Pamela L. Clemens

Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference

Abstract Background: Monoclonal antibodies are promising anti-myeloma treatments. As immunoglobulins, monoclonal antibodies have the potential to be identified by serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). Therapeutic antibody interference with standard clinical SPE and IFE can confound the use of these tests for response assessment in clinical trials and disease monitoring. Methods: To discriminate between endogenous myeloma protein and daratumumab, a daratumumab-specific immunofixation electrophoresis reflex assay (DIRA) was developed using a mouse anti-daratumumab antibody. To evaluate whether anti-daratumumab bound to and shifted the migration pattern of daratumumab, it was spiked into daratumumab-containing serum and resolved by IFE/SPE. The presence (DIRA positive) or absence (DIRA negative) of residual M-protein in daratumumab-treated patient samples was evaluated using predetermined assessment criteria. DIRA was evaluated for specificity, limit of sensitivity, and reproducibility. Results: In all of the tested samples, DIRA distinguished between daratumumab and residual M-protein in commercial serum samples spiked with daratumumab and in daratumumab-treated patient samples. The DIRA limit of sensitivity was 0.2 g/L daratumumab, using spiking experiments. Results from DIRA were reproducible over multiple days, operators, and assays. The anti-daratumumab antibody was highly specific for daratumumab and did not shift endogenous M-protein. Conclusions: As the treatment of myeloma evolves to incorporate novel monoclonal antibodies, additional solutions will be needed for clinical monitoring of patient responses to therapeutic regimens. In the interim, assays such as DIRA can inform clinical outcomes by distinguishing daratumumab from endogenous M-protein by IFE.

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029.

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent daratumumab studies, GEN501 and SIRIUS. In daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between daratumumab dose and maximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from daratumumab-treated patients induced lysis by ADCC of CD38+ tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of daratumumab. Furthermore, although NK cell numbers are reduced after daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma

New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first‐in‐class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for daratumumab is challenging due to its target‐mediated drug disposition, leading to time‐ and concentration‐dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM.

Abstract 4089: Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach

Duvortuxizumab (also known as JNJ-64052781 and MGD011) is a bispecific CD19 x CD3 DART® molecule designed to simultaneously target CD19-positive cells for recognition and elimination by CD3-expressing T-lymphocytes as effector cells. Duvortuxizumab is currently in clinical development for the potential treatment of B-cell malignancies. Here we report the results from a translational PK model that utilized duvortuxizumab pharmacokinetic (PK) data from cynomolgus monkeys to predict duvortuxizumab PK in humans. The PK of duvortuxizumab administered by intravenous infusion was evaluated in cynomolgus monkeys in two separate studies. Study 1 evaluated intra-animal escalating doses from 0.5 to 100 µg/kg or repeated doses from 0.005 to 0.5 µg/kg administered over a period of up to 4 weeks. Serum concentrations of duvortuxizumab above the lower limit of quantification were obtained at dose levels >0.5 µg/kg. Study 2 evaluated duvortuxizumab doses of 0.2, 2, 5, or 10 µg/kg administered once weekly for 4 weeks. Dose-proportional increases in maximum concentration (Cmax) were observed across the dose ranges evaluated, and no significant differences between male and female animals were observed. PK modeling analysis, which integrated data from both study 1 and study 2 at 0.2 to 100 µg/kg dose levels, was performed to further understand the PK behavior of duvortuxizumab in cynomolgus monkeys. Duvortuxizumab PK was reasonably characterized using a two compartment model with linear clearance (CL) from the central compartment. Model estimated parameters were CL = 0.797 mL/h/kg; volume of distribution for the central compartment (V1) = 51.7 mL/kg; intercompartmental clearance (Q) = 2.29 mL/h/kg; and volume of distribution for the peripheral compartment (V2) = 88.8 mL/kg. Assuming a body weight of 3 kg and 70 kg for a cynomolgus monkey and a human, respectively, human PK parameters were estimated using an allometric scaling factor of 0.75 for CL and 1.0 for volume in the translational PK model. Observed duvortuxizumab PK values obtained from an ongoing, first-in-human (FIH), phase 1 dose-escalation trial in patients with relapsed or refractory B-cell malignancies (NCT02454270) were used to validate the translational PK model. Comparison of the predicted and observed duvortuxizumab PK profiles suggested that the translational PK model using the allometric scaling method reasonably predicted duvortuxizumab PK profiles in humans at multiple dose levels (15 to 100 ng/kg). In conclusion, the developed translational PK model successfully predicted duvortuxizumab PK in humans and has been used to aid dose escalation of duvortuxizumab in the ongoing FIH study. This work showcases the potential of translational PK modeling in supporting the selection of a FIH dose escalation strategy utilizing preclinical PK information. Citation Format: Xiling Jiang, Hua Li, Jeff Nordstrom, Jennifer Brown, Liqin Liu, Syd Johnson, Ralph Alderson, Pamela L. Clemens, Jacintha Shenton, Imran Khan, Olivia Gardner, Yu-Nien Sun, Weirong Wang. Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2017-4089