Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial

Moreau, Philippe; Dimopoulos, Meletios-Athanasios; Mıkhael, Joseph; Yong, Kwee; Capra, Marcelo; Facon, Thierry; Hájek, Roman; Špıčka, Ivan; Baker, Ross; Kım, Kihyun; Martínez, Gracia; Min, Chang‐Ki; Pour, Luděk; Leleu, Xavier; Oriol, Albert; Koh, Youngil; Suzuki, Kenshi; Risse, Marie‐Laure; Asset, Gaëlle; Macé, Sandrine; Martin, Thomas G.

doi:10.1016/s0140-6736(21)00592-4

Cited by 207 publications

(253 citation statements)

References 26 publications

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“…The indirect Coombs test was positive in 68% and 63% of the tested isatuximab-treated patients in the phase III studies in patients with RRMM (ICARIA-MM) or relapsed or refractory MM (IKEMA) (Sect. 4 ) [ 17 , 28 , 29 ].…”

Section: Pharmacodynamic Properties Of Isatuximabmentioning

confidence: 99%

“…To be eligible for inclusion in IKEMA, adults with relapsed or refractory MM had to have measurable disease and to have received 1–3 prior lines of therapy, including IMiDs and PIs. Ineligible patients included those previously treated with carfilzomib, those refractory to prior anti-CD38 mAb therapy, and those with primary refractory disease [ 16 , 29 , 32 ].…”

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

“…Randomization to isatuximab–carfilzomib–dexamethasone ( n = 179) or carfilzomib–dexamethasone alone ( n = 123) was stratified according to the number of prior lines of therapy (1 vs > 1) and disease stage (Revised-ISS I or II vs III vs not classified) [ 29 , 32 ]. As in ICARIA-MM (Sect.…”

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

“…Based partly on the results of an ongoing phase 1b study [ 44 ], patients in the isatuximab arm received IV isatuximab 10 mg/kg weekly for 4 weeks and then every 2 weeks; patients in both arms received IV carfilzomib twice weekly for the first 3 weeks of each cycle (20 mg/m 2 on days 1 and 2 of cycle 1; 56 mg/m 2 on days 8, 9, 15 and 16 of cycle 1 and thereafter) and dexamethasone 20 mg twice weekly (on days 1, 2, 8, 9, 15, 16, 22 and 23 of each cycle; IV on days of isatuximab and/or carfilzomib infusions; orally on other days) [ 29 , 32 ]. All patients were premedicated prior to isatuximab and/or carfilzomib infusions; the premedication regimen included the dexamethasone component of carfilzomib–dexamethasone [ 29 , 32 ]. Treatment continued until disease progression, unacceptable toxicity or patient choice [ 29 , 32 ].…”

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

“…All patients were premedicated prior to isatuximab and/or carfilzomib infusions; the premedication regimen included the dexamethasone component of carfilzomib–dexamethasone [ 29 , 32 ]. Treatment continued until disease progression, unacceptable toxicity or patient choice [ 29 , 32 ].…”

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

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Isatuximab: A Review of Its Use in Multiple Myeloma

Frampton

2021

Targ Oncol

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Isatuximab (Sarclisa ® ; isatuximab-irfc in the USA) is an anti-CD38 monoclonal antibody (mAb) approved for use in the treatment of adults with multiple myeloma (MM): in combination with pomalidomide and dexamethasone for those with relapsed and refractory MM (RRMM) who have received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor; and in combination with carfilzomib and dexamethasone for those with relapsed MM who have received ≥ 1 prior therapy. In phase III studies, the addition of isatuximab to pomalidomide and dexamethasone significantly prolonged progression-free survival (PFS) and improved the depth of tumour response in patients with RRMM, as did the addition of isatuximab to carfilzomib and dexamethasone in patients with relapsed or refractory MM. Health-related quality of life was maintained when isatuximab was combined with these other therapies. Isatuximab-based combination therapies were generally well tolerated and demonstrated a manageable safety profile with no new safety signals. Although mature overall survival data are awaited, available evidence indicates that the combinations of isatuximab with pomalidomide and dexamethasone and isatuximab with carfilzomib and dexamethasone are important additional treatment options for RRMM and relapsed MM, respectively. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00827-0.

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Section: Pharmacodynamic Properties Of Isatuximabmentioning

confidence: 99%

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

Section: Therapeutic Efficacy Of Isatuximabmentioning

confidence: 99%

See 3 more Smart Citations

Isatuximab: A Review of Its Use in Multiple Myeloma

Frampton

2021

Targ Oncol

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Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

Patel,

Ivanov,

Jocelyn

et al. 2024

JAMA Netw Open

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ImportancePublished research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms.ObjectiveTo evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications.Evidence ReviewAll issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting.FindingsNinety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P &lt; .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01).Conclusions and RelevanceIn this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.

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Monoclonal Antibody and Targeted Toxin Therapy

Bast¹,

Zalutsky²

2022

Holland‐Frei Cancer Medicine

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Overview Monoclonal antibodies have impacted significantly on the care of patients with cancer. Overall, the US FDA has approved 100 different monoclonal antibodies for the treatment of human diseases. More than 40 monoclonal antibodies, cytotoxic drug conjugates, radionuclide conjugates, and targeted toxins have been approved for the treatment of more than two dozen different malignancies. Useful monoclonal antibodies have most frequently targeted structural proteins and receptors on the cancer cell surface (CD20 by rituximab, HER2 by trastuzumab, and pertuzumab), inhibiting growth, inducing apoptosis, and enhancing chemotherapy, but some have targeted cytokines (IL‐6 by siltuximab), growth factors (vascular endothelial growth factor (VEGF) by bevacizumab), and growth factor receptors (VEGFR2 by ramucirumab) that affect both cancer cells and normal stromal cells including endothelial cells and lymphocytes. Monoclonal antibodies have disrupted checkpoint inhibition of effector T lymphocytes by blocking CTLA4 (ipilimumab), PD1 (pembrolizumab, nivolumab, and cemiplimab), and PD‐L1 (atezolizumab, durvalumab, and avelumab). In the case of trastuzumab and pertuzumab, binding of the two antibodies to different sites on the HER2 cell surface receptor has produced greater antitumor activity than either alone. Enhanced cancer cell killing has also been achieved by conjugation of antibodies with cytotoxic drugs (emtansine to anti‐HER2 trastuzumab and vedotin to anti‐CD30 brentuximab) or radionuclide conjugates ( 90 Y to anti‐CD20 ibritumomab tiuxetan) permitting effective treatment of patients who had failed therapy with unconjugated antibodies. There are several barriers to effective therapy with monoclonal antibodies including antigen specificity, antigenic modulation, heterogeneity of antigen expression, effective delivery of antibodies to cancer cells, potency of effector mechanisms, and response to immunologically foreign globulin. The latter problem has been circumvented with the use of chimeric constructs, humanization of murine antibodies, and developing genetically engineered mice with the ability to develop fully human antibodies. Use of unconjugated antibodies is likely to improve as our knowledge of tumor biology and immunology grows, identifying targets such as OX‐40 ligand. Use of smaller molecularly engineered binding constructs may improve pharmacokinetics and pharmacodynamics of monoclonal antibody and conjugate therapy. Combinations of antibodies may be required to compensate for antigenic heterogeneity. Development of more effective antibody–drug conjugates will require the identification of monoclonal reagents that target tumor‐initiating stem cells. Use of antibody fragments, pretargeting, and the use of alpha‐emitters are promising approaches to improving antibody–radionuclide conjugates. Development of targeted toxins must be further explored.

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Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial

Cited by 207 publications

References 26 publications

Isatuximab: A Review of Its Use in Multiple Myeloma

Isatuximab: A Review of Its Use in Multiple Myeloma

Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

Monoclonal Antibody and Targeted Toxin Therapy

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