Jordan Mark Schecter

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.

Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX

In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs. 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P<0.0001). The overall response rate was 92.9% versus 76.4%, and 51.2% versus 21.0% achieved a complete response or better, respectively (both P<0.0001). At the 10−5 sensitivity threshold, 26.2% versus 6.4% were minimal residual disease–negative, respectively (P<0.0001). Post hoc analyses of clinically relevant patient subgroups demonstrated that progression-free survival was significantly prolonged for daratumumab plus lenalidomide/dexamethasone versus lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P<0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs. 10.2 months; hazard ratio, 0.53; 95% confidence interval, 0.25-1.13; P=0.0921) and patients with treatment-free intervals of >12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009.

Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR

Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease–negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

Response to “The Role of FcRn in the Pharmacokinetics of Biologics in Patients with Multiple Myeloma”

To the Editor: Daratumumab, a therapeutic immunoglobulin G (IgG) 1j monoclonal antibody, targets CD38 for the treatment of multiple myeloma. In our article, we reported that daratumumab exhibited time-dependent and concentration-dependent pharmacokinetics (PK) consistent with target-mediated drug disposition, based on data from studies of daratumumab as a monotherapy. Jacobs and Mould posit that saturation of the neonatal Fc-receptor (FcRn) contributes to the nonlinear PK of daratumumab. We agree that interactions between FcRn, IgG M-protein, and daratumumab are likely to influence daratumumab PK. When recycled, IgG proteins are protected from degradation by FcRn. Daratumumab and IgG-type M-protein may compete for FcRn and, thus, in the presence of IgG M-protein, daratumumab (or other therapeutic IgGs) may have a shorter half-life. Jacobs and Mould present modeling data suggesting that, to offset this effect, the daratumumab dose should be increased from 16 mg/kg to 30 mg/kg in patients with 60 mg/L of IgG Mprotein. Similarly, our modeling data demonstrate that daratumumab concentrations in non-IgG patients are 50% (95% confidence interval (CI) 5 38–60%) higher than in IgG patients. However, current data do not support adjustment of daratumumab dose based on IgG status. First, despite lower concentrations of daratumumab in IgG patients, efficacy data indicate that overall response rates among patients receiving daratumumab 16 mg/kg are similar between IgG and non-IgG patients (32.0%; 95% CI 5 22.5–43.3 vs. 30.3%; 95% CI 5 21.0–41.4, respectively). Even among patients with baseline levels of IgG M-protein 30 mg/mL, overall response rate was similar to that of nonIgG patients. Second, preliminary data from an ongoing study suggest that higher doses increased exposure in IgG patients but did not increase target saturation (which was maximized at 16 mg/kg) or improve efficacy. Modeling data estimate that IgG patients have lower thresholds of effective concentration (half-maximal effective concentration) than non-IgG patients. Finally, current data demonstrated similar safety profiles in IgG and non-IgG patients at 16 mg/kg. Increasing daratumumab doses would increase peak concentrations, with unknown effects on the safety of daratumumab. Jacobs and Mould note that, as patients respond to daratumumab and IgG M-protein levels decrease, dose adjustment may be possible given the decreasing clearance over time. This idea is consistent with our observations and a report by Liu et al. on clearance of nivolumab. For daratumumab, weekly dosing overcame the initial high clearance, establishing efficacious concentrations. Every 2 weeks or monthly dosing schedules were sufficient to maintain target saturation, thus reducing the risk of disease progression. Potential effects of FcRn and IgG Mprotein on the PK and efficacy of therapeutic antibodies for the treatment of multiple myeloma should be investigated as this therapeutic class becomes more prevalent. CONFLICT OF INTEREST The authors declared no conflict of interest.