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Monitoring Multiple Myeloma Patients Treated with Daratumumab: Teasing out Monoclonal Antibody Interference

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Monitoring Multiple Myeloma Patients Treated with Daratumumab: Teasing out Monoclonal Antibody Interference Clin Chem Lab Med 2016; 54(6): 1095–1104 Open Access Christopher McCuddena, Amy E. Axela, Dominique Slaets, Thomas Dejoie, Pamela L. Clemens, Sandy Frans, Jaime Bald, Torben Plesner, Joannes F.M. Jacobs, Niels W.C.J. van de Donk, Philippe Moreau, Jordan M. Schecter, Tahamtan Ahmadi and A. Kate Sasser* Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference DOI 10.1515/cclm-2015-1031 developed using a mouse anti-daratumumab antibody. To Received October 21, 2015; accepted February 10, 2016; previously evaluate whether anti-daratumumab bound to and shifted published online March 30, 2016 the migration pattern of daratumumab, it was spiked into Abstract daratumumab-containing serum and resolved by IFE/SPE. The presence (DIRA positive) or absence (DIRA negative) Background: Monoclonal antibodies are promising anti- of residual M-protein in daratumumab-treated patient myeloma treatments. As immunoglobulins, monoclonal samples was evaluated using predetermined assessment antibodies have the potential to be identified by serum criteria. DIRA was evaluated for specificity, limit of sensi- protein electrophoresis (SPE) and immunofixation elec- tivity, and reproducibility. trophoresis (IFE). Therapeutic antibody interference with Results: In all of the tested samples, DIRA distinguished standard clinical SPE and IFE can confound the use of between daratumumab and residual M-protein in com- these tests for response assessment in clinical trials and mercial serum samples spiked with daratumumab and disease monitoring. in daratumumab-treated patient samples. The DIRA Methods: To discriminate between endogenous myeloma limit of sensitivity was 0.2 g/L daratumumab, using protein and daratumumab, a daratumumab-specific spiking experiments. Results from DIRA were repro- immunofixation electrophoresis reflex assay (DIRA) was ducible over multiple days, operators, and assays. The anti- daratumumab antibody was highly specific for daratumumab and did not shift endogenous M-protein. aChristopher McCudden and Amy E. Axel contributed equally. *Corresponding author: A. Kate Sasser, Janssen Research & Conclusions: As the treatment of myeloma evolves to Development, LLC, Spring House, PA, USA, incorporate novel monoclonal antibodies, additional E-mail: [email protected] solutions will be needed for clinical monitoring of patient Christopher McCudden: Department of Pathology and Laboratory responses to therapeutic regimens. In the interim, assays Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, such as DIRA can inform clinical outcomes by distinguish- Canada Amy E. Axel, Pamela L. Clemens, Jaime Bald and Tahamtan Ahmadi: ing daratumumab from endogenous M-protein by IFE. Janssen Research & Development, LLC, Spring House, PA, USA Keywords: complete response; daratumumab; immuno- Dominique Slaets: BARC, a division of CERBA European Lab, Ghent, fixation electrophoresis; monoclonal antibody; multiple Belgium Thomas Dejoie: Biochemistry Laboratory, Hospital of Nantes, myeloma. Nantes, France Sandy Frans: Janssen Research & Development, Beerse, Belgium Torben Plesner: Vejle Hospital and University of Southern Denmark, Vejle, Denmark Introduction Joannes F.M. Jacobs: Department of Laboratory Medicine, RadboudUMC, Nijmegen, The Netherlands Multiple myeloma (MM) is an incurable disease character- Department of Hematology, VU University Niels W.C.J. van de Donk: ized by the presence of malignant plasma cells that secrete Medical Center, Amsterdam, The Netherlands Philippe Moreau: University Hospital of Nantes, Nantes, France high levels of a monoclonal immunoglobulin protein Jordan M. Schecter: Janssen Research & Development, LLC, Raritan, (M-protein) [1, 2]. The International Myeloma Working NJ, USA Group (IMWG) has established criteria for clinical response ©2016, A. Kate Sasser et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. 1096 McCudden et al.: Mitigation of antibody interference with IFE to treatment in MM, which include changes in serum/urine [6]. SIRIUS, a phase 2 study, examined daratumumab in M-protein levels by serum protein electrophoresis (SPE) patients with at least three lines of prior therapy or double and immunofixation electrophoresis (IFE), percentage of refractory MM [8]. Overall response rate (ORR) was 29% and bone marrow plasma cells, and free light chain (FLC) ratios responses deepened with continued treatment; median [3–5]. For a patient to be classified as having a complete overall survival was 17.5 months (95% confidence interval, response (CR) by IMWG criteria, the serum and urine must 13.7–not estimable) in these heavily pretreated patients be negative for M-protein, as determined by IFE and SPE, (median of 5 prior lines of treatment) [8]. On the basis of and bone marrow plasma cells must be ≤ 5%. In serum these studies, daratumumab was recently approved in the FLC-only patients, CR is defined as a normal FLC ratio United States for the treatment of patients with MM who in addition to the other criteria required to classify a CR have received 3 or more lines of prior therapy including [4]. For the more robust, deeper classification of stringent a proteasome inhibitor (PI) and immunomodulatory drug complete response (sCR), all of the criteria for CR must be (IMiD), or are double refractory to a PI and an IMiD [17]. met, along with a normal FLC ratio and absence of clonal Daratumumab is also being investigated in phase 3 clini- plasma cells in the bone marrow, as measured by 2- to cal studies in combination with other therapeutic agents 4-color flow cytometry or immunohistochemistry. in patients with MM. The treatment of MM is evolving with the introduc- At the recommended dosing schedule (16 mg/kg tion of therapeutic monoclonal antibodies (mAbs) [6–8]. weekly for 8 weeks, then every 2 weeks for 16 weeks, Since SPE and IFE are used to quantify and characterize and every 4 weeks thereafter), daratumumab reaches the clonal nature of immunoglobulins, respectively, these peak serum concentrations of approximately 915 μg/mL assays are subject to interference from therapeutic mAbs (0.915 g/L) at the end of the weekly dosing period [18], [9, 10]. Experiments with spiked samples demonstrated making it readily detectable on most SPE/IFE assays [1]. that all mAbs evaluated could be detected by SPE and As a human IgGκ immunoglobulin, daratumumab may IFE, down to 0.1 g/L [10]. Interference on serum IFE from be detected by IFE and can thus be misinterpreted as a treated patients has been reported with several mAbs, myeloma-associated M-protein, thereby interfering with including siltuximab, ofatumumab, and daratumumab [1, the response criteria [19]. 9, 10], and similar interference has been observed with elo- To help distinguish daratumumab from endogenous tuzumab [7, 11]. The IMWG criteria for achieving CR specify M-protein in serum IFE, the daratumumab-specific immu- no detectable M-protein by IFE and SPE [3]; thus, antibody nofixation electrophoresis reflex assay (DIRA) was devel- interference can have a clinically important impact on the oped to confirm suspected daratumumab interference and assessment of response to treatment and may result in to allow separation of daratumumab bands from residual underestimation of CR rates for mAb therapies. As thera- endogenous M-protein. DIRA relies on the use of an anti- peutic mAbs become utilized in myeloma, methods are daratumumab antibody that binds daratumumab and needed to assess clinical responses, particularly CR/sCR, alters its migration on IFE. The present study describes the in light of this potential interference. validation of DIRA for clinical trial testing, which included Daratumumab, a human IgG1κ mAb, binds with determination of the assay’s limit of sensitivity, specific- high affinity to a unique CD38 epitope, inducing tumor ity, and reproducibility. This assay is currently being uti- cell death through a variety of mechanisms, including lized in clinical trials to distinguish daratumumab from complement-dependent cytotoxicity, antibody-dependent endogenous M-protein by IFE and has triggered additional cell-mediated cytotoxicity, antibody-dependent cellular clinical response assessments to confirm CRs in myeloma phagocytosis, and induction of apoptosis [12–15]. Addi- patients treated with daratumumab. tionally, subpopulations of regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells with high CD38 expression are sensitive to daratumumab [16]. Cyto- toxic T cell activation, expansion, and increased T cell Materials and methods clonality have been observed after monotherapy treat- ment in relapsed or refractory disease, suggesting a possi- Serum sample collection ble immunomodulatory role for daratumumab in MM [16]. In GEN501, a phase 1/2 study of patients with relapsed Human serum samples from patients with MM or healthy donors were acquired from a commercial source (Bioreclamation, Westbury, or refractory MM, daratumumab monotherapy was well NY, USA) or from daratumumab-treated patients (n = 33). Serum sam- tolerated, and 36% of patients receiving daratumumab at ples from clinical trials of daratumumab as monotherapy (GEN501 16 mg/kg achieved at least a partial response (PR) or better and SIRIUS) or as combination therapy with lenalidomide in an McCudden et al.: Mitigation of antibody interference with IFE 1097 ongoing study (GEN503; ClinicalTrials.gov Identifier: NCT01615029) determine the effectiveness
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