Evaluating Isatuximab Interference with Monoclonal Protein Detection By Immuno-Capture and Liquid Chromatography Coupled to High Resolution Mass Spectrometry in the Pivotal Phase 3 Multiple Myeloma Trial, Icaria-MM

Finn, Greg; Macé, Sandrine; Campana, Frank; Le-Guennec, Solenn; Muccio, Stephané; Tavernier, Alexandra; Rouchon, Marie-Claude; Roccon, Alain; Dai, Shujia; Boutet, Valérie; Mouret, Dominique; Pradeilles, Béatrice; Hugla, Sébastien; Engelvin, Graziella; DiNoto, Deborah; Velde, Helgi van de; Fedeli, Olivier

doi:10.1182/blood-2019-129963

Cited by 8 publications

(4 citation statements)

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“…Various other assays are being developed for isatuximab since obviously all MoAbs share this ability to interfere. Mass spectrometry has been a successfully used method to distinguish isatuximab from original M-protein [ 79 ].…”

Section: Anti-cd38 Monoclonal Antibodiesmentioning

confidence: 99%

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Radocha

Donk

Weisel

2021

Cancers

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Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as relapsed and refractory multiple myeloma patients. In this respect, the incorporation of monoclonal antibodies into standard-of-care regimens markedly improved prognosis of myeloma patients during the last years. More specifically, monoclonal anti-CD38 antibodies, daratumumab and isatuximab, have been implemented into treatment strategies from first-line treatment to refractory disease. In addition, the monoclonal anti-SLAM-F7 antibody elotuzumab in combination with immunomodulatory drugs has improved the clinical outcomes of patients with relapsed/refractory disease. Belantamab mafodotin is the first approved antibody drug conjugate directed against B cell maturation antigen and is currently used as a monotherapy for patients with advanced disease. This review focuses on clinical efficacy and safety of monoclonal antibodies as well as antibody drug conjugates in multiple myeloma.

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Section: Anti-cd38 Monoclonal Antibodiesmentioning

confidence: 99%

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Radocha

Donk

Weisel

2021

Cancers

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“…Based on a threshold of 250 μg/mL for IFE positivity (sensitivity threshold of IFE test per Covance central lab), 11 out of 22 patients with a very good partial response (VGPR), according to the International Myeloma Working Group criteria for the diagnosis of MM, were identified as having M-protein levels below this threshold; this suggests that true complete response (CR) in the Isa-Pd arm was underestimated by approximately 7% due to interference with isatuximab . Interestingly, M-protein interference mediated by isatuximab, an IgG kappa mAb, was predominantly observed in patients with the IgG isotype (mainly IgG kappa) and in patients in whom a detectable IgG heavy chain could not be identified.…”

Section: Results and Discussionmentioning

confidence: 99%

Validated Method Based on Immunocapture and Liquid Chromatography Coupled to High-Resolution Mass Spectrometry to Eliminate Isatuximab Interference with M-Protein Measurement in Serum

et al. 2021

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In multiple myeloma (MM) disease, malignant plasma cells produce excessive quantities of a monoclonal immunoglobulin (Ig), known as M-protein. M-protein levels are measured in the serum of patients with MM using electrophoresis techniques to determine the response to treatment. However, therapeutic monoclonal antibodies, such as isatuximab, may confound signals using electrophoresis assays. We developed a robust assay based on immunocapture and liquid chromatography coupled to high-resolution mass spectrometry (IC-HPLC-HRMS) in order to eliminate this interference. Following immunocapture of Ig and free light chains (LC) in serum, heavy chains (HC) and LC were dissociated using dithiothreitol, sorted by liquid chromatography and analyzed using HRMS (Q-Orbitrap). This method allowed the M-proteins to be characterized and the signals from isatuximab and M-proteins to be discriminated. As Mprotein is specific to each patient, no standards were available for absolute quantification. We therefore used alemtuzumab (an IgG kappa mAb) as a surrogate analyte for the semiquantification of M-protein in serum. This assay was successfully validated in terms of selectivity/specificity, accuracy/precision, robustness, dilution linearity, and matrix variability from 10.0 to 200 μg/mL in human serum. This method was used for clinical assessment of samples and eliminated potential interference due to isatuximab when monitoring patients with MM.

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“… 31, 32 Consequently, more sensitive and specific assays have been introduced to detect M-protein. 33, 34, 35, 36, 37 An isatuximab-specific antibody-capture assay to mitigate M-protein interference on immunofixation is now Conformité Européenne marked in the European Union, US Food and Drug Administration 510(k) approved, 38 and submitted for regulatory clearance in other regions. 39 However, at the time of the interim analysis of the IKEMA study, the isatuximab-specific assay was not available for use; therefore, M-protein interference was analyzed through high-resolution mass spectrometry, preceded by immuno-capture and liquid chromatography.…”

Section: Discussionmentioning

confidence: 99%

Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma

et al. 2022

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The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10−5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd.

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Evaluating Isatuximab Interference with Monoclonal Protein Detection By Immuno-Capture and Liquid Chromatography Coupled to High Resolution Mass Spectrometry in the Pivotal Phase 3 Multiple Myeloma Trial, Icaria-MM

Cited by 8 publications

References 0 publications

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Validated Method Based on Immunocapture and Liquid Chromatography Coupled to High-Resolution Mass Spectrometry to Eliminate Isatuximab Interference with M-Protein Measurement in Serum

Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma

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