Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial
Abstract Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenal...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55308-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559223323852800 |
|---|---|
| author | Omar Nadeem Michelle P. Aranha Robert Redd Michael Timonian Sophie Magidson Elizabeth D. Lightbody Jean-Baptiste Alberge Luca Bertamini Ankit K. Dutta Habib El-Khoury Mark Bustoros Jacob P. Laubach Giada Bianchi Elizabeth O’Donnell Ting Wu Junko Tsuji Kenneth C. Anderson Gad Getz Lorenzo Trippa Paul G. Richardson Romanos Sklavenitis-Pistofidis Irene M. Ghobrial |
| author_facet | Omar Nadeem Michelle P. Aranha Robert Redd Michael Timonian Sophie Magidson Elizabeth D. Lightbody Jean-Baptiste Alberge Luca Bertamini Ankit K. Dutta Habib El-Khoury Mark Bustoros Jacob P. Laubach Giada Bianchi Elizabeth O’Donnell Ting Wu Junko Tsuji Kenneth C. Anderson Gad Getz Lorenzo Trippa Paul G. Richardson Romanos Sklavenitis-Pistofidis Irene M. Ghobrial |
| author_sort | Omar Nadeem |
| collection | DOAJ |
| description | Abstract Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7–NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9–NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10-5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes. |
| format | Article |
| id | doaj-art-828d7782a73e4f958d1693c3b7db4868 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-828d7782a73e4f958d1693c3b7db48682025-01-05T12:40:39ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55308-5Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trialOmar Nadeem0Michelle P. Aranha1Robert Redd2Michael Timonian3Sophie Magidson4Elizabeth D. Lightbody5Jean-Baptiste Alberge6Luca Bertamini7Ankit K. Dutta8Habib El-Khoury9Mark Bustoros10Jacob P. Laubach11Giada Bianchi12Elizabeth O’Donnell13Ting Wu14Junko Tsuji15Kenneth C. Anderson16Gad Getz17Lorenzo Trippa18Paul G. Richardson19Romanos Sklavenitis-Pistofidis20Irene M. Ghobrial21Center for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteAmyloidosis Program, Division of Hematology, Brigham and Women’s Hospital and Dana Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteBroad Institute of MIT and HarvardBroad Institute of MIT and HarvardCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteHarvard Medical SchoolDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteCenter for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer InstituteAbstract Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7–NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9–NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10-5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes.https://doi.org/10.1038/s41467-024-55308-5 |
| spellingShingle | Omar Nadeem Michelle P. Aranha Robert Redd Michael Timonian Sophie Magidson Elizabeth D. Lightbody Jean-Baptiste Alberge Luca Bertamini Ankit K. Dutta Habib El-Khoury Mark Bustoros Jacob P. Laubach Giada Bianchi Elizabeth O’Donnell Ting Wu Junko Tsuji Kenneth C. Anderson Gad Getz Lorenzo Trippa Paul G. Richardson Romanos Sklavenitis-Pistofidis Irene M. Ghobrial Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial Nature Communications |
| title | Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial |
| title_full | Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial |
| title_fullStr | Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial |
| title_full_unstemmed | Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial |
| title_short | Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial |
| title_sort | deeper response predicts better outcomes in high risk smoldering myeloma results of the i prism phase ii clinical trial |
| url | https://doi.org/10.1038/s41467-024-55308-5 |
| work_keys_str_mv | AT omarnadeem deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT michelleparanha deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT robertredd deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT michaeltimonian deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT sophiemagidson deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT elizabethdlightbody deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT jeanbaptistealberge deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT lucabertamini deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT ankitkdutta deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT habibelkhoury deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT markbustoros deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT jacobplaubach deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT giadabianchi deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT elizabethodonnell deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT tingwu deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT junkotsuji deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT kennethcanderson deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT gadgetz deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT lorenzotrippa deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT paulgrichardson deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT romanossklavenitispistofidis deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial AT irenemghobrial deeperresponsepredictsbetteroutcomesinhighrisksmolderingmyelomaresultsoftheiprismphaseiiclinicaltrial |