; GEM2005MENOS65; GEM2010MAS65) | NDMM | 609 | t(4;14) | Flow cytometry | 43% | PFS: |
| HR + SR | HR: 60 (of 370 with FISH data) | t(14;16), deletion 17p | 1 × 10−4 to 1 × 10−5 | HR: data not available | HR: 38 vs 14 mo, P < .001 | |||
| Evaluation 9 mo after enrollment (postinduction in non-ASCT group or post-ASCT) | Hazard ratio for PFS (adjusted for ISS stage and transplant) | |||||||
| HR: 0.30, 0.16-0.58, P < .001 | ||||||||
| SR: 0.44, 0.33-0.59, P < .001 | ||||||||
| OS: | ||||||||
| HR: 128 vs 26 mo, P < .001 | ||||||||
| Hazard ratio for OS (adjusted for ISS stage and transplant) | ||||||||
| HR: 0.21, 0.09-0.50, P < .001 | ||||||||
| SR: 0.40, 0.26-0.61, P < .001 | ||||||||
| 3 | Rawstron et al5 | Prospective (MRC IX trial) | NDMM | Post ASCT | t(4;14), t(14;16), t(14;20), deletion 17p, gain1q, del1p | Flow cytometry | All: 62.2% | PFS: |
| HR + SR | 397 | 1 × 10−4 | HR: 61.5% | HR: 15.7 vs 8.7 mo, P < .001 | ||||
| Day 100 post-ASCT assessment reported here | HR: 109 | SR: 59.8% | SR: 44.2 vs 33.7 mo, P = .014 | |||||
| Both HR cytogenetics and MRD status predictive of PFS and OS | ||||||||
| 4 | Li et al6 | Prospective (NCT02086942; NCT02248428) | NDMM | 123 | t(4;14), t(14;16), deletion 17p, gain1q | Flow cytometry | All: 25% | PFS: |
| HR + SR | HR: 72 | 1 × 10−4 | HR: 25% | HR: PFS: 45 vs 22 mo, P = .016 | ||||
| SR: PFS: NR vs 34 mo, P = .009 | ||||||||
| PFS in MRD– HR vs SR: 45 mo vs NR, P = .035 | ||||||||
| 4 y OS: | ||||||||
| HR: 100% vs 54%, P = −.012 | ||||||||
| SR: 87.5% vs 83.6%, P = .508 | ||||||||
| OS in MRD– HR vs SR: 100% vs 87.5%, P = .48 | ||||||||
| MRD status and HR cytogenetics: independent prognostic factors for PFS and OS in multivariate analysis | ||||||||
| 5 | Paiva et al12 | Prospective (PETHEMA/GEM 2000 and GEM2005) | NDMM (in CR) | 241 | t(4;14), t(14;16), deletion 17p | Flow cytometry | All: 64% | TTP: |
| HR + SR | HR: 16% | 1 × 10−4 to 1 × 10−5 | HR: not available | SR and MRD–: 83 mo, HR or MRD+ SR: 26 mo, HR and MRD+: 6 mo; P < .001 | ||||
| Day 100 post-ASCT | OS | |||||||
| HR and MRD–: NR, HR or MRD+ SR: 47 mo, HR and MRD+: 21 mo; P < .001 | ||||||||
| HR FISH and MRD+ were independent prognostic factors for unsustained CR (progression from CR within 1 y of ASCT) | ||||||||
| 6 | Paiva et al7 | Prospective (PETHEMA/GEM2010MAS65) | NDMM, older adults | 162 | (4;14), t(14;16), deletion 17p | Flow cytometry | HR: 27% | TTP: |
| HR + SR | HR: 26 (of 132 with FISH) | 1 × 10−4 to 1 × 10−5 | SR: 38% | HR: NR vs 12 mo | ||||
| All: 33% (22% of ITT population, N = 241) | SR: NR vs 15 mo | |||||||
| TTP HR MRD– vs SR MRD–: P = .70 | ||||||||
| TTP HR MRD+ vs SR MRD+: P = .02 | ||||||||
| MRD status and HR FISH: independent prognostic factors for TTP and OS | ||||||||
| 7 | Chakraborty et al9 | Retrospective | NDMM | HR: 185 | t(4;14), t(14;16), t(14;20), deletion 17p, gain1q | Flow cytometry | HR: 56% | PFS: |
| HR only | 1 × 10−4 | t(4;14): 60% | HR: 26 vs 17 mo, P < .001 | |||||
| Day 100 post-ASCT | Deletion 17p: 48% | t(4;14): 24 vs 12 mo, P = .002 | ||||||
| Deletion 17p: 22.5 vs 22 mo, P = .464 | ||||||||
| ≥2 HR abnormalities: 12 vs 14 mo, P = .293 | ||||||||
| OS: | ||||||||
| HR: NR vs 50 mo, P = .023 | ||||||||
| t(4;14): NR vs 31 mo, P = .039 | ||||||||
| Deletion 17p: 52 vs 50 mo, P = .774 | ||||||||
| ≥2 HR abnormalities: 36 vs 31 mo, P = .419 | ||||||||
| 8 | Hu et al8 | Retrospective | NDMM | 96 | t(4;14), t(14;16), deletion 17p, gain1q, del1p | Flow cytometry | All: 60% | PFS: |
| HR + SR | HR: 31 | 1 × 10−4 | HR: 42% | HR: NR vs 19 mo | ||||
| (matched) | HR vs SR MRD: 42% vs 69%, P = .014 | SR: 45.6 vs 24.1 mo | ||||||
| Day 100 post-ASCT | MRD status and HR FISH: independent prognostic factors for PFS | |||||||
| 9 | Goicoechea et al11 | Prospective (GEM2012MENOS65; abstract) | NDMM | 419 | t(4;14), deletion 17p, and t(14;16) | Flow cytometry | del17p: 24% | PFS: |
| HR + SR | HR: 90 (of 390 with FISH data) | 1 × 10−5 to 10−6 | t(4;14): 43% | HR: NR vs 25 mo | ||||
| t(14;16): 60% | del17p: NR vs 14 mo | |||||||
| SR: 50% | t(4;14): NR vs 28 mo | |||||||
| SR: NR vs 46 mo | ||||||||
| 10 | Kunacheewa et al13 | Retrospective (abstract) | NDMM | 136 | t(4;14), t(14;16), deletion 17p, gain1q (≥4 copies) and HR GEP signature | Flow cytometry | HR: 41% | PFS: |
| HR + SR | HR: 29 | 1 × 10−5 | SR: 54% | At median follow-up of 14 mo, median PFS was NR in HR or SR group; proportion of patients who relapsed or died in each group were | ||||
| End of initial therapy | HR: 40% vs 45%, | |||||||
| SR: 10% vs 20%, and | ||||||||
| PFS: HR vs SR; P = .004 | ||||||||
| 11 | Hahn et al14 | Prospective (PRIMeR, BMT CTN 0702; abstract) | NDMM | 445 | t(4;14), t(14;16), t(14;20), deletion 17p, deletion13, aneuploidy, β2-microglobulin > 5.5 mg/L | Flow cytometry | Post-ASCT | PFS: |
| HR + SR | HR: not known | 2.5 × 10−5 to 1 × 10−6 | All: 78% | MRD status and HR myeloma: independent prognostic factors for PFS in multivariate analysis | ||||
| Before transplant, post-ASCT before maintenance and 1 y post-ASCT | HR: not known | Hazard ratio for PFS (adjusting for MRD status and treatment arm) | ||||||
| 1 y post-ASCT: all: 84% | HR vs SR: 3.29, 2.09-5.18 | |||||||
| HR: not known |
ASCT, autologous stem cell transplant; BMT CTN, Blood and Marrow Transplant Clinical Trials Network; CR, complete response; GEM, Grupo Español de Mieloma; GEP, gene expression profiling; IFM, Intergroupe Francophone du Myélome; ITT, intention to treat MRC, Medical Research Council; NDMM, newly diagnosed multiple myeloma; NR, not reached; PETHEMA, Programa para el Estudio de la Terapéutica en Hemopatías Malignas; PRIMeR, Prognostic Immunophenotyping in Myeloma Response; TTP, time to progression.