B. Dhakal, M. Hultcrantz, N. Nathwani, C. P. Venner, J. Lu, M. J. Slade, J. L. Kaufman, H. Chuah, C. Min, K. Kim, H. Cheng, A. Idoine, W. Zhang, X. Wang, A. Agarwal, H. Quach
{"title":"sonrotoclax +地塞米松治疗t（11;14）阳性复发/难治性多发性骨髓瘤（r / r mm）患者的最新中期结果：全口服治疗","authors":"B. Dhakal, M. Hultcrantz, N. Nathwani, C. P. Venner, J. Lu, M. J. Slade, J. L. Kaufman, H. Chuah, C. Min, K. Kim, H. Cheng, A. Idoine, W. Zhang, X. Wang, A. Agarwal, H. Quach","doi":"10.1002/hon.70093_123","DOIUrl":null,"url":null,"abstract":"<p><b>Introduction:</b> Despite the clinical efficacy of BCL2 inhibition in t(11;14)-positive MM, no BCL2-targeted treatments (tx) are approved. Sonrotoclax (sonro; BGB-11417), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 study of sonro as mono- or combination tx in patients (pts) with t(11;14)-positive R/R MM. Updated results in pts treated with sonro + dexamethasone (dex) are presented.</p><p><b>Methods:</b> Eligible pts had R/R MM with centrally confirmed t(11;14) and received oral sonro (320 or 640 mg QD) + dex (40 mg QW). Tx-emergent adverse events (TEAEs) were graded by CTCAE v5.0 and efficacy was assessed by the investigator per IMWG criteria.</p><p><b>Results:</b> As of January 20, 2025, 14 and 36 evaluable pts were enrolled in the sonro 320-mg and 640-mg cohorts, respectively; median (range) follow-up was 6.2 mo (2.6–34.5) and 12.1 mo (0.1–28.9), respectively. The median (range) prior lines of tx were 3 (1–7) in the 320-mg cohort and 3 (1–12) in the 640-mg cohort; 78.6% and 66.7% of pts were refractory to 3 tx classes, respectively. At data cutoff, 7 pts (50.0%) in the 320-mg cohort and 14 (38.9%) in the 640-mg cohort remained on tx; progression was the most common reason for discontinuation (35.7% and 41.7%, respectively). The ORR (95% CI) was 64.3% (35.1–87.2) in the 320-mg cohort and 80.6% (64.0–91.8) in the 640-mg cohort, with VGPR or better rates (95% CI) of 35.7% (12.8–64.9) and 55.6% (38.1–72.1), respectively (Figure). The median time to response was 0.7 mo in both cohorts. Median (95% CI) duration of response was 5.9 mo (1.8-not estimable [NE]) in the 320-mg cohort and 12.2 mo (8.3–18.9) in the 640-mg cohort. Median (95% CI) PFS was 6.6 mo (2.9-NE) in the 320-mg cohort and 13.3 mo (9.0–19.6) in the 640-mg cohort.</p><p>The most common TEAEs were fatigue (35.7%) in the 320-mg cohort, and insomnia (38.9%) and diarrhea (38.9%, all grade 1/2) in the 640-mg cohort. Grade ≥ 3 TEAEs occurred in 5 pts (35.7%) in the 320-mg cohort and 17 pts (47.2%) in the 640-mg cohort; serious TEAEs occurred in 3 (21.4%) and 10 (27.8%), respectively. Grade ≥ 3 hematologic TEAEs occurred in 1 (7.1%) and 9 (25.0%) and grade ≥ 3 infections in 3 (21.4%) and 4 (11.1%) pts, respectively. Two pts (14.3%) in the 320-mg cohort and 2 (5.6%) in the 640-mg cohort died during the tx-emergent part for reasons unrelated to tx (320 mg, pneumonia RSV and COVID-19; 640 mg, hypoventilation [related to pulmonary involvement with PD] and metastatic pancreatic cancer). Four more deaths occurred > 30 d after the last 640-mg dose.</p><p><b>Conclusions:</b> This ongoing study showed that the all-oral combination of sonro + dex is tolerable, with low rates of infection and hematologic toxicity, and promising efficacy, with an ORR of 81% in the 640-mg cohort, in this t(11;14)-positive R/R MM population. Additional tx combinations with sonro are being investigated.</p><p><b>Research</b> <b>funding declaration:</b> This study was sponsored by BeiGene, Ltd.</p><p><b>Encore Abstract:</b> EHA 2025</p><p><b>Keywords:</b> combination therapies; ongoing trials; multiple myeloma</p><p><b>Potential sources of conflict of interest:</b></p><p><b>B. Dhakal</b></p><p><b>Consultant or advisory role:</b> BMS, Janssen, Arcellx, Kite, Pfizer, Karyopharm, Genentech, Natera, Sanofi</p><p><b>Honoraria:</b> BMS, Karyopharm</p><p><b>Other remuneration:</b> Speaker's bureau: Janssen, Sanofi, Karypharm, BMS</p><p><b>M. Hultcrantz</b></p><p><b>Consultant or advisory role:</b> BMS, Johnson & Johnson</p><p><b>Other remuneration:</b> Research funding: GSK, AbbVie, BeiGene, Daiichi Sankyo</p><p><b>C. P. Venner</b></p><p><b>Honoraria:</b> Forus, AbbVie, Pfizer, Johnson & Johnson, Amgen, Sanofi</p><p><b>M. J. Slade</b></p><p><b>Honoraria:</b> Menarini Silicon Biosystems</p><p><b>Other remuneration:</b> Research funding: Pfizer</p><p><b>J. L. Kaufman</b></p><p><b>Consultant or advisory role:</b> AbbVie, Ascentage, BMS, Genentech, Sanofi, Sebia, Incyte</p><p><b>Other remuneration:</b> Research funding: AbbVie, BeiGene, BMS, Genentech, Heidelberg Pharma AG, Janssen, Novartis, Pfizer, Takeda</p><p><b>H. Chuah</b></p><p><b>Consultant or advisory role:</b> AbbVie</p><p><b>Other remuneration:</b> Speaker's bureau: BeiGene; Travel, accommodations, expenses: Janssen</p><p><b>H. Cheng</b></p><p><b>Employment or leadership position:</b> BeiGene</p><p><b>Stock ownership:</b> BeiGene</p><p><b>A. Idoine</b></p><p><b>Employment or leadership position:</b> BeiGene</p><p><b>Stock ownership:</b> BeiGene</p><p><b>Other remuneration:</b> Travel, accommodations, expenses: BeiGene</p><p><b>W. Zhang</b></p><p><b>Employment or leadership position:</b> BeiGene</p><p><b>Stock ownership:</b> BeiGene</p><p><b>X. Wang</b></p><p><b>Employment or leadership position:</b> BeiGene</p><p><b>Stock ownership:</b> BeiGene</p><p><b>A. Agarwal</b></p><p><b>Employment or leadership position:</b> BeiGene</p><p><b>Stock ownership:</b> BeiGene</p><p><b>H. Quach</b></p><p><b>Consultant or advisory role:</b> GSK, AbbVie, BMS, Pfizer, Johnson & Johnson, Roche</p><p><b>Other remuneration:</b> Research funding: GSK, AbbVie, BMS</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":"43 S3","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.70093_123","citationCount":"0","resultStr":"{\"title\":\"UPDATED INTERIM RESULTS OF SONROTOCLAX + DEXAMETHASONE IN PATIENTS WITH T(11;14)-POSITIVE RELAPSED/REFRACTORY MULTIPLE MYELOMA (R/R MM): AN ALL-ORAL TREATMENT\",\"authors\":\"B. Dhakal, M. Hultcrantz, N. Nathwani, C. P. Venner, J. Lu, M. J. Slade, J. L. Kaufman, H. Chuah, C. Min, K. Kim, H. Cheng, A. Idoine, W. Zhang, X. Wang, A. Agarwal, H. Quach\",\"doi\":\"10.1002/hon.70093_123\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><b>Introduction:</b> Despite the clinical efficacy of BCL2 inhibition in t(11;14)-positive MM, no BCL2-targeted treatments (tx) are approved. Sonrotoclax (sonro; BGB-11417), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 study of sonro as mono- or combination tx in patients (pts) with t(11;14)-positive R/R MM. Updated results in pts treated with sonro + dexamethasone (dex) are presented.</p><p><b>Methods:</b> Eligible pts had R/R MM with centrally confirmed t(11;14) and received oral sonro (320 or 640 mg QD) + dex (40 mg QW). Tx-emergent adverse events (TEAEs) were graded by CTCAE v5.0 and efficacy was assessed by the investigator per IMWG criteria.</p><p><b>Results:</b> As of January 20, 2025, 14 and 36 evaluable pts were enrolled in the sonro 320-mg and 640-mg cohorts, respectively; median (range) follow-up was 6.2 mo (2.6–34.5) and 12.1 mo (0.1–28.9), respectively. The median (range) prior lines of tx were 3 (1–7) in the 320-mg cohort and 3 (1–12) in the 640-mg cohort; 78.6% and 66.7% of pts were refractory to 3 tx classes, respectively. At data cutoff, 7 pts (50.0%) in the 320-mg cohort and 14 (38.9%) in the 640-mg cohort remained on tx; progression was the most common reason for discontinuation (35.7% and 41.7%, respectively). The ORR (95% CI) was 64.3% (35.1–87.2) in the 320-mg cohort and 80.6% (64.0–91.8) in the 640-mg cohort, with VGPR or better rates (95% CI) of 35.7% (12.8–64.9) and 55.6% (38.1–72.1), respectively (Figure). The median time to response was 0.7 mo in both cohorts. Median (95% CI) duration of response was 5.9 mo (1.8-not estimable [NE]) in the 320-mg cohort and 12.2 mo (8.3–18.9) in the 640-mg cohort. Median (95% CI) PFS was 6.6 mo (2.9-NE) in the 320-mg cohort and 13.3 mo (9.0–19.6) in the 640-mg cohort.</p><p>The most common TEAEs were fatigue (35.7%) in the 320-mg cohort, and insomnia (38.9%) and diarrhea (38.9%, all grade 1/2) in the 640-mg cohort. Grade ≥ 3 TEAEs occurred in 5 pts (35.7%) in the 320-mg cohort and 17 pts (47.2%) in the 640-mg cohort; serious TEAEs occurred in 3 (21.4%) and 10 (27.8%), respectively. Grade ≥ 3 hematologic TEAEs occurred in 1 (7.1%) and 9 (25.0%) and grade ≥ 3 infections in 3 (21.4%) and 4 (11.1%) pts, respectively. Two pts (14.3%) in the 320-mg cohort and 2 (5.6%) in the 640-mg cohort died during the tx-emergent part for reasons unrelated to tx (320 mg, pneumonia RSV and COVID-19; 640 mg, hypoventilation [related to pulmonary involvement with PD] and metastatic pancreatic cancer). Four more deaths occurred > 30 d after the last 640-mg dose.</p><p><b>Conclusions:</b> This ongoing study showed that the all-oral combination of sonro + dex is tolerable, with low rates of infection and hematologic toxicity, and promising efficacy, with an ORR of 81% in the 640-mg cohort, in this t(11;14)-positive R/R MM population. Additional tx combinations with sonro are being investigated.</p><p><b>Research</b> <b>funding declaration:</b> This study was sponsored by BeiGene, Ltd.</p><p><b>Encore Abstract:</b> EHA 2025</p><p><b>Keywords:</b> combination therapies; ongoing trials; multiple myeloma</p><p><b>Potential sources of conflict of interest:</b></p><p><b>B. Dhakal</b></p><p><b>Consultant or advisory role:</b> BMS, Janssen, Arcellx, Kite, Pfizer, Karyopharm, Genentech, Natera, Sanofi</p><p><b>Honoraria:</b> BMS, Karyopharm</p><p><b>Other remuneration:</b> Speaker's bureau: Janssen, Sanofi, Karypharm, BMS</p><p><b>M. Hultcrantz</b></p><p><b>Consultant or advisory role:</b> BMS, Johnson & Johnson</p><p><b>Other remuneration:</b> Research funding: GSK, AbbVie, BeiGene, Daiichi Sankyo</p><p><b>C. P. Venner</b></p><p><b>Honoraria:</b> Forus, AbbVie, Pfizer, Johnson & Johnson, Amgen, Sanofi</p><p><b>M. J. Slade</b></p><p><b>Honoraria:</b> Menarini Silicon Biosystems</p><p><b>Other remuneration:</b> Research funding: Pfizer</p><p><b>J. L. Kaufman</b></p><p><b>Consultant or advisory role:</b> AbbVie, Ascentage, BMS, Genentech, Sanofi, Sebia, Incyte</p><p><b>Other remuneration:</b> Research funding: AbbVie, BeiGene, BMS, Genentech, Heidelberg Pharma AG, Janssen, Novartis, Pfizer, Takeda</p><p><b>H. Chuah</b></p><p><b>Consultant or advisory role:</b> AbbVie</p><p><b>Other remuneration:</b> Speaker's bureau: BeiGene; Travel, accommodations, expenses: Janssen</p><p><b>H. Cheng</b></p><p><b>Employment or leadership position:</b> BeiGene</p><p><b>Stock ownership:</b> BeiGene</p><p><b>A. 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UPDATED INTERIM RESULTS OF SONROTOCLAX + DEXAMETHASONE IN PATIENTS WITH T(11;14)-POSITIVE RELAPSED/REFRACTORY MULTIPLE MYELOMA (R/R MM): AN ALL-ORAL TREATMENT
Introduction: Despite the clinical efficacy of BCL2 inhibition in t(11;14)-positive MM, no BCL2-targeted treatments (tx) are approved. Sonrotoclax (sonro; BGB-11417), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 study of sonro as mono- or combination tx in patients (pts) with t(11;14)-positive R/R MM. Updated results in pts treated with sonro + dexamethasone (dex) are presented.
Methods: Eligible pts had R/R MM with centrally confirmed t(11;14) and received oral sonro (320 or 640 mg QD) + dex (40 mg QW). Tx-emergent adverse events (TEAEs) were graded by CTCAE v5.0 and efficacy was assessed by the investigator per IMWG criteria.
Results: As of January 20, 2025, 14 and 36 evaluable pts were enrolled in the sonro 320-mg and 640-mg cohorts, respectively; median (range) follow-up was 6.2 mo (2.6–34.5) and 12.1 mo (0.1–28.9), respectively. The median (range) prior lines of tx were 3 (1–7) in the 320-mg cohort and 3 (1–12) in the 640-mg cohort; 78.6% and 66.7% of pts were refractory to 3 tx classes, respectively. At data cutoff, 7 pts (50.0%) in the 320-mg cohort and 14 (38.9%) in the 640-mg cohort remained on tx; progression was the most common reason for discontinuation (35.7% and 41.7%, respectively). The ORR (95% CI) was 64.3% (35.1–87.2) in the 320-mg cohort and 80.6% (64.0–91.8) in the 640-mg cohort, with VGPR or better rates (95% CI) of 35.7% (12.8–64.9) and 55.6% (38.1–72.1), respectively (Figure). The median time to response was 0.7 mo in both cohorts. Median (95% CI) duration of response was 5.9 mo (1.8-not estimable [NE]) in the 320-mg cohort and 12.2 mo (8.3–18.9) in the 640-mg cohort. Median (95% CI) PFS was 6.6 mo (2.9-NE) in the 320-mg cohort and 13.3 mo (9.0–19.6) in the 640-mg cohort.
The most common TEAEs were fatigue (35.7%) in the 320-mg cohort, and insomnia (38.9%) and diarrhea (38.9%, all grade 1/2) in the 640-mg cohort. Grade ≥ 3 TEAEs occurred in 5 pts (35.7%) in the 320-mg cohort and 17 pts (47.2%) in the 640-mg cohort; serious TEAEs occurred in 3 (21.4%) and 10 (27.8%), respectively. Grade ≥ 3 hematologic TEAEs occurred in 1 (7.1%) and 9 (25.0%) and grade ≥ 3 infections in 3 (21.4%) and 4 (11.1%) pts, respectively. Two pts (14.3%) in the 320-mg cohort and 2 (5.6%) in the 640-mg cohort died during the tx-emergent part for reasons unrelated to tx (320 mg, pneumonia RSV and COVID-19; 640 mg, hypoventilation [related to pulmonary involvement with PD] and metastatic pancreatic cancer). Four more deaths occurred > 30 d after the last 640-mg dose.
Conclusions: This ongoing study showed that the all-oral combination of sonro + dex is tolerable, with low rates of infection and hematologic toxicity, and promising efficacy, with an ORR of 81% in the 640-mg cohort, in this t(11;14)-positive R/R MM population. Additional tx combinations with sonro are being investigated.
Researchfunding declaration: This study was sponsored by BeiGene, Ltd.
期刊介绍：
Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged:
-Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders
-Diagnostic investigations, including imaging and laboratory assays
-Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases
-Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies
-Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems.
Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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