Clinical studies specifically targeting high-risk disease in newly diagnosed myeloma patients
| . | NCT number . | Status . | Location . | Phase . | Treatment schema . | Definition of high risk used in the study . |
|---|---|---|---|---|---|---|
| Reported studies | ||||||
| TT5 2008-02: A Trial for High-risk Myeloma Evaluating Accelerating and Sustaining Complete Remission | NCT00869232 | Active, not recruiting | US | 2 | Induction: M-VTd-PACE | GEP70-defined high-risk gene expression profiling |
| Two ASCTs: | ||||||
| MEL80-VRd-PACE and 2 intertransplant cycles with MEL20-VTd-PACE | ||||||
| Maintenance (3 years): VRd alternating with VMd | ||||||
| Ongoing studies | ||||||
| Novel intensified combinations | ||||||
| TT5b 2012-02: A Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission | NCT02128230 | Recruiting | US | 2 | Induction: M-KTd-PACE | GEP70-defined high-risk gene expression profiling |
| Two ASCTs: | ||||||
| MEL80-KTd-PACE, and 1 intertransplant cycle with MEL20-KTd-PACE | ||||||
| Consolidation: KTd-PACE | ||||||
| Maintenance (year 1): KRd | ||||||
| Maintenance (year 2): Kd | ||||||
| MUK9b: OPTIMUM treatment protocol | NCT03188172 | Recruiting | UK | 2 | Induction: Dara-CVRd | 2 of (4;14), t(14;16), t(14;20), del(17p), gain(1q), or del(1p) |
| ASCT (with ongoing bortezomib) | SKY92-defined high-risk gene expression profiling | |||||
| Consolidation 1: Dara-VRd | Plasma cell leukemia | |||||
| Consolidation 2: Dara-VR | ||||||
| Maintenance: Dara-R | ||||||
| TT7 2015-12: a study exploring the use of early and late consolidation/maintenance therapy | NCT03004287 | Recruiting | US | 2 | Induction: KTd-Dara-PACE | GEP70-defined high-risk gene expression profiling |
| ASCT1 with Dara immunological consolidation | LDH ≥360 U/L Plasma cell leukemia | |||||
| Consolidation 1: Dara-Kd | ||||||
| ASCT2 with Dara immunological consolidation | ||||||
| Maintenance: Dara-Kd alternating with Dara-Rd in 3 month blocks | ||||||
| GMMG-CONCEPT: Evaluation induction, consolidation and maintenance treatment with isatuximab, carfilzomib, lenalidomide and dexamethasone | NCT03104842 | Recruiting | DE | 2 | TE and TNE pathways | Presence of ≥1 of the following cytogenetic abnormalities (determined by FISH): del(17p) in ≥10% of purified cells, t(4;14), >3 copies +1q21 |
| Induction: Isatuximab-KRd | ISS stage II or III (all patients) | |||||
| ASCT (if TE eligible) | ||||||
| Consolidation (if TE eligible): Isatuximab-KRd | ||||||
| Maintenance: Isatuximab-KR | ||||||
| S1211: bortezomib, dexamethasone, and lenalidomide with or without elotuzumab in treating patients with newly diagnosed high-risk multiple myeloma | NCT01668719 | Recruiting | US | 1/2 | Induction: Elotuzumab-VRd | GEP70- or SKY92-defined high-risk gene expression profiling t(14;16) and/or t(14;20) and/or del(17p) by FISH or cytogenetics |
| Maintenance: Elotuzumab-VRd | Plasma cell leukemia | |||||
| vs | LDH ≥2× IULN | |||||
| Induction: VRd | 1q21 amplification by FISH analysis | |||||
| Maintenance: VRd | ||||||
| IFM 2018-04: An intensive program with quadruplet induction and consolidation plus tandem autologous stem cell transplantation in newly diagnosed high risk multiple myeloma patients: a phase 2 study of the Intergroupe Francophone du Myélome | NCT03606577 | Not yet recruiting | FR | 2 | Induction: Dara-KRd | FISH analysis: del(17p), or t(14;16) or t(4;14). The FISH-positivity cutoff value for defining the presence of del(17p) in this study is specified as 50% |
| Tandem ASCT | ||||||
| Consolidation: Dara-KRd | ||||||
| Maintenance: Dara-R | ||||||
| A single arm study of carfilzomib in transplant eligible high risk multiple myeloma | NCT02217163 | Active, not recruiting | SG | 2 | Induction: KCd | ISS III |
| ASCT | Del(17p), t(4;14), t(14;16), t(14;20), gain(1q) | |||||
| Subsequent treatment at clinician discretion | ||||||
| Autogenic/allogenic approaches | ||||||
| Autologous or syngeneic stem cell transplant followed by donor stem cell transplant and bortezomib in treating patients with newly diagnosed high-risk, relapsed, or refractory multiple myeloma | NCT00793572 | Active, not recruiting | US | 2 | Induction: VAD | Any abnormal karyotype by metaphase analysis except for isolated t(11,14) and constitutional cytogenetic abnormality |
| ASCT | FISH detection of t(4;14), t(14;16), or del(17p) | |||||
| Allogeneic transplant (related or unrelated) | β2-microglobulin >5.5 mg/L | |||||
| Maintenance: V | Cytogenetic hypodiploidy | |||||
| Plasmablastic morphology (≥2%) | ||||||
| Allogeneic hematopoietic stem cell transplantation with ixazomib for high risk multiple myeloma (BMT CTN 1302) | NCT02440464 | Recruiting | US | 2 | Ixazomib vs placebo after allogeneic transplant | Del(13), gain(1q), del(1p), t(4;14), t(14;16), t(14;20), del(17p), or high-risk criteria based on commercially available GEP |
| Plasma cell leukemia | ||||||
| Relapsed within 18 mo of first-line therapy | ||||||
| ECT-001 (UM171): expanded cord blood transplant to treat high-risk multiple myeloma | NCT03441958 | Recruiting | CA | 1/2 | ECT-001 (UM171) expanded cord blood allogeneic transplant | t(4;14), t(14;16), t(14;20), del(17p13), chromosome 1 abnormalities with ISS II or III |
| Revised-ISS III | ||||||
| Plasma cell leukemia | ||||||
| Refractory to first line triplet bortezomib-based induction treatment. | ||||||
| ≥2 cytogenetics abnormalities as defined above regardless of ISS stage | ||||||
| Nonmyeloablative allogeneic stem cell transplant followed by bortezomib in high-risk multiple myeloma patients | NCT02308280 | Recruiting | CA | 2 | Nonmyeloablative allogeneic transplantation followed by bortezomib for 1 y after a bortezomib-based induction and ASCT | ISS III |
| Del(17p13), t(4;14) with ISS II or III, t(14;16), t(14;20), and chromosome 1 abnormalities by FISH | ||||||
| Plasma cell leukemia | ||||||
| Patients ≤50 y, regardless of cytogenetics or ISS stage | ||||||
| Immunotherapy approaches | ||||||
| Upfront CAR T-BCMA with or without huCART19 in high-risk multiple myeloma | NCT03549442 | Recruiting | US | 1 | CART-BCMA ± huCART19 | β2-microglobulin ≥5.5 mg/L and LDH greater than upper limit of normal |
| High-risk FISH features: del(17p), t(14;16), t(14;20), t(4;14) in conjunction with β2-microglobulin ≥5.5 mg/L (ie, revised ISS stage III) | ||||||
| Metaphase karyotype with >3 structural abnormalities (except hyperdiploidy) | ||||||
| Plasma cell leukemia (>20% plasma cells in peripheral blood) | ||||||
| Failure to achieve partial response or better to initial therapy with an “IMiD/PI” combination (thalidomide, lenalidomide, or pomalidomide in combination with bortezomib, ixazomib, or carfilzomib) | ||||||
| Early progression on first-line therapy | ||||||
| CAR T-19 post-ASCT for multiple myeloma | NCT02794246 | Active, not recruiting | US | 2 | CD19 CAR T administered after ASCT | Any of the following high-risk cytogenetic features, documented by FISH or metaphase karyotyping: del(17p), t(4;14), t(14;16), t(14;20) |
| Standard-risk cytogenetics but elevated LDH and β2-microglobulin > 5.5 mg/L (ie, R-ISS stage III) | ||||||
| Study of T cells targeting CD19/BCMA (CAR T-19/BCMA) for high-risk multiple myeloma following ACST | NCT03455972 | Recruiting | CN | 1 | Anti-CD19/BCMA CAR T administered after ASCT | Not achieved VGPR before stem cell mobilization |
| R-ISS stage III | ||||||
| Extramedullary disease | ||||||
| Del(17p), t(4;14), t(14;16) | ||||||
| Pembrolizumab + lenalidomide post-ASCT in high-risk multiple myeloma | NCT02906332 | Active, not recruiting | US | 2 | Pembrolizumab and lenalidomide maintenance post-ASCT | ISS stage III |
| Del(13q), amp(1q), del(1p), p53 deletions (17p deletions), t(4;14), t(14;16), t(14;20), hypodiploidy | ||||||
| High-risk GEP scores | ||||||
| 2015-10: Expanded natural killer cells and elotuzumab for high-risk myeloma post-ASCT | NCT03003728 | Not yet recruiting | US | 2 | Elotuzumab and expanded natural killer cells post-ASCT | GEP70 or GEP80-defined high-risk gene expression profiling |
| Metaphase cytogenetic abnormalities | ||||||
| LDH ≥360 U/L | ||||||
| Completed, as yet unreported studies | ||||||
| Bortezomib, doxorubicin hydrochloride liposome, and dexamethasone followed by thalidomide and dexamethasone with or without bortezomib in treating patients with multiple myeloma | NCT00458705 | Completed | US | 2 | Induction: VDd (D = liposomal doxorubicin) Consolidation: VTd or Td | ISS stage II or III |
| Soft-tissue plasmacytoma | ||||||
| Primary resistant myeloma, defined as unchanged or progressive disease despite 2 courses of standard treatment | ||||||
| Combination bortezomib-containing regimens in newly diagnosed patients with t(4;14)-positive multiple myeloma | NCT00570180 | Completed | CA | 2 | Induction: VDd (D = liposomal doxorubicin) | t(4;14) |
| ASCT | ||||||
| Consolidation: CV prednisolone | ||||||
| Maintenance: prednisolone | ||||||
| Celgene high-risk multiple myeloma Revlimid induction and maintenance therapy | NCT00691704 | Completed | US | 2 | Induction: Rd | Deletion of chromosome 13 by cytogenetics |
| Del(17p) by FISH or metaphase analysis | ||||||
| FISH detection of t(4;14), t(14;16), t(8;14), or t(14;20) | ||||||
| Hypodiploidy detected by FISH or metaphase analysis | ||||||
| Sequential maintenance: bortezomib, M-prednisolone, lenalidomide | Any complex cytogenetic abnormality detected by cytogenetics, with the exception of hyperdiploidy | |||||
| Vismodegib after stem cell transplant in treating patients with high-risk first remission or relapsed multiple myeloma | NCT01330173 | Completed | US | 1 | Vismodegib (hedgehog inhibitor) after ASCT | Del(13), t(4;14), t(14;16), or del(17p); β2-microglobulin >5.5 g/dL IgA phenotype |
| . | NCT number . | Status . | Location . | Phase . | Treatment schema . | Definition of high risk used in the study . |
|---|---|---|---|---|---|---|
| Reported studies | ||||||
| TT5 2008-02: A Trial for High-risk Myeloma Evaluating Accelerating and Sustaining Complete Remission | NCT00869232 | Active, not recruiting | US | 2 | Induction: M-VTd-PACE | GEP70-defined high-risk gene expression profiling |
| Two ASCTs: | ||||||
| MEL80-VRd-PACE and 2 intertransplant cycles with MEL20-VTd-PACE | ||||||
| Maintenance (3 years): VRd alternating with VMd | ||||||
| Ongoing studies | ||||||
| Novel intensified combinations | ||||||
| TT5b 2012-02: A Trial For High-Risk Myeloma Evaluating Accelerating and Sustaining Complete Remission | NCT02128230 | Recruiting | US | 2 | Induction: M-KTd-PACE | GEP70-defined high-risk gene expression profiling |
| Two ASCTs: | ||||||
| MEL80-KTd-PACE, and 1 intertransplant cycle with MEL20-KTd-PACE | ||||||
| Consolidation: KTd-PACE | ||||||
| Maintenance (year 1): KRd | ||||||
| Maintenance (year 2): Kd | ||||||
| MUK9b: OPTIMUM treatment protocol | NCT03188172 | Recruiting | UK | 2 | Induction: Dara-CVRd | 2 of (4;14), t(14;16), t(14;20), del(17p), gain(1q), or del(1p) |
| ASCT (with ongoing bortezomib) | SKY92-defined high-risk gene expression profiling | |||||
| Consolidation 1: Dara-VRd | Plasma cell leukemia | |||||
| Consolidation 2: Dara-VR | ||||||
| Maintenance: Dara-R | ||||||
| TT7 2015-12: a study exploring the use of early and late consolidation/maintenance therapy | NCT03004287 | Recruiting | US | 2 | Induction: KTd-Dara-PACE | GEP70-defined high-risk gene expression profiling |
| ASCT1 with Dara immunological consolidation | LDH ≥360 U/L Plasma cell leukemia | |||||
| Consolidation 1: Dara-Kd | ||||||
| ASCT2 with Dara immunological consolidation | ||||||
| Maintenance: Dara-Kd alternating with Dara-Rd in 3 month blocks | ||||||
| GMMG-CONCEPT: Evaluation induction, consolidation and maintenance treatment with isatuximab, carfilzomib, lenalidomide and dexamethasone | NCT03104842 | Recruiting | DE | 2 | TE and TNE pathways | Presence of ≥1 of the following cytogenetic abnormalities (determined by FISH): del(17p) in ≥10% of purified cells, t(4;14), >3 copies +1q21 |
| Induction: Isatuximab-KRd | ISS stage II or III (all patients) | |||||
| ASCT (if TE eligible) | ||||||
| Consolidation (if TE eligible): Isatuximab-KRd | ||||||
| Maintenance: Isatuximab-KR | ||||||
| S1211: bortezomib, dexamethasone, and lenalidomide with or without elotuzumab in treating patients with newly diagnosed high-risk multiple myeloma | NCT01668719 | Recruiting | US | 1/2 | Induction: Elotuzumab-VRd | GEP70- or SKY92-defined high-risk gene expression profiling t(14;16) and/or t(14;20) and/or del(17p) by FISH or cytogenetics |
| Maintenance: Elotuzumab-VRd | Plasma cell leukemia | |||||
| vs | LDH ≥2× IULN | |||||
| Induction: VRd | 1q21 amplification by FISH analysis | |||||
| Maintenance: VRd | ||||||
| IFM 2018-04: An intensive program with quadruplet induction and consolidation plus tandem autologous stem cell transplantation in newly diagnosed high risk multiple myeloma patients: a phase 2 study of the Intergroupe Francophone du Myélome | NCT03606577 | Not yet recruiting | FR | 2 | Induction: Dara-KRd | FISH analysis: del(17p), or t(14;16) or t(4;14). The FISH-positivity cutoff value for defining the presence of del(17p) in this study is specified as 50% |
| Tandem ASCT | ||||||
| Consolidation: Dara-KRd | ||||||
| Maintenance: Dara-R | ||||||
| A single arm study of carfilzomib in transplant eligible high risk multiple myeloma | NCT02217163 | Active, not recruiting | SG | 2 | Induction: KCd | ISS III |
| ASCT | Del(17p), t(4;14), t(14;16), t(14;20), gain(1q) | |||||
| Subsequent treatment at clinician discretion | ||||||
| Autogenic/allogenic approaches | ||||||
| Autologous or syngeneic stem cell transplant followed by donor stem cell transplant and bortezomib in treating patients with newly diagnosed high-risk, relapsed, or refractory multiple myeloma | NCT00793572 | Active, not recruiting | US | 2 | Induction: VAD | Any abnormal karyotype by metaphase analysis except for isolated t(11,14) and constitutional cytogenetic abnormality |
| ASCT | FISH detection of t(4;14), t(14;16), or del(17p) | |||||
| Allogeneic transplant (related or unrelated) | β2-microglobulin >5.5 mg/L | |||||
| Maintenance: V | Cytogenetic hypodiploidy | |||||
| Plasmablastic morphology (≥2%) | ||||||
| Allogeneic hematopoietic stem cell transplantation with ixazomib for high risk multiple myeloma (BMT CTN 1302) | NCT02440464 | Recruiting | US | 2 | Ixazomib vs placebo after allogeneic transplant | Del(13), gain(1q), del(1p), t(4;14), t(14;16), t(14;20), del(17p), or high-risk criteria based on commercially available GEP |
| Plasma cell leukemia | ||||||
| Relapsed within 18 mo of first-line therapy | ||||||
| ECT-001 (UM171): expanded cord blood transplant to treat high-risk multiple myeloma | NCT03441958 | Recruiting | CA | 1/2 | ECT-001 (UM171) expanded cord blood allogeneic transplant | t(4;14), t(14;16), t(14;20), del(17p13), chromosome 1 abnormalities with ISS II or III |
| Revised-ISS III | ||||||
| Plasma cell leukemia | ||||||
| Refractory to first line triplet bortezomib-based induction treatment. | ||||||
| ≥2 cytogenetics abnormalities as defined above regardless of ISS stage | ||||||
| Nonmyeloablative allogeneic stem cell transplant followed by bortezomib in high-risk multiple myeloma patients | NCT02308280 | Recruiting | CA | 2 | Nonmyeloablative allogeneic transplantation followed by bortezomib for 1 y after a bortezomib-based induction and ASCT | ISS III |
| Del(17p13), t(4;14) with ISS II or III, t(14;16), t(14;20), and chromosome 1 abnormalities by FISH | ||||||
| Plasma cell leukemia | ||||||
| Patients ≤50 y, regardless of cytogenetics or ISS stage | ||||||
| Immunotherapy approaches | ||||||
| Upfront CAR T-BCMA with or without huCART19 in high-risk multiple myeloma | NCT03549442 | Recruiting | US | 1 | CART-BCMA ± huCART19 | β2-microglobulin ≥5.5 mg/L and LDH greater than upper limit of normal |
| High-risk FISH features: del(17p), t(14;16), t(14;20), t(4;14) in conjunction with β2-microglobulin ≥5.5 mg/L (ie, revised ISS stage III) | ||||||
| Metaphase karyotype with >3 structural abnormalities (except hyperdiploidy) | ||||||
| Plasma cell leukemia (>20% plasma cells in peripheral blood) | ||||||
| Failure to achieve partial response or better to initial therapy with an “IMiD/PI” combination (thalidomide, lenalidomide, or pomalidomide in combination with bortezomib, ixazomib, or carfilzomib) | ||||||
| Early progression on first-line therapy | ||||||
| CAR T-19 post-ASCT for multiple myeloma | NCT02794246 | Active, not recruiting | US | 2 | CD19 CAR T administered after ASCT | Any of the following high-risk cytogenetic features, documented by FISH or metaphase karyotyping: del(17p), t(4;14), t(14;16), t(14;20) |
| Standard-risk cytogenetics but elevated LDH and β2-microglobulin > 5.5 mg/L (ie, R-ISS stage III) | ||||||
| Study of T cells targeting CD19/BCMA (CAR T-19/BCMA) for high-risk multiple myeloma following ACST | NCT03455972 | Recruiting | CN | 1 | Anti-CD19/BCMA CAR T administered after ASCT | Not achieved VGPR before stem cell mobilization |
| R-ISS stage III | ||||||
| Extramedullary disease | ||||||
| Del(17p), t(4;14), t(14;16) | ||||||
| Pembrolizumab + lenalidomide post-ASCT in high-risk multiple myeloma | NCT02906332 | Active, not recruiting | US | 2 | Pembrolizumab and lenalidomide maintenance post-ASCT | ISS stage III |
| Del(13q), amp(1q), del(1p), p53 deletions (17p deletions), t(4;14), t(14;16), t(14;20), hypodiploidy | ||||||
| High-risk GEP scores | ||||||
| 2015-10: Expanded natural killer cells and elotuzumab for high-risk myeloma post-ASCT | NCT03003728 | Not yet recruiting | US | 2 | Elotuzumab and expanded natural killer cells post-ASCT | GEP70 or GEP80-defined high-risk gene expression profiling |
| Metaphase cytogenetic abnormalities | ||||||
| LDH ≥360 U/L | ||||||
| Completed, as yet unreported studies | ||||||
| Bortezomib, doxorubicin hydrochloride liposome, and dexamethasone followed by thalidomide and dexamethasone with or without bortezomib in treating patients with multiple myeloma | NCT00458705 | Completed | US | 2 | Induction: VDd (D = liposomal doxorubicin) Consolidation: VTd or Td | ISS stage II or III |
| Soft-tissue plasmacytoma | ||||||
| Primary resistant myeloma, defined as unchanged or progressive disease despite 2 courses of standard treatment | ||||||
| Combination bortezomib-containing regimens in newly diagnosed patients with t(4;14)-positive multiple myeloma | NCT00570180 | Completed | CA | 2 | Induction: VDd (D = liposomal doxorubicin) | t(4;14) |
| ASCT | ||||||
| Consolidation: CV prednisolone | ||||||
| Maintenance: prednisolone | ||||||
| Celgene high-risk multiple myeloma Revlimid induction and maintenance therapy | NCT00691704 | Completed | US | 2 | Induction: Rd | Deletion of chromosome 13 by cytogenetics |
| Del(17p) by FISH or metaphase analysis | ||||||
| FISH detection of t(4;14), t(14;16), t(8;14), or t(14;20) | ||||||
| Hypodiploidy detected by FISH or metaphase analysis | ||||||
| Sequential maintenance: bortezomib, M-prednisolone, lenalidomide | Any complex cytogenetic abnormality detected by cytogenetics, with the exception of hyperdiploidy | |||||
| Vismodegib after stem cell transplant in treating patients with high-risk first remission or relapsed multiple myeloma | NCT01330173 | Completed | US | 1 | Vismodegib (hedgehog inhibitor) after ASCT | Del(13), t(4;14), t(14;16), or del(17p); β2-microglobulin >5.5 g/dL IgA phenotype |
As per a www.clinicaltrials.gov search for “high-risk myeloma” and including studies where the high-risk definition was included.
M, melphalan; V, bortezomib; T, thalidomide; d, dexamethasone; PACE, 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide; ASCT, autologous stem cell transplant; Mel80, melphalan 20 mg/m2/day × 4 days; R, lenalidomide, Mel20, melphalan 5 mg/m2/day × 4 days; K, carfilzomib; Dara, daratumumab; C, cyclophosphamide; TE, transplant eligible; TNE, transplant ineligible; IULN, institutional upper limit of normal; VAD, vincristine, doxorubicin, dexamethasone; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; VGPR, very good partial response.