1 Introduction
Daratumumab, a human immunoglobulin G1κ (IgG1κ) monoclonal antibody (mAb), binds with high affinity to CD38, which is ubiquitously expressed on myeloma cells [
1,
2]. Daratumumab induces CD38 immune-mediated activities, apoptosis, and modulation of CD38 enzymatic activity [
3‐
6], and has immunomodulatory effects that minimize the functions of CD38
+ immunosuppressive cells, expand T-cell numbers, and increase T-cell clonality [
7]. Daratumumab has been shown to provide clinical benefit for the treatment of multiple myeloma (MM) in patients with one or more prior line of therapy [
8,
9]. It received approval from the US FDA and European Medicines Agency (EMA) for use as monotherapy in heavily treated patients with relapsed or refractory MM [
10,
11], and was recently approved in combination with bortezomib and dexamethasone, or lenalidomide and dexamethasone, in MM patients who have received at least one prior therapy [
12].
The malignant cells of MM patients can produce excessive amounts of monoclonal Ig (so-called myeloma protein or M-protein), including IgG [
13], which may affect IgG-based mAb treatments such as daratumumab. Excessive endogenous IgG M-protein can cause elevated clearance of IgG-based mAbs due to the competition between endogenous disease-produced IgG and exogenous therapeutic IgG for neonatal Fc receptor (FcRn)–mediated IgG protection [
14]. Therefore, IgG myeloma patients may have lower exposure to daratumumab compared with non-IgG myeloma patients. In addition, it was of interest to investigate whether the predicted difference in daratumumab exposure between IgG and non-IgG patients might impact its efficacy and safety.
Additionally, albumin, a factor used in the International Staging System (ISS) for defining prognosis in myeloma and which is also a substrate of FcRn, can also potentially affect exposure to mAbs and the drug effect in MM patients at different ISS classifications [
15]. Furthermore, up to 50% of MM patients experience a decrease in creatinine clearance [
16]. It remains unknown how these disease characteristics of MM patients may affect the clinical pharmacology, efficacy, and safety of daratumumab.
In two studies of daratumumab monotherapy (GEN501 and SIRIUS), deep and durable responses were achieved in patients with heavily treated relapsed and refractory MM [
17,
18]. Data collected from patients with pharmacokinetic (PK) samples from these two phase II studies provided a unique opportunity to understand the influence of the mechanism-based interaction between a therapeutic mAb and IgG M-protein, disease-induced renal insufficiency, and albumin levels on exposure and, consequently, the clinical outcomes of daratumumab-treated patients in relapsed or refractory MM. In addition, we also explored the impact of other disease and patient characteristics, such as body weight, age, sex, race, hepatic function, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies on daratumumab PK, efficacy, and safety.
4 Discussion
Many factors may affect therapeutic mAb distribution [
21]. MM patients exhibit several unique disease characteristics, such as excessive production of IgG, and reduced albumin levels and renal dysfunction as disease progresses. These characteristics could potentially interact with disposition of mAbs and impact clinical outcomes. Our research is the first report to reveal significantly lower concentrations of a therapeutic mAb (i.e. daratumumab) in patients with IgG MM compared with non-IgG MM. Overall, these results suggest that IgG patients may be more sensitive to daratumumab at a given exposure compared with non-IgG patients. Therefore, even though IgG myeloma patients had significantly lower daratumumab concentrations compared with non-IgG myeloma patients, the clinical efficacy of daratumumab was comparable between the two groups.
In addition, there was a significant correlation between baseline IgG M-protein levels and linear clearance of daratumumab, which represents non-specific clearance of mAbs due to protein catabolism (electronic supplementary Fig. 1). It is likely that this effect was due to the unique interaction between IgG clearance and the excessive amount of monoclonal M-protein produced in MM patients. The levels of M-protein in MM patients are usually in the g/L range, which is at least 10 times higher than most therapeutic mAb concentrations [
22]. FcRn, expressed on various organs, including the reticuloendothelial system [
14,
23], has been shown to protect IgG or IgG-based monoclonal antibodies from degradation due to intracellular catabolism, resulting in low clearance and long half-lives for these classes of mAbs in serum [
14]. The lower daratumumab exposure observed in patients with IgG MM compared with non-IgG MM was likely due to the competition between the high concentration of disease-produced IgG M-protein secreted by myeloma cells and daratumumab, an IgG antibody, for FcRn protection from elimination. Since most existing therapeutic antibodies are of the IgG isotype, the influence of type of myeloma and IgG M-protein on mAb exposure should be considered for daratumumab and other therapeutic antibodies used in MM patients [
24].
The lower daratumumab exposure observed in patients with IgG myeloma raises the question of whether higher doses of daratumumab might improve efficacy in these patients. When considering this question, it is important to note that exposure is not the only factor that may drive response to daratumumab; density of CD38 receptors, receptor occupancy, and disease severity, among other cellular or physiologic conditions, may impact outcomes. To date, published data and ongoing clinical studies with higher doses do not support adjustment to the recommended daratumumab dose in patients with IgG myeloma. PK modeling indicates that increasing the intravenous daratumumab dose beyond the threshold of maximal effect, which is reached in the majority of patients treated with the recommended 16 mg/kg dose, would not result in a benefit to efficacy [
25]. This is consistent with preliminary data in patients with IgG myeloma from an ongoing clinical study with a higher dose (NCT02519452). Current data show that at a dose of 16 mg/kg, ORRs in IgG patients were similar to those seen in non-IgG patients, suggesting that, compared with non-IgG patients, IgG patients may need lower concentrations to attain similar clinical response rates (i.e. they have a lower threshold of effective concentration). Future studies are planned in which patients will be stratified based on MM type; data from those studies are likely to inform the need for additional evaluation of the interaction between daratumumab exposure, outcomes, and IgG.
FcRn also binds to and protects albumin from protein catabolism [
15,
22]. A higher albumin concentration indicates the presence of higher FcRn levels, which, in turn, may also increase the protection of daratumumab from protein catabolism. Baseline albumin concentration had a statistically significant effect on linear clearance of daratumumab; however, the magnitude of the difference between normal and abnormal albumin levels on daratumumab exposure was relatively small (26%). In addition, although the ORR in patients with normal albumin levels appeared to be higher than in patients with abnormal albumin levels, the ORR in both groups was generally consistent with that of the overall population and the CIs overlapped each other. Logistic regression also showed that albumin levels did not have a statistically significant effect on ORR when albumin was evaluated as a continuous variable. The lower ORR in patients with abnormal albumin [
26] may be explained by severity of disease: as albumin is a factor used to stage MM, patients with more advanced disease have lower albumin levels and tend to be less responsive to daratumumab treatment. Furthermore, patients with abnormal albumin also tended to have a higher rate of grade 3 or higher AEs, despite a lower concentration of daratumumab. Thus, increasing the daratumumab dose in patients with abnormal albumin in order to improve ORR is unlikely to improve the overall risk–benefit profile.
Proliferation of M-protein has several deleterious effects on many organs, including the kidneys [
13]. Two-thirds of patients evaluated in this analysis had some degree of pre-existing renal impairment. The analysis presented here demonstrates that renal function did not have a significant effect on daratumumab clearance and exposure and also had a minimal impact on efficacy and safety. The trend toward a higher rate of overall grade 3 or higher AEs in patients with renal impairment was likely a result of the large proportion of double refractory patients included in this patient population.
Similarly, mild hepatic impairment did not have a significant impact on the exposure and clinical outcomes for daratumumab. The seemingly lower exposure in patients with mild hepatic impairment (approximately 20%) [Fig.
2] may have been the result of the unbalanced distribution of patients with IgG MM to groups with mild hepatic impairment (65%;
n = 24 at 16 mg/kg) versus normal hepatic function (46%;
n = 127 at 16 mg/kg). The ORR was almost identical for patients with mild hepatic impairment (33%; 95% CI 16.9–53.2%) and normal hepatic function (31%; 95% CI 23.1–39.1%) at 16 mg/kg. The incidence of overall grade 3 or higher AEs and infections (3 or higher, or any grade) in both groups was consistent with that of the overall population.
Natural killer (NK) cells regulate immune activity, thus providing protection against infection [
27]. Because CD38 is expressed on NK cells, daratumumab tends to reduce NK cells in a dose-dependent manner [
28]. Thus, the possibility that daratumumab treatment might result in different rates of infection in subgroups was examined. The present analysis demonstrates that the incidence of infection was consistent among the subgroups for all investigated disease and patient characteristics, including type of myeloma. Our previous research demonstrated that there was a weak trend toward higher rates of infection of any grade with greater daratumumab exposure, but this observation did not reach statistical significance and a similar trend was not observed for grade 3 or higher infections. The consistent infection rates may be partly explained by the lack of a significant exposure–response relationship for infections within the therapeutic dose range for daratumumab.
Acknowledgements
The clinical studies were supported by research funding from Janssen Research & Development and Genmab, and the analyses presented here were supported by research funding from Janssen Research & Development. The authors thank the patients who participated in the GEN501 and SIRIUS studies and their families, as well as the study co-investigators, research nurses, and coordinators at each of the clinical sites. Medical writing and editorial support were provided by Erica S. Chevalier-Larsen, PhD, of MedErgy and funded by Janssen Global Services, LLC.
Compliance with Ethical Standards
Conflict of interest
XY, PLC, T. Puchalski, KL, RJ, TA, KL, JJPR, HZ, and XSX are employees of Janssen Research & Development. XY, PLC, T. Puchalski, RJ, TA, KL, JJPR, HZ, and XSX own stock in Johnson & Johnson, and JJRP owns stock in Amgen. SL reports consultancy and research funding from Millennium, Novartis, Bristol-Myers Squibb, Onyx, Celgene, and Janssen. HL reports honoraria from Amgen and honoraria and research funding from Genmab and Janssen. PMV reports consultancy for Janssen, Millennium/Takeda, Celgene, Novartis, Array BioPharma, and Oncopeptides; and research funding from Janssen, Celgene, GlaxoSmithKline, Onyx, and Oncopeptides. SU reports consulting for Celgene, Millennium/Takeda, Onyx, and Sanofi; speaker’s fees from Celgene, Millennium/Takeda, and Onyx; and research funding from Array BioPharma, Celgene, Janssen Oncology, Onyx, Pharmacyclics, and Sanofi. PGR reports being a member of the advisory committee for Genmab. T. Plesner reports research support from Janssen and participation in advisory boards for Janssen, Celgene, AbbVie, and Takeda. RZO reports consulting for Array BioPharma, Bristol-Myers Squibb, Celgene, FORMA Therapeutics, Janssen, Millennium, and Onyx; and research funding from Bristol-Myers Squibb, Celgene, Janssen, Onyx, and Spectrum Pharmaceuticals. NL is an employee of and owns stock in Genmab A/S.
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