30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-11-05 DOI:10.1002/hem3.70041
Enrique M. Ocio, Aurore Perrot, Philippe Moreau, Maria-Victoria Mateos, Sara Bringhen, Joaquín Martínez-López, Lionel Karlin, Song-Yau Wang, Corina Oprea, Yi Li, Ercem Kodas, Jesus San-Miguel
{"title":"30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis","authors":"Enrique M. Ocio,&nbsp;Aurore Perrot,&nbsp;Philippe Moreau,&nbsp;Maria-Victoria Mateos,&nbsp;Sara Bringhen,&nbsp;Joaquín Martínez-López,&nbsp;Lionel Karlin,&nbsp;Song-Yau Wang,&nbsp;Corina Oprea,&nbsp;Yi Li,&nbsp;Ercem Kodas,&nbsp;Jesus San-Miguel","doi":"10.1002/hem3.70041","DOIUrl":null,"url":null,"abstract":"<p>The addition of an anti-CD38 antibody to standard treatment regimens, in combination with an immunomodulatory drug or a proteasome inhibitor and dexamethasone, provides benefit to multiple myeloma (MM) patients in the relapsed/refractory setting (RRMM), as well as at an earlier disease stage in quadruplet combinations for transplant-eligible or non-eligible patients with newly diagnosed MM (NDMM).<span><sup>1-3</sup></span> Isatuximab (Isa) is approved in various countries in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone for the treatment of RRMM patients.<span><sup>4-6</sup></span></p><p>Study findings in transplant-eligible NDMM patients demonstrated significant efficacy of Isa in quadruplet combinations with bortezomib-lenalidomide-dexamethasone (VRd) for induction therapy in the Phase 3 GMMG-HD7 trial (minimal residual disease [MRD] negativity: 50% with Isa-VRd vs 36% with VRd; <i>p</i> = 0.00017), and with carfilzomib-lenalidomide-dexamethasone (KRd) for induction/consolidation treatment in the Phase 3 IsKia/EMN24 trial (MRD negativity after consolidation: 77% with Isa-KRd vs 67% with KRd; <i>p</i> = 0.049), without new safety signals.<span><sup>7, 8</sup></span></p><p>In transplant-ineligible NDMM patients, significant PFS benefit (hazard ratio [HR], 0.60; 98.5% confidence interval [CI], 0.41–0.88; <i>p</i> &lt; 0.001) and deep, sustained responses were reported with Isa in combination with VRd followed by Isa-Rd versus VRd followed by Rd, in a prespecified interim analysis of the Phase 3 IMROZ trial, with a manageable safety profile.<span><sup>9</sup></span> In the Phase 3 BENEFIT trial, the addition of weekly bortezomib to Isa-Rd (reduced-dose VRd) induced a significant improvement in MRD negativity at 18 months versus Isa-Rd (53% vs. 26%, <i>p</i> &lt; 0.0001).<span><sup>10</sup></span></p><p>The evaluation of Isa with either bortezomib-cyclophosphamide-dexamethasone (VCd) or VRd has shown safety and efficacy of these quadruplet regimens in the Phase 1b trial TCD13983 (NCT02513186) in transplant-ineligible NDMM patients (all cohorts) or patients with no immediate intent for autologous stem cell transplantation included in Isa-VRd/Part-B, as previously reported.<span><sup>11, 12</sup></span></p><p>To enhance the convenience of long-term treatment with IV Isa for patients and healthcare providers, by improving the current duration of Isa infusion (75 min), we prospectively evaluated the feasibility, safety, and tolerability of a novel, fast, 30-min infusion method for Isa in patients who were on maintenance therapy in the TCD13983 study.</p><p>All patients on maintenance treatment, regardless of treatment cohort, were switched to 30-min infusion with Isa at 10 mg/kg (250-mL fixed-volume infusion). Details on study treatments before switching, premedications, and patient characteristics are provided in Supporting Information and Supporting Information S1: Figure S1. To accelerate the infusions to a target duration of 30-min, Isa 10 mg/kg diluted in a 250-mL infusion bag of 0.9% sodium chloride was administered for the first infusion at an initial 250 mL/h rate for 30 min, then at 500 mL/h for 15 min (Supporting Information S1: Table S1). In the absence of infusion reactions (IRs), subsequent infusions were to be administered at a 500 mL/h rate in ~30 min. There were no exclusion criteria for switching patients based on health status or previous IRs; however, the last Isa dose should have been administered 1 month before switching (±7 days). The study objective (secondary endpoint per protocol amendment) was to evaluate safety in terms of incidence and severity of IRs during the first 2 full 30-min Isa infusions.</p><p>Between January 2023 and January 5, 2024, 45 patients in maintenance treatment were switched to the new 30-min infusion method: 4 in Isa-VCd, 13 in Isa-VRd/Part-A, and 28 in Isa-VRd/Part-B. At the time of this analysis (last patient last visit, January 22, 2024), median follow-up was 71.1 months in the Isa-VCd cohorts (<i>n</i> = 15), 55.1 months in Isa-VRd/Part-A (<i>n</i> = 26), and 38.1 months in Isa-VRd/Part-B (<i>n</i> = 45), with a median duration of overall treatment exposure of 63.3 (range, 0.2–87.2), 53.9 (0.2–79.5), and 41.5 months (1.4–49.4), respectively.</p><p>During the evaluation period, 210 fast infusions were administered to the 45 patients switched across cohorts: 45 first infusions with the intermediate rate (starting at 250 mL/h for 30 min then 500 mL/h for 15 min) and 165 subsequent infusions at the fast rate (500 mL/h) (Supporting Information S1: Table S2). By data cut-off, the median number of 30-min infusion cycles was 4 (range, 2–11); 45 patients received the first intermediate-rate infusion and a first 30-min infusion; 44 patients received ≥2 30-min infusions, with a median duration of exposure after switch of 16 weeks (8.0–46.1). Switching occurred at a median of 45 cycles (38–88) for all 45 patients, with a median of 80, 64, and 41 cycles in the Isa-VCd, Isa-VRd/Part-A, and Isa-VRd/Part-B cohorts, respectively (Supporting Information S1: Table S3).</p><p>With the new fast procedure, the median duration of Isa infusion in all switched patients was 49 min at the first infusion (intermediate rate; 31–67), 32 min at the second infusion (30–75), 32 min at third infusion (30–80), and 30 min at subsequent infusions (23–75) across the Isa-VCd, Isa-VRd/Part-A, and Isa-VRd/Part-B cohorts (Table 1). The median relative dose intensity for Isa after the switch was 99.7% (52.6%–105.0%).</p><p>30-min infusion of Isa was well tolerated as only 1 of the 45 (2.2%) patients switched to the new method (0.5% of all fast-infusion cycles) had an IR (grade 2, in Isa-VRd/Part-A), who recovered within the same day with interruption of the infusion and steroid therapy (Table 2). Study treatment had been held for 5 months in this patient, after 3 full fast infusions, while awaiting cholelithiasis surgery and then recovering from the surgery. Treatment was restarted with Isa infusion directly at the 500 mL/h rate and the IR occurred near the end of the infusion (30 min after start). Afterward, this patient entered the long-term safety study and received one full fast Isa infusion without IRs. Although only one IR was observed in this analysis, it suggests that after a period of time without Isa infusion, it is preferable to restart treatment at the intermediate infusion rate (250 mL/h for 30 min followed by 500 mL/h for 15 min), rather than directly at 500 mL/h.</p><p>No dose delays or dose omissions occurred during treatment across all study cohorts. IR premedications received by the switched patients are listed in Supporting Information S1: Table S4. All patients received diphenhydramine or equivalent and 95.6% received acetaminophen/paracetamol at the first infusion; 48.9%, 44.4%, and 31.8% of switched patients received montelukast at the first, second, and third infusion, respectively.</p><p>Overall, since the study started, in Isa-VCd, Isa-VRd/Part-A, and Isa-VRd/Part-B, 41.2%, 14.8%, and 10.9%, of patients definitively discontinued treatment due to progressive disease, and 29.4%, 33.3%, and 17.4%, respectively, due to AEs (Supporting Information S1: Table S5). After switching to fast, 30-min infusion during maintenance, 0%, 0%, and 3.6% (<i>n</i> = 1) of patients definitively discontinued treatment due to progressive disease, and 0%, 15.4% (<i>n</i> = 2), and 0%, respectively, due to AEs (Supporting Information S1: Table S5).</p><p>Overall, the most common AEs reported in the maintenance phase were arthralgia, hypertension, and upper respiratory tract infection (41.2% each; 7/17) in the Isa-VCd cohort and diarrhea in the Isa-VRd/Part-A (59.3%; 16/27) and Isa-VRd/Part-B cohorts (56.5%; 26/46). After the switch to 30-min infusion, the most common AEs were upper respiratory tract infection in Isa-VCd (50.0%; 2/4) and diarrhea in Isa-VRd/Part-A (38.5%; 5/13) and Isa-VRd/Part-B (10.7%; 3/28).</p><p>The results of this prospective clinical trial analysis show that 30-min infusion is a feasible and well-tolerated option for IV Isa administration in patients who have been on long-term treatment with Isa. Although the time at which patients were switched to the 30-min infusions was shorter in Isa-VRd/Part-B (41 cycles) compared with the Isa-VRd/Part-A (64 cycles) and Isa-VCd (80 cycles) cohorts, due to sequential cohort initiation, no differences were observed in tolerability and incidence of IRs between the Isa-VRd/Part-B and Isa-VCd cohorts. Reports from other, prior studies to improve IV administration of anti-CD38 therapy did not show safety challenges in RRMM patients.<span><sup>13, 14</sup></span></p><p>Although the open-label design represents a limitation, the results of this prespecified, prospective analysis on the feasibility of switching to the new 30-min, fixed-volume Isa infusion method and particularly its tolerability were consistent across the cohorts evaluated in this study throughout several administrations. These findings suggest that MM patients could switch to fast, 30-min Isa infusion after prior fixed-volume infusions, thus deriving benefit from the increased convenience and time savings (Supporting Information S1: Figure S2) in settings where subcutaneous treatment may not be available or IV infusion is the preferred delivery route.</p><p>While these results were obtained in NDMM patients on long-term treatment, 30-min Isa infusion is currently being evaluated in the Phase 2 UMBRELLA trial (NCT04643002) to assess the switch to fast infusion from an earlier timepoint in RRMM patients. Furthermore, in addition to the 30-min infusion, subcutaneous administration of Isa by an on-body delivery system is being evaluated in Phase 3 trials in RRMM (IRAKLIA, NCT05405166) and NDMM patients (GMMG-HD8/HD9, NCT05804032/NCT06216158) and other Phase 2 studies, as an alternative, convenient option for Isa treatment delivery.</p><p>Fast, 30-min Isa administration will benefit patients across the MM therapeutic spectrum, in both the newly diagnosed and relapsed/refractory settings, with substantial time savings (Supporting Information S1: Figure S2). As this new infusion method reduces the length of the clinical visits associated with Isa administration, it offers more convenience to patients on a routine basis with improved quality of life and efficiencies in hospital care delivery.</p><p>In conclusion, reducing the overall duration of Isa infusion from 75 to 30 min with the new method, which is 2.5 times faster, is feasible, safe, and well tolerated, thereby facilitating IV administration in clinical practice and resulting in time savings for MM patients and their healthcare providers.</p><p>Enrique M. Ocio, Aurore Perrot, Philippe Moreau, Maria-Victoria Mateos, Corina Oprea, Ercem Kodas, and Jesus San-Miguel contributed to the study design, analyzed the data, wrote/critically revised the manuscript, and approved the final version. Sara Bringhen, Joaquín Martínez-López, Lionel Karlin, Song-Yau Wang, and Yi Li analyzed the data, critically reviewed/revised the manuscript, and approved the final version.</p><p>Enrique M. Ocio received honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Pfizer, Regeneron, Sanofi, and Takeda; disclosed consulting/advisory role for AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Menarini/Stemline Therapeutics, Oncopeptides, Pfizer, Sanofi, and Takeda, and participation in speakers' bureau for Janssen; received travel/accommodation expenses from Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Lilly. Aurore Perrot: received honoraria from AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Pfizer, Sanofi, and Takeda; research funding from Takeda; and support for attending meetings and/or travel from Amgen, Janssen. Philippe Moreau: disclosed honoraria and consulting/advisory role for AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Roche, and Sanofi. Maria-Victoria Mateos: received honoraria from AbbVie, Adaptive, Amgen, Bluebird bio, Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Sea-Gen, and Takeda, and is on the Editorial Board of <i>HemaSphere</i>. Sara Bringhen: received honoraria from Amgen, BMS/Celgene, and Janssen, and consulting fees from BMS/Celgene, Janssen, and Takeda; disclosed participation on a data safety monitoring board or advisory board for Amgen, Celgene, GSK, Janssen, Karyopharm, and Sanofi. Joaquín Martínez-López received honoraria and consulting fees from BMS/Celgene, Incyte, Janssen, Novartis, Roche, and Sanofi; travel and accommodation support from BMS, Janssen, Novartis, Roche, and Sanofi. Lionel Karlin: received honoraria from AbbVie, Amgen, Celgene, Janssen, Sanofi, and Takeda; disclosed advisory role for Amgen, Celgene, GSK, Janssen, and Takeda. Song-Yau Wang: disclosed no conflicts. Corina Oprea, Yi Li, and Ercem Kodas are employed by Sanofi and may hold stock and/or stock options in the company. Jesus San-Miguel: received honoraria and consulting fees from Amgen, BMS/Celgene, GSK, Janssen, Karyopharma, Sanofi, and Takeda.</p><p>This study was funded by Sanofi.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538320/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"HemaSphere","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/hem3.70041","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The addition of an anti-CD38 antibody to standard treatment regimens, in combination with an immunomodulatory drug or a proteasome inhibitor and dexamethasone, provides benefit to multiple myeloma (MM) patients in the relapsed/refractory setting (RRMM), as well as at an earlier disease stage in quadruplet combinations for transplant-eligible or non-eligible patients with newly diagnosed MM (NDMM).1-3 Isatuximab (Isa) is approved in various countries in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone for the treatment of RRMM patients.4-6

Study findings in transplant-eligible NDMM patients demonstrated significant efficacy of Isa in quadruplet combinations with bortezomib-lenalidomide-dexamethasone (VRd) for induction therapy in the Phase 3 GMMG-HD7 trial (minimal residual disease [MRD] negativity: 50% with Isa-VRd vs 36% with VRd; p = 0.00017), and with carfilzomib-lenalidomide-dexamethasone (KRd) for induction/consolidation treatment in the Phase 3 IsKia/EMN24 trial (MRD negativity after consolidation: 77% with Isa-KRd vs 67% with KRd; p = 0.049), without new safety signals.7, 8

In transplant-ineligible NDMM patients, significant PFS benefit (hazard ratio [HR], 0.60; 98.5% confidence interval [CI], 0.41–0.88; p < 0.001) and deep, sustained responses were reported with Isa in combination with VRd followed by Isa-Rd versus VRd followed by Rd, in a prespecified interim analysis of the Phase 3 IMROZ trial, with a manageable safety profile.9 In the Phase 3 BENEFIT trial, the addition of weekly bortezomib to Isa-Rd (reduced-dose VRd) induced a significant improvement in MRD negativity at 18 months versus Isa-Rd (53% vs. 26%, p < 0.0001).10

The evaluation of Isa with either bortezomib-cyclophosphamide-dexamethasone (VCd) or VRd has shown safety and efficacy of these quadruplet regimens in the Phase 1b trial TCD13983 (NCT02513186) in transplant-ineligible NDMM patients (all cohorts) or patients with no immediate intent for autologous stem cell transplantation included in Isa-VRd/Part-B, as previously reported.11, 12

To enhance the convenience of long-term treatment with IV Isa for patients and healthcare providers, by improving the current duration of Isa infusion (75 min), we prospectively evaluated the feasibility, safety, and tolerability of a novel, fast, 30-min infusion method for Isa in patients who were on maintenance therapy in the TCD13983 study.

All patients on maintenance treatment, regardless of treatment cohort, were switched to 30-min infusion with Isa at 10 mg/kg (250-mL fixed-volume infusion). Details on study treatments before switching, premedications, and patient characteristics are provided in Supporting Information and Supporting Information S1: Figure S1. To accelerate the infusions to a target duration of 30-min, Isa 10 mg/kg diluted in a 250-mL infusion bag of 0.9% sodium chloride was administered for the first infusion at an initial 250 mL/h rate for 30 min, then at 500 mL/h for 15 min (Supporting Information S1: Table S1). In the absence of infusion reactions (IRs), subsequent infusions were to be administered at a 500 mL/h rate in ~30 min. There were no exclusion criteria for switching patients based on health status or previous IRs; however, the last Isa dose should have been administered 1 month before switching (±7 days). The study objective (secondary endpoint per protocol amendment) was to evaluate safety in terms of incidence and severity of IRs during the first 2 full 30-min Isa infusions.

Between January 2023 and January 5, 2024, 45 patients in maintenance treatment were switched to the new 30-min infusion method: 4 in Isa-VCd, 13 in Isa-VRd/Part-A, and 28 in Isa-VRd/Part-B. At the time of this analysis (last patient last visit, January 22, 2024), median follow-up was 71.1 months in the Isa-VCd cohorts (n = 15), 55.1 months in Isa-VRd/Part-A (n = 26), and 38.1 months in Isa-VRd/Part-B (n = 45), with a median duration of overall treatment exposure of 63.3 (range, 0.2–87.2), 53.9 (0.2–79.5), and 41.5 months (1.4–49.4), respectively.

During the evaluation period, 210 fast infusions were administered to the 45 patients switched across cohorts: 45 first infusions with the intermediate rate (starting at 250 mL/h for 30 min then 500 mL/h for 15 min) and 165 subsequent infusions at the fast rate (500 mL/h) (Supporting Information S1: Table S2). By data cut-off, the median number of 30-min infusion cycles was 4 (range, 2–11); 45 patients received the first intermediate-rate infusion and a first 30-min infusion; 44 patients received ≥2 30-min infusions, with a median duration of exposure after switch of 16 weeks (8.0–46.1). Switching occurred at a median of 45 cycles (38–88) for all 45 patients, with a median of 80, 64, and 41 cycles in the Isa-VCd, Isa-VRd/Part-A, and Isa-VRd/Part-B cohorts, respectively (Supporting Information S1: Table S3).

With the new fast procedure, the median duration of Isa infusion in all switched patients was 49 min at the first infusion (intermediate rate; 31–67), 32 min at the second infusion (30–75), 32 min at third infusion (30–80), and 30 min at subsequent infusions (23–75) across the Isa-VCd, Isa-VRd/Part-A, and Isa-VRd/Part-B cohorts (Table 1). The median relative dose intensity for Isa after the switch was 99.7% (52.6%–105.0%).

30-min infusion of Isa was well tolerated as only 1 of the 45 (2.2%) patients switched to the new method (0.5% of all fast-infusion cycles) had an IR (grade 2, in Isa-VRd/Part-A), who recovered within the same day with interruption of the infusion and steroid therapy (Table 2). Study treatment had been held for 5 months in this patient, after 3 full fast infusions, while awaiting cholelithiasis surgery and then recovering from the surgery. Treatment was restarted with Isa infusion directly at the 500 mL/h rate and the IR occurred near the end of the infusion (30 min after start). Afterward, this patient entered the long-term safety study and received one full fast Isa infusion without IRs. Although only one IR was observed in this analysis, it suggests that after a period of time without Isa infusion, it is preferable to restart treatment at the intermediate infusion rate (250 mL/h for 30 min followed by 500 mL/h for 15 min), rather than directly at 500 mL/h.

No dose delays or dose omissions occurred during treatment across all study cohorts. IR premedications received by the switched patients are listed in Supporting Information S1: Table S4. All patients received diphenhydramine or equivalent and 95.6% received acetaminophen/paracetamol at the first infusion; 48.9%, 44.4%, and 31.8% of switched patients received montelukast at the first, second, and third infusion, respectively.

Overall, since the study started, in Isa-VCd, Isa-VRd/Part-A, and Isa-VRd/Part-B, 41.2%, 14.8%, and 10.9%, of patients definitively discontinued treatment due to progressive disease, and 29.4%, 33.3%, and 17.4%, respectively, due to AEs (Supporting Information S1: Table S5). After switching to fast, 30-min infusion during maintenance, 0%, 0%, and 3.6% (n = 1) of patients definitively discontinued treatment due to progressive disease, and 0%, 15.4% (n = 2), and 0%, respectively, due to AEs (Supporting Information S1: Table S5).

Overall, the most common AEs reported in the maintenance phase were arthralgia, hypertension, and upper respiratory tract infection (41.2% each; 7/17) in the Isa-VCd cohort and diarrhea in the Isa-VRd/Part-A (59.3%; 16/27) and Isa-VRd/Part-B cohorts (56.5%; 26/46). After the switch to 30-min infusion, the most common AEs were upper respiratory tract infection in Isa-VCd (50.0%; 2/4) and diarrhea in Isa-VRd/Part-A (38.5%; 5/13) and Isa-VRd/Part-B (10.7%; 3/28).

The results of this prospective clinical trial analysis show that 30-min infusion is a feasible and well-tolerated option for IV Isa administration in patients who have been on long-term treatment with Isa. Although the time at which patients were switched to the 30-min infusions was shorter in Isa-VRd/Part-B (41 cycles) compared with the Isa-VRd/Part-A (64 cycles) and Isa-VCd (80 cycles) cohorts, due to sequential cohort initiation, no differences were observed in tolerability and incidence of IRs between the Isa-VRd/Part-B and Isa-VCd cohorts. Reports from other, prior studies to improve IV administration of anti-CD38 therapy did not show safety challenges in RRMM patients.13, 14

Although the open-label design represents a limitation, the results of this prespecified, prospective analysis on the feasibility of switching to the new 30-min, fixed-volume Isa infusion method and particularly its tolerability were consistent across the cohorts evaluated in this study throughout several administrations. These findings suggest that MM patients could switch to fast, 30-min Isa infusion after prior fixed-volume infusions, thus deriving benefit from the increased convenience and time savings (Supporting Information S1: Figure S2) in settings where subcutaneous treatment may not be available or IV infusion is the preferred delivery route.

While these results were obtained in NDMM patients on long-term treatment, 30-min Isa infusion is currently being evaluated in the Phase 2 UMBRELLA trial (NCT04643002) to assess the switch to fast infusion from an earlier timepoint in RRMM patients. Furthermore, in addition to the 30-min infusion, subcutaneous administration of Isa by an on-body delivery system is being evaluated in Phase 3 trials in RRMM (IRAKLIA, NCT05405166) and NDMM patients (GMMG-HD8/HD9, NCT05804032/NCT06216158) and other Phase 2 studies, as an alternative, convenient option for Isa treatment delivery.

Fast, 30-min Isa administration will benefit patients across the MM therapeutic spectrum, in both the newly diagnosed and relapsed/refractory settings, with substantial time savings (Supporting Information S1: Figure S2). As this new infusion method reduces the length of the clinical visits associated with Isa administration, it offers more convenience to patients on a routine basis with improved quality of life and efficiencies in hospital care delivery.

In conclusion, reducing the overall duration of Isa infusion from 75 to 30 min with the new method, which is 2.5 times faster, is feasible, safe, and well tolerated, thereby facilitating IV administration in clinical practice and resulting in time savings for MM patients and their healthcare providers.

Enrique M. Ocio, Aurore Perrot, Philippe Moreau, Maria-Victoria Mateos, Corina Oprea, Ercem Kodas, and Jesus San-Miguel contributed to the study design, analyzed the data, wrote/critically revised the manuscript, and approved the final version. Sara Bringhen, Joaquín Martínez-López, Lionel Karlin, Song-Yau Wang, and Yi Li analyzed the data, critically reviewed/revised the manuscript, and approved the final version.

Enrique M. Ocio received honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Pfizer, Regeneron, Sanofi, and Takeda; disclosed consulting/advisory role for AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Menarini/Stemline Therapeutics, Oncopeptides, Pfizer, Sanofi, and Takeda, and participation in speakers' bureau for Janssen; received travel/accommodation expenses from Bristol Myers Squibb, GlaxoSmithKline, Janssen, and Lilly. Aurore Perrot: received honoraria from AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Pfizer, Sanofi, and Takeda; research funding from Takeda; and support for attending meetings and/or travel from Amgen, Janssen. Philippe Moreau: disclosed honoraria and consulting/advisory role for AbbVie, Amgen, Celgene, Janssen, Oncopeptides, Roche, and Sanofi. Maria-Victoria Mateos: received honoraria from AbbVie, Adaptive, Amgen, Bluebird bio, Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Sea-Gen, and Takeda, and is on the Editorial Board of HemaSphere. Sara Bringhen: received honoraria from Amgen, BMS/Celgene, and Janssen, and consulting fees from BMS/Celgene, Janssen, and Takeda; disclosed participation on a data safety monitoring board or advisory board for Amgen, Celgene, GSK, Janssen, Karyopharm, and Sanofi. Joaquín Martínez-López received honoraria and consulting fees from BMS/Celgene, Incyte, Janssen, Novartis, Roche, and Sanofi; travel and accommodation support from BMS, Janssen, Novartis, Roche, and Sanofi. Lionel Karlin: received honoraria from AbbVie, Amgen, Celgene, Janssen, Sanofi, and Takeda; disclosed advisory role for Amgen, Celgene, GSK, Janssen, and Takeda. Song-Yau Wang: disclosed no conflicts. Corina Oprea, Yi Li, and Ercem Kodas are employed by Sanofi and may hold stock and/or stock options in the company. Jesus San-Miguel: received honoraria and consulting fees from Amgen, BMS/Celgene, GSK, Janssen, Karyopharma, Sanofi, and Takeda.

This study was funded by Sanofi.

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对新诊断的多发性骨髓瘤患者进行 30 分钟伊沙妥昔单抗输注:1b期研究分析结果。
在标准治疗方案中加入抗CD38抗体,与免疫调节药物或蛋白酶体抑制剂和地塞米松联合使用,可使复发/难治性多发性骨髓瘤(MM)患者获益,也可使符合移植条件或不符合移植条件的新诊断MM(NDMM)患者在四联疗法的早期疾病阶段获益。1-3 伊沙妥昔单抗(Isa)与泊马度胺-地塞米松或卡非佐米-地塞米松联合治疗 RRMM 患者已在多个国家获得批准。对符合移植条件的 NDMM 患者进行的研究结果表明,在 GMMG-HD7 3 期试验中,Isa 与硼替佐米-来那度胺-地塞米松(VRd)四联用进行诱导治疗具有显著疗效(最小残留病[MRD]阴性率:Isa-VRd 为 50%,VRd 为 36%;P = 0.00017),以及在 IsKia/EMN24 3 期试验中使用卡非佐米-来那度胺-地塞米松(KRd)进行诱导/巩固治疗(巩固治疗后 MRD 阴性:Isa-KRd 77% vs VRd 36%;P = 0:Isa-KRd为77%,KRd为67%;p = 0.049),没有出现新的安全性信号、8 在 IMROZ 3 期试验的预设中期分析中,符合移植条件的 NDMM 患者使用 Isa 联合 VRd 后再使用 Isa-Rd 与 VRd 后再使用 Rd 相比,获得了显著的 PFS 益处(危险比 [HR],0.60;98.5% 置信区间 [CI],0.41-0.88;p &lt; 0.001)和深度、持续的应答,且安全性可控。在 3 期 BENEFIT 试验中,Isa-Rd(减量 VRd)与 Isa-Rd 相比,在 18 个月时每周添加硼替佐米可显著改善 MRD 阴性率(53% 对 26%,p &lt; 0.0001)。10 在TCD13983(NCT02513186)的1b期试验中,对Isa与硼替佐米-环磷酰胺-地塞米松(VCd)或VRd联合治疗不符合移植条件的NDMM患者(所有组别)或Isa-VRd/Part-B中无立即进行自体干细胞移植意向的患者进行了评估,结果显示这些四联疗法具有安全性和有效性、12为了提高患者和医护人员长期静脉输注Isa治疗的便利性,改善目前Isa输注的持续时间(75分钟),我们对TCD13983研究中正在接受维持治疗的患者采用30分钟快速输注Isa的新型方法的可行性、安全性和耐受性进行了前瞻性评估。所有接受维持治疗的患者,无论治疗队列如何,均改用30分钟输注10 mg/kg的Isa(250 mL固定容量输注)。有关切换前的研究治疗、预处理和患者特征的详细信息,请参阅《佐证资料》和《佐证资料 S1:图 S1》。为了加快输液速度,使目标输液时间达到 30 分钟,第一次输液时将伊萨 10 mg/kg 稀释在 250 毫升的 0.9% 氯化钠输液袋中,以 250 毫升/小时的速度输注 30 分钟,然后以 500 毫升/小时的速度输注 15 分钟(佐证资料 S1:表 S1)。如果没有出现输液反应(IR),随后的输液将在约 30 分钟内以 500 毫升/小时的速度进行。没有基于健康状况或既往输注反应的患者转换排除标准;但是,最后一次 Isa 剂量应在转换前 1 个月(±7 天)给药。2023 年 1 月至 2024 年 1 月 5 日期间,45 名接受维持治疗的患者改用了新的 30 分钟输注方法:在 2023 年 1 月至 2024 年 1 月 5 日期间,45 名接受维持治疗的患者改用了新的 30 分钟输注方法:4 人接受 Isa-VCd,13 人接受 Isa-VRd/Part-A ,28 人接受 Isa-VRd/Part-B 。在进行本分析时(最后一名患者的最后一次就诊时间为 2024 年 1 月 22 日),Isa-VCd 组群的中位随访时间为 71.1 个月(n = 15),Isa-VRd/Part-A 组群的中位随访时间为 55.1 个月(n = 26),Isa-VRd/Part-B 组群的中位随访时间为 38.1 个月。在评估期间,45名患者在不同组别间进行了210次快速输注:45例首次输注采用中速输注(从250毫升/小时开始,持续30分钟,然后500毫升/小时,持续15分钟),165例后续输注采用快速输注(500毫升/小时)(佐证资料S1:表S2)。数据截止时,30 分钟输注周期的中位数为 4 次(范围为 2-11);45 名患者接受了首次中速输注和首次 30 分钟输注;44 名患者接受了≥2 次 30 分钟输注,切换后的中位暴露持续时间为 16 周(8.0-46.1)。所有 45 例患者的中位转换周期为 45 个周期(38-88),Isa-VCd、Isa-VRd/Part-A 和 Isa-VRd/Part-B 组的中位转换周期分别为 80、64 和 41 个周期(佐证资料 S1:表 S3)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
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