Purpose:

ABBV-838 is an antibody–drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-in-human, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM).

Patients and Methods:

Eligible patients (≥18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel.

Results:

As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838–related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively.

Conclusions:

These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.

Translational Relevance

Despite recent progress, there remains a high unmet medical need for effective treatments in relapsed and refractory multiple myeloma (RRMM). Herein, results from the first-in-human study of ABBV-838, a CD2 subset 1–directed antibody–drug conjugate (ADC), are reported. While ABBV-838 showed promising results in preclinical models, ABBV-838 treatment did not translate into substantial clinical benefit in patients with RRMM. Despite the limited antitumor activity, ABBV-838 was seen to have a favorable safety profile. Thus, these data demonstrate that a ratio of two cytotoxin molecules conjugated to one antibody result in an ADC that is well tolerated and that is suitable for use in humans. It is interesting to note that another ADC with a similar warhead exhibited substantial clinical activity. Further investigations may be required to determine the reasons for the limited antitumor activity of ABBV-838.

Multiple myeloma is a malignant disease characterized by the abnormal proliferation of plasma cells in the bone marrow, leading to bone destruction, anemia, infections, hypercalcemia, and renal failure (1, 2). Multiple myeloma constitutes approximately 10% of all hematologic malignancies and is the second most common hematologic malignancy (3). Despite advances in high-dose chemotherapy and stem cell transplantation, as well as the introduction of new therapeutic agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), multiple myeloma is still incurable, and the majority of patients will relapse or become refractory regardless of line of therapy, resulting in high morbidity and mortality (4, 5). There remains a high unmet medical need for novel therapeutic agents for curative treatment in this patient population in general, as well as to treat patients with relapsed and refractory multiple myeloma (RRMM).

Antibody–drug conjugates (ADC) are a novel class of targeted anticancer therapy composed of a mAb, a covalent linker, and a cytotoxic agent. The key advantage of ADCs lies in the highly specific targeting properties of mAbs combining with the antitumor effects of potent cytotoxic drugs (6, 7). Upon binding to specific antigen(s) on the tumor cell surface, the antigen–ADC complex is internalized, leading to the release of the cytotoxic agent (8). ABBV-838 is an ADC comprising a humanized recombinant immunoglobulin G1κ directed against a unique epitope of CD2 subset 1 (CS1, also known as SLAMF7) conjugated to the cytotoxic monomethyl auristatin E (MMAE) through a valine-citrulline linker. CS1 is a cell-surface glycoprotein that is highly and uniformly expressed on multiple myeloma cells, is detectable in over 90% of multiple myeloma bone marrow samples with only limited expression on other cell types such as natural killer cells, and represents an attractive therapeutic target for patients with multiple myeloma (9, 10). Studies with the anti-CS1 mAb elotuzumab have demonstrated clinical activity when combined with IMiDs (11, 12), but failed to demonstrate single-agent activity (13).

Multiple cytotoxin molecules can be conjugated per mAb; for example, brentuximab vedotin contains up to eight units of MMAE per mAb (14). However, preclinical studies have shown that the higher the drug load of an ADC, the higher the toxicity and the lower the therapeutic index (15). For potential improvement in safety and efficacy, ABBV-838 generally contains two MMAE per mAb. Cynomolgus monkey and rat studies demonstrated that this distribution was better tolerated than ADCs containing higher drug antibody ratios of MMAE. MMAE binds to tubulin, thereby inhibiting mitosis and causing tumor cell death (16, 17). Preclinical studies demonstrated potent cytotoxic activity of ABBV-838 against cancer cells that expressed CS1, and single-agent antitumor activity in mouse models using human myeloma xenografts (18). While targeting CS1 with a naked mAb did not elicit clinical activity on its own (13), the expectation for ABBV-838 is single-agent clinical activity by virtue of delivering a potent cytotoxic payload to the myeloma cells.

Herein we describe the results of a phase I/Ib first-in-human, open-label study evaluating the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with RRMM.

Study design

This phase I/Ib first-in-human, open-label study (trial registration ID: NCT02462525) was conducted between April 23, 2015 and December 6, 2017. The primary objectives of the study were to evaluate the safety, tolerability, and pharmacokinetics of ABBV-838 and to identify the MTD and/or the recommended phase II dose (RP2D) of ABBV-838 monotherapy and in combination with approved agents for the treatment of RRMM. The secondary objective was to evaluate the preliminary activity of ABBV-838 monotherapy. Exploratory objectives were to evaluate pharmacodynamics and potential predictive biomarkers associated with clinical activity and/or safety. Data cutoff was April 3, 2018.

The study was planned to be conducted in four parts: dose escalation, dose expansion, alternate dosing regimen [weekly (Q1W) and every 2 weeks (Q2W)], and evaluation with combination agents. As defined efficacy was not achieved, the combination therapy part (part 4) was not enrolled.

In the dose-escalation part of the study, a classical 3+3 dose-escalation design was used that enrolled 3–6 patients per dose level for the purpose of exploring the MTD and/or RP2D. ABBV-838 was administered intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for a Q3W dosing interval dose-escalation regimen. The study design for the Q3W dosing regimen is shown in Supplementary Fig. S1. Dose-limiting toxicity (DLT) was assessed to make decisions regarding monotherapy administered Q3W with sequential dose escalation. Patients in each dose cohort could continue ABBV-838 dosing for up to 24 months, per protocol. Assessment of alternate dosing regimen (Q1W and Q2W) dosing intervals was conducted in parallel with the Q3W dose-escalation regimen, with the goal of exploring an MTD and/or RP2D. On the basis of safety and pharmacokinetic data from the dose-escalation parts of the study, patients were enrolled in the dose-expansion part. The ABBV-838 dose selected for the expansion part was at or below the highest exposure level successfully tolerated in the Q3W dose-escalation part. Futility was assessed when 19 patients completed four cycles of treatment or discontinued early.

At each trial site, the study was approved by an independent ethics committee/institutional review board prior to initiation. The study was performed in accordance with the International Conference on Harmonization Good Clinical Practices guidelines and the Declaration of Helsinki. Prior to any study-related procedures, written informed consent was obtained from all patients.

Patients

Eligible patients were ≥18 years of age; had RRMM and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; were not eligible for stem cell/bone marrow transplant or had refused stem cell/bone marrow transplant, or had relapsed after autologous or allogeneic stem cell/bone marrow transplant; were eligible for and agreed to bone marrow aspirate prior to treatment start; had measurable disease M component, in serum (≥0.5 g/dL) and/or urine (≥0.2 g excreted in a 24-hour collection sample); had received at least three prior lines of therapy including a PI and an IMiD, or alternatively, patients were double refractory to a PI and an IMiD; and had demonstrated disease progression on, or within 60 days of, completion of the last therapy (patients previously treated with an alkylating agent, in addition to an IMiD or PI, were allowed). Eligible patients had adequate liver, kidney, and bone marrow function. If there was a history of chronic heart failure, the patient must have had an echocardiogram indicating left ventricular ejection fraction ≥45% within 21 days prior to first dose of study drug.

Exclusion criteria were: received anticancer therapy including chemotherapy, immunotherapy, radiation, biologic, any investigational therapy, or herbal therapy within a period of 21 days prior to the first dose of ABBV-838, and have unresolved toxicities grade ≥2, concurrent metastatic solid tumors, nonmeasurable M protein (serum or urine), or measurable serum-free light chain (<100 mg/mL), and major surgery within 21 days prior to the first dose of ABBV-838.

Assessments

For each part of the study, assessments were performed at screening, at prespecified points during the first, second, and third cycle, on day 1 of each subsequent cycle, and at the final visit. Adverse events (AE), concomitant medications, laboratory profiles, physical exams, and vital signs were assessed throughout the study. Blood samples were collected at designated time points throughout the study to evaluate safety and pharmacokinetic parameters. Serum and urine M protein were assessed every cycle per International Myeloma Working Group (IMWG) 4.0 criteria. Bone marrow was collected for all dosing regimens during screening and at designated time points during the study. Radiologic assessments (X-ray, CT scan, or MRI) were performed at screening; subsequent radiologic assessments were made using the same modality used at baseline to evaluate the extent of tumor burden at predetermined time points during the study. CS1 receptor occupancy and reductions in CS1 levels were determined by receptor competition assays on day-old, EDTA-anticoagulated bone marrow aspirate samples using fluorescently labeled antibodies, and molecules of equivalent soluble fluorochrome, in combination with validated flow cytometric (FACS) assays conducted at LabCorp and at the Universidad de Navarra (Pamplona-Navarra, Spain).

Pharmacokinetics

The pharmacokinetic population included all patients who received at least one dose of ABBV-838 and from whom drug concentrations were obtainable during the study. Blood samples for ABBV-838 pharmacokinetic analyses were collected in cycles 1 and 3, prior to start of the infusion (predose) and at the end of the infusion (within 15 minutes), and at 3, 72, 168, 336 (only Q2W and Q3W), and 504 (only Q3W) hours. Serum concentrations of ABBV-838 conjugates, total antibody, and free MMAE in plasma were determined using a validated method. Pharmacokinetic parameters were estimated using noncompartmental analyses. Immunogenicity was determined by collecting serum samples for antidrug antibody assay before each dose in a cycle and day 15 of cycle 1.

Statistical analysis

AEs were graded according to the NCI Common Terminology Criteria for Adverse Events version 4.03. Serum concentrations of ABBV-838, total mAb, and MMAE pharmacokinetic parameter values were tabulated for each patient and each dose level, and summary statistics were calculated for each sampling time and each parameter. The objective response rate (ORR) was analyzed for all evaluable dosed patients. Receptor occupancy was calculated as:

100% −(competing antibody MESF at day 5)/([(competing antibody MESF at baseline/noncompeting antibody MESF at baseline) × noncompeting antibody MESF at day 15]) × 100%)

Reductions in CS1 levels were calculated using:

100% −([noncompeting antibody MESF at day 15/noncompeting antibody MESF at baseline] × 100%)

Data sharing statement

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis datasets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan, and execution of a data sharing agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.

Patient demographics and baseline characteristics

As of March 9, 2017, a total of 75 patients were enrolled in the study. Baseline demographics and clinical characteristics are presented in Table 1. The median age was 64 years (range, 41–87). Most patients had an ECOG performance status of 1 (65.3%), and a similar proportion of patients was categorized as International Staging System (ISS) stage 1 (34.7%) or stage 3 (37.3%). Baseline characteristics were similar for patients across all treatment groups. The median prior lines of therapy was 5 (range, 1–12). Of 75 patients treated, 38 (51%) were refractory to at least one IMiD, 27 (36%) were refractory to at least one PI, and 25 (33%) were refractory to both IMiD and PI. All patients analyzed received at least one dose of ABBV-838: 32 patients in the Q3W dose-escalation part of the study, 14 patients in the alternate dosing part (n = 8 received 1.5 mg/kg Q1W and n = 6 received 3.0 mg/kg Q2W), and 29 patients in the dose-expansion part (5.0 mg/kg Q3W). A total of 41 patients received a dose of 5.0 mg/kg or more: 6 patients each in the 5.0 mg/kg and 6.0 mg/kg Q3W treatment groups, and 29 patients in the 5.0 mg/kg Q3W dose-expansion treatment group.

Table 1.

Patient demographics and clinical characteristics.

Total
(N = 75)
Median age, years (range) 64 (41–87) 
Sex, n (%) 
 Female 31 (41.3) 
 Male 44 (58.7) 
Race, n (%) 
 White 53 (70.7) 
 Black 5 (6.7) 
 Asian/other 
 Missing 17 (22.7) 
Ethnicity, n (%) 
 Hispanic or Latino 1 (1.3) 
 No ethnicity given 56 (74.7) 
 Not reported 18 (24.0) 
ECOG performance status, n (%) 
 0 17 (22.7) 
 1 49 (65.3) 
 2 9 (12.0) 
 ≥3 
ISS staging at the time of study entry 
 1 26 (34.7) 
 2 12 (16.0) 
 3 28 (37.3) 
 Not evaluable 8 (10.7) 
Total
(N = 75)
Median age, years (range) 64 (41–87) 
Sex, n (%) 
 Female 31 (41.3) 
 Male 44 (58.7) 
Race, n (%) 
 White 53 (70.7) 
 Black 5 (6.7) 
 Asian/other 
 Missing 17 (22.7) 
Ethnicity, n (%) 
 Hispanic or Latino 1 (1.3) 
 No ethnicity given 56 (74.7) 
 Not reported 18 (24.0) 
ECOG performance status, n (%) 
 0 17 (22.7) 
 1 49 (65.3) 
 2 9 (12.0) 
 ≥3 
ISS staging at the time of study entry 
 1 26 (34.7) 
 2 12 (16.0) 
 3 28 (37.3) 
 Not evaluable 8 (10.7) 

All 75 (100%) patients discontinued from the study (Table 2). The most common reasons for discontinuation were progressive disease per IMWG [n = 52 (69.3%)], and AEs not related to progression [n = 12 (16.0%); Table 2]. There were a total of three DLTs in the study, 1 patient dosed at 6.0 mg/kg Q3W during dose escalation experienced a DLT of febrile neutropenia, 1 patient dosed at 1.5 mg/kg Q1W in dose escalation reported a DLT of cholestasis and hepatotoxicity, and 1 patient dosed at 5.0 mg/kg Q3W during cohort expansion experienced grade 3 leukopenia.

Table 2.

Reasons for ABBV-838 discontinuation.

0.6 mg/kg0.9 mg/kg1.4 mg/kg2.0 mg/kg3.0 mg/kg4.0 mg/kg5.0 mg/kg6.0 mg/kg1.5 mg/kg3.0 mg/kgExpansion 5.0 mg/kg
Q3WQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ1WQ2WQ3WTotal
Primary reason for study drug discontinuation, n (%)(n = 3)(n = 3)(n = 3)(n = 4)(n = 3)(n = 4)(n = 6)(n = 6)(n = 8)(n = 6)(n = 29)(N = 75)
AEs related to progression 1 (16.7) 1 (12.5) 2 (33.3) 3 (10.3) 7 (9.3) 
AEs not related to progression 2 (50.0) 1 (25.0) 1 (16.7) 2 (33.3) 1 (16.7) 5 (17.2) 12 (16.0) 
Withdrew consent 
Lost to follow-up 
DLT 1 (3.4) 1 (1.3) 
Progressive disease – per IMWG 3 (100) 3 (100) 3 (100) 2 (50.0) 3 (100) 3 (75.0) 3 (50.0) 4 (66.7) 7 (87.5) 2 (33.3) 19 (65.5) 52 (69.3) 
Sponsor discontinued study 
Other 1 (16.7) 1 (16.7) 1 (3.4) 3 (4.0) 
0.6 mg/kg0.9 mg/kg1.4 mg/kg2.0 mg/kg3.0 mg/kg4.0 mg/kg5.0 mg/kg6.0 mg/kg1.5 mg/kg3.0 mg/kgExpansion 5.0 mg/kg
Q3WQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ1WQ2WQ3WTotal
Primary reason for study drug discontinuation, n (%)(n = 3)(n = 3)(n = 3)(n = 4)(n = 3)(n = 4)(n = 6)(n = 6)(n = 8)(n = 6)(n = 29)(N = 75)
AEs related to progression 1 (16.7) 1 (12.5) 2 (33.3) 3 (10.3) 7 (9.3) 
AEs not related to progression 2 (50.0) 1 (25.0) 1 (16.7) 2 (33.3) 1 (16.7) 5 (17.2) 12 (16.0) 
Withdrew consent 
Lost to follow-up 
DLT 1 (3.4) 1 (1.3) 
Progressive disease – per IMWG 3 (100) 3 (100) 3 (100) 2 (50.0) 3 (100) 3 (75.0) 3 (50.0) 4 (66.7) 7 (87.5) 2 (33.3) 19 (65.5) 52 (69.3) 
Sponsor discontinued study 
Other 1 (16.7) 1 (16.7) 1 (3.4) 3 (4.0) 

Safety

Treatment-emergent AEs (TEAE) were reported in a total of 74 (99.7%) patients across all treatment groups and are summarized in Table 3. Most common any-grade TEAEs were neutropenia and anemia [n = 21 (28.0%) each], fatigue [n = 20 (26.7%)], and nausea [n = 19 (25.3%)]. TEAEs considered to have a reasonable possibility of relationship to ABBV-838 were reported by a total of 53 (70.7%) patients across all treatment groups (Supplementary Table S1). Peripheral neuropathy, a TEAE often observed with microtubule inhibitors, was observed in 14 patients (18.7%). Corneal deposits were seen in 12 patients (16.0%) and were often accompanied by loss in visual acuity that was reversible following discontinuation of study drug. Grade 3/4/5 TEAEs were reported in 55 (73.3%) patients across all treatment groups (Table 3); most common were neutropenia [n = 15 (20.0%)], anemia [n = 14 (18.7%)], and leukopenia [n = 10 (13.3%)]. Grade 3/4/5 TEAEs considered to have a reasonable possibility of relationship to ABBV-838 were reported by a total of 30 (40.0%) patients across all treatment groups (Supplementary Table S1). Serious TEAEs were reported in 27 (36.0%) patients across all treatment groups (Table 3); progression was the most common, reported by 9 (12.0%) patients. Other serious TEAEs reported by more than 1 patient included corneal deposits [n = 5 (6.7%)] and acute kidney injury [n = 2 (2.7%)]; all other serious TEAEs were reported in single patients only. Serious TEAEs were considered possibly related to ABBV-838 in 10 (13.3%) patients (Supplementary Table S1).

Table 3.

Summary of TEAEs.

0.6 mg/kg Q3W0.9 mg/kg Q3W1.4 mg/kg Q3W2.0 mg/kg Q3W3.0 mg/kg Q3W4.0 mg/kg Q3W5.0 mg/kg Q3W6.0 mg/kg Q3W1.5 mg/kg Q1W3.0 mg/kg Q2WExpansion 5.0 mg/kg Q3WTotal
TEAEs(n = 3)(n = 3)(n = 3)(n = 4)(n = 3)(n = 4)(n = 6)(n = 6)(n = 8)(n = 6)(n = 29)(N = 75)
Any AE (≥10% total patients), n (%) 3 (100.0) 3 (100.0) 3 (100.0) 4 (100.0) 3 (100.0) 4 (100.0) 6 (100.0) 6 (100.0) 8 (100.0) 6 (100.0) 28 (96.6) 74 (98.7) 
 Anemia 2 (66.7) 2 (66.7) 1 (33.3) 1 (25.0) 2 (50.0) 1 (16.7) 3 (37.5) 1 (16.7) 8 (27.6) 21 (28.0) 
 Neutropenia 1 (33.3) 1 (25.0) 3 (50.0) 3 (50.0) 1 (12.5) 2 (33.3) 10 (34.5) 21 (28.0) 
 Fatigue 1 (33.3) 3 (100.0) 1 (25.0) 1 (16.7) 1 (16.7) 3 (37.5) 1 (16.7) 9 (31.0) 20 (26.7) 
 Nausea 1 (33.3) 1 (33.3) 2 (50.0) 1 (33.3) 1 (25.0) 1 (16.7) 4 (50.0) 2 (33.3) 6 (20.7) 19 (25.3) 
 Asthenia 1 (33.3) 1 (33.3) 1 (25.0) 3 (50.0) 2 (33.3) 3 (37.5) 7 (24.1) 18 (24.0) 
 Diarrhea 1 (33.3) 1 (33.3) 1 (25.0) 1 (33.3) 1 (25.0) 3 (50.0) 1 (16.7) 2 (25.0) 2 (33.3) 3 (10.3) 16 (21.3) 
 Leukopenia 1 (25.0) 2 (33.3) 2 (33.3) 2 (25.0) 1 (16.7) 8 (27.6) 16 (21.3) 
 Neuropathy peripheral 2 (50.0) 1 (33.3) 3 (75.0) 1 (16.7) 1 (16.7) 6 (20.7) 14 (18.7) 
 Thrombocytopenia 1 (25.0) 1 (16.7) 1 (16.7) 4 (50.0) 1 (16.7) 5 (17.2) 13 (17.3) 
 Corneal deposits 1 (25.0) 1 (16.7) 2 (33.3) 1 (16.7) 7 (24.1) 12 (16.0) 
 Malignant neoplasm progression 1 (25.0) 1 (16.7) 2 (33.3) 3 (37.5) 1 (16.7) 3 (10.3) 11 (14.7) 
 Back pain 1 (33.3) 1 (25.0) 1 (33.3) 1 (25.0) 1 (16.7) 2 (33.3) 2 (25.0) 1 (3.4) 10 (13.3) 
 Decreased appetite 1 (33.3) 2 (50.0) 1 (33.3) 1 (25.0) 2 (33.3) 1 (16.7) 2 (6.9) 10 (13.3) 
 Bone pain 1 (25.0) 2 (33.3) 1 (16.7) 2 (25.0) 3 (10.3) 9 (12.0) 
 Constipation 1 (33.3) 1 (33.3) 1 (33.3) 1 (16.7) 5 (17.2) 9 (12.0) 
 Dyspnea exertional 1 (33.3) 1 (25.0) 1 (33.3) 1 (25.0) 1 (16.7) 3 (10.3) 8 (10.7) 
 Headache 1 (33.3) 1 (33.3) 2 (33.3) 4 (13.8) 8 (10.7) 
 Hypokalemia 1 (33.3) 2 (33.3) 1 (16.7) 1 (12.5) 3 (10.3) 8 (10.7) 
 Insomnia 2 (66.7) 1 (33.3) 1 (25.0) 2 (33.3) 1 (16.7) 1 (3.4) 8 (10.7) 
Grade 3/4/5 AEs (≥5% total patients), n (%) 2 (66.7) 2 (66.7) 1 (33.3) 2 (50.0) 1 (33.3) 3 (75.0) 4 (66.7) 6 (100.0) 7 (87.5) 3 (50.0) 24 (82.8) 55 (73.3) 
 Neutropenia 1 (33.3) 1 (25.0) 2 (33.3) 1 (16.7) 1 (12.5) 1 (16.7) 8 (27.6) 15 (20.0) 
 Anemia 2 (66.7) 1 (33.3) 1 (33.3) 2 (50.0) 2 (25.0) 6 (20.7) 14 (18.7) 
 Leukopenia 1 (25.0) 2 (33.3) 1 (16.7) 2 (25.0) 4 (13.8) 10 (13.3) 
 Malignant neoplasm progression 1 (25.0) 1 (16.7) 2 (33.3) 3 (37.5) 2 (6.9) 9 (12.0) 
 Thrombocytopenia 1 (25.0) 1 (16.7) 2 (25.0) 1 (16.7) 1 (3.4) 6 (8.0) 
Serious AEs (≥2% total patients), n (%) 1 (33.3) 1 (33.3) 1 (33.3) 1 (33.3) 2 (50.0) 2 (33.3) 5 (83.3) 3 (37.5) 1 (16.7) 10 (34.5) 27 (36.0) 
 Malignant neoplasm progression 1 (25.0) 1 (16.7) 2 (33.3) 3 (37.5) 2 (6.9) 9 (12.0) 
 Corneal deposits 2 (33.3) 3 (10.3) 5 (6.7) 
 Acute kidney injury 1 (33.3) 1 (16.7) 2 (2.7) 
0.6 mg/kg Q3W0.9 mg/kg Q3W1.4 mg/kg Q3W2.0 mg/kg Q3W3.0 mg/kg Q3W4.0 mg/kg Q3W5.0 mg/kg Q3W6.0 mg/kg Q3W1.5 mg/kg Q1W3.0 mg/kg Q2WExpansion 5.0 mg/kg Q3WTotal
TEAEs(n = 3)(n = 3)(n = 3)(n = 4)(n = 3)(n = 4)(n = 6)(n = 6)(n = 8)(n = 6)(n = 29)(N = 75)
Any AE (≥10% total patients), n (%) 3 (100.0) 3 (100.0) 3 (100.0) 4 (100.0) 3 (100.0) 4 (100.0) 6 (100.0) 6 (100.0) 8 (100.0) 6 (100.0) 28 (96.6) 74 (98.7) 
 Anemia 2 (66.7) 2 (66.7) 1 (33.3) 1 (25.0) 2 (50.0) 1 (16.7) 3 (37.5) 1 (16.7) 8 (27.6) 21 (28.0) 
 Neutropenia 1 (33.3) 1 (25.0) 3 (50.0) 3 (50.0) 1 (12.5) 2 (33.3) 10 (34.5) 21 (28.0) 
 Fatigue 1 (33.3) 3 (100.0) 1 (25.0) 1 (16.7) 1 (16.7) 3 (37.5) 1 (16.7) 9 (31.0) 20 (26.7) 
 Nausea 1 (33.3) 1 (33.3) 2 (50.0) 1 (33.3) 1 (25.0) 1 (16.7) 4 (50.0) 2 (33.3) 6 (20.7) 19 (25.3) 
 Asthenia 1 (33.3) 1 (33.3) 1 (25.0) 3 (50.0) 2 (33.3) 3 (37.5) 7 (24.1) 18 (24.0) 
 Diarrhea 1 (33.3) 1 (33.3) 1 (25.0) 1 (33.3) 1 (25.0) 3 (50.0) 1 (16.7) 2 (25.0) 2 (33.3) 3 (10.3) 16 (21.3) 
 Leukopenia 1 (25.0) 2 (33.3) 2 (33.3) 2 (25.0) 1 (16.7) 8 (27.6) 16 (21.3) 
 Neuropathy peripheral 2 (50.0) 1 (33.3) 3 (75.0) 1 (16.7) 1 (16.7) 6 (20.7) 14 (18.7) 
 Thrombocytopenia 1 (25.0) 1 (16.7) 1 (16.7) 4 (50.0) 1 (16.7) 5 (17.2) 13 (17.3) 
 Corneal deposits 1 (25.0) 1 (16.7) 2 (33.3) 1 (16.7) 7 (24.1) 12 (16.0) 
 Malignant neoplasm progression 1 (25.0) 1 (16.7) 2 (33.3) 3 (37.5) 1 (16.7) 3 (10.3) 11 (14.7) 
 Back pain 1 (33.3) 1 (25.0) 1 (33.3) 1 (25.0) 1 (16.7) 2 (33.3) 2 (25.0) 1 (3.4) 10 (13.3) 
 Decreased appetite 1 (33.3) 2 (50.0) 1 (33.3) 1 (25.0) 2 (33.3) 1 (16.7) 2 (6.9) 10 (13.3) 
 Bone pain 1 (25.0) 2 (33.3) 1 (16.7) 2 (25.0) 3 (10.3) 9 (12.0) 
 Constipation 1 (33.3) 1 (33.3) 1 (33.3) 1 (16.7) 5 (17.2) 9 (12.0) 
 Dyspnea exertional 1 (33.3) 1 (25.0) 1 (33.3) 1 (25.0) 1 (16.7) 3 (10.3) 8 (10.7) 
 Headache 1 (33.3) 1 (33.3) 2 (33.3) 4 (13.8) 8 (10.7) 
 Hypokalemia 1 (33.3) 2 (33.3) 1 (16.7) 1 (12.5) 3 (10.3) 8 (10.7) 
 Insomnia 2 (66.7) 1 (33.3) 1 (25.0) 2 (33.3) 1 (16.7) 1 (3.4) 8 (10.7) 
Grade 3/4/5 AEs (≥5% total patients), n (%) 2 (66.7) 2 (66.7) 1 (33.3) 2 (50.0) 1 (33.3) 3 (75.0) 4 (66.7) 6 (100.0) 7 (87.5) 3 (50.0) 24 (82.8) 55 (73.3) 
 Neutropenia 1 (33.3) 1 (25.0) 2 (33.3) 1 (16.7) 1 (12.5) 1 (16.7) 8 (27.6) 15 (20.0) 
 Anemia 2 (66.7) 1 (33.3) 1 (33.3) 2 (50.0) 2 (25.0) 6 (20.7) 14 (18.7) 
 Leukopenia 1 (25.0) 2 (33.3) 1 (16.7) 2 (25.0) 4 (13.8) 10 (13.3) 
 Malignant neoplasm progression 1 (25.0) 1 (16.7) 2 (33.3) 3 (37.5) 2 (6.9) 9 (12.0) 
 Thrombocytopenia 1 (25.0) 1 (16.7) 2 (25.0) 1 (16.7) 1 (3.4) 6 (8.0) 
Serious AEs (≥2% total patients), n (%) 1 (33.3) 1 (33.3) 1 (33.3) 1 (33.3) 2 (50.0) 2 (33.3) 5 (83.3) 3 (37.5) 1 (16.7) 10 (34.5) 27 (36.0) 
 Malignant neoplasm progression 1 (25.0) 1 (16.7) 2 (33.3) 3 (37.5) 2 (6.9) 9 (12.0) 
 Corneal deposits 2 (33.3) 3 (10.3) 5 (6.7) 
 Acute kidney injury 1 (33.3) 1 (16.7) 2 (2.7) 

A total of 30 (40.0%) patients reported a TEAE that led to ABBV-838 discontinuation, 16 (21.3%) of which had a reasonable possibility of being related to ABBV-838 (Supplementary Table S1). Overall, 3 (4.0%) patients experienced TEAEs leading to death (1 patient each from the 4.0 mg/kg Q3W, 6.0 mg/kg Q3W, and 3.0 mg/kg Q2W treatment groups). There were 2 (2.7%) patients who experienced progression leading to death (1 patient in the 4.0 mg/kg Q3W treatment group and 1 patient in the 6.0 mg/kg Q3W treatment group), and 1 (1.3%) patient experienced sepsis leading to death (in the 3.0 mg/kg Q2W treatment group). No TEAEs leading to death were considered to be related to ABBV-838 treatment (Supplementary Table S1). An additional two deaths occurred outside the protocol-defined treatment-emergent window (1 patient in the 1.5 mg/kg Q1W treatment group and 1 patient in the 5.0 mg/kg Q3W treatment group experienced progression of preexisting cancer that led to death). While no MTD was identified, the recommended dose for the expansion cohort was selected to be 5.0 mg/kg Q3W. This was primarily based on the observed dose-dependent toxicity and a subsequent decreasing margin for safety with each dose-escalation cohort. The assessment was made that the dose regimen of 5 mg/kg Q3W exhibited a tolerable safety profile while reaching exposure levels, predicted by preclinical studies, to be in the efficacious range.

Pharmacokinetics, pharmacodynamics, and immunogenicity

Pharmacokinetic parameters of the conjugated antibody are summarized in Table 4. The exposures of conjugated antibody, total antibody, and unconjugated MMAE generally increased with increasing doses from 0.6 mg/kg to 6.0 mg/kg, with the exposure of total antibody similar to ABBV-838. However, the small number of patients per cohort limited the data interpretation. Linear and log-linear mean serum concentrations of ABBV-838 conjugate in cycles 1 and 3 are shown in Fig. 1. The t1/2 was approximately 3 to 10.6 days for the conjugated antibody, and approximately 4 to 6 days for the unconjugated MMAE.

Table 4.

ABBV-838 conjugate pharmacokinetic parameters in cycle 1 and cycle 3.

PK parameters,0.6 mg/kg0.9 mg/kg1.4 mg/kg2.0 mg/kg3.0 mg/kg4.0 mg/kg5.0 mg/kg6.0 mg/kg1.5 mg/kg3.0 mg/kg
unitQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ1WQ2W
Cycle 1n = 3n = 3n = 3n = 4n = 3n = 4n = 35an = 6n = 8n = 6b
Tmax, hrc 1.8 (0.3–2.5) 0.3 (0.3–3.0) 3.0 (0.3–3.0) 3.0 (3.0–3.0)d 3.0 (2.5–3.0) 2.8 (0.3–3.0) 0.4 (0.3–72.0) 0.3 (0.3–3.0) 0.3 (0.3–3.0) 3.0 (0.3–3.0) 
Cmax, μg/mL 11.1 (11.8–45) 22.4 (22.6–16) 23.2 (23.3–11) 39.4 (44.3–56) 89.3 (89.5–8) 88.5 (90.0–20) 92.4 (94.9–20) 154 (161–34) 24.1 (24.7–34) 61.8 (63.1–22) 
AUCtau, μg·day/mL 35.6 (48.0–90) 68.3 (75.5–56) 96.1 (104–48) 162 (221–98) 374 (378–18) 305 (326–40) 402 (424–32) 632 (707–53) 54.5 (61.7–57) 221 (243–47) 
AUCinf, μg·day/mL 36.3 (50.0–90) 51.3 (41.6–63.2)e 99.9 (62.4–106)e 165 (225–98) 403 (413–28) 312 (332–39) 425 (456–39)f 764 (841–48)g 45.2 (51.7–60)h 235 (262–50) 
t1/2, dayi 3.32 (1.34) 5.21 (4.97–5.47)e 2.91 (2.59–3.34)e 3.47 (2.30) 4.79 (2.11) 4.12 (0.80) 4.56 (1.77)f 4.38 (2.27)g 4.38 (2.27)h 3.05 (1.19) 
Cycle 3 n = 2e n = 2e n = 2e n = 3 n = 3 n = 2e n = 15 n = 4 n = 2e n = 4 
Tmax, hrc 1.6 (0.3–3.0) 0.8 (0.3–1.3) 1.6 (0.3–3.0) 3.0 (2.4–72) 2.2 (0.3–3.0) 1.6 (0.3–3.0) 0.3 (0.3–3.0) 1.6 (0.3–3.0) 1.6 (0.3–3.0) 1.6 (0.3–3.0) 
Cmax, μg/mL 16.6 (13.9–19.8) 20.1 (17.3–23.4) 31.0 (29.3–32.7) 25.6 (39.9–81) 76.1 (76.4–11) 100 (98.1–102) 101 (26–104) 111 (144–53) 12.9 (13.3–29) 56.8 (64.2–56) 
AUCtau, μg·day/mL 62.4 (40.0–97.2) 46.1 (37.8–56.1) — 132 (226–105) 608j 429 (414–444) 549 (35–587)k 765 (854–52) 22.2j 174 (208–52) 
AUCinf, μg·day/mL 64.4 (36.1–115) 48.0 (39.4–58.6) — 304 (160–577)e 794j 450 (430–470) 630 (40–692)l 1130 (1230–45)d — 165 (217–74)d 
t1/2, dayi 3.07 (1.86–8.79) 8.88 (7.34–11.2) — 4.91 (3.38–8.94)e 10.6j 4.98 (4.87–5.09) 6.76 (3.08)l 6.53 (2.14)d — 3.29 (1.25)d 
PK parameters,0.6 mg/kg0.9 mg/kg1.4 mg/kg2.0 mg/kg3.0 mg/kg4.0 mg/kg5.0 mg/kg6.0 mg/kg1.5 mg/kg3.0 mg/kg
unitQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ1WQ2W
Cycle 1n = 3n = 3n = 3n = 4n = 3n = 4n = 35an = 6n = 8n = 6b
Tmax, hrc 1.8 (0.3–2.5) 0.3 (0.3–3.0) 3.0 (0.3–3.0) 3.0 (3.0–3.0)d 3.0 (2.5–3.0) 2.8 (0.3–3.0) 0.4 (0.3–72.0) 0.3 (0.3–3.0) 0.3 (0.3–3.0) 3.0 (0.3–3.0) 
Cmax, μg/mL 11.1 (11.8–45) 22.4 (22.6–16) 23.2 (23.3–11) 39.4 (44.3–56) 89.3 (89.5–8) 88.5 (90.0–20) 92.4 (94.9–20) 154 (161–34) 24.1 (24.7–34) 61.8 (63.1–22) 
AUCtau, μg·day/mL 35.6 (48.0–90) 68.3 (75.5–56) 96.1 (104–48) 162 (221–98) 374 (378–18) 305 (326–40) 402 (424–32) 632 (707–53) 54.5 (61.7–57) 221 (243–47) 
AUCinf, μg·day/mL 36.3 (50.0–90) 51.3 (41.6–63.2)e 99.9 (62.4–106)e 165 (225–98) 403 (413–28) 312 (332–39) 425 (456–39)f 764 (841–48)g 45.2 (51.7–60)h 235 (262–50) 
t1/2, dayi 3.32 (1.34) 5.21 (4.97–5.47)e 2.91 (2.59–3.34)e 3.47 (2.30) 4.79 (2.11) 4.12 (0.80) 4.56 (1.77)f 4.38 (2.27)g 4.38 (2.27)h 3.05 (1.19) 
Cycle 3 n = 2e n = 2e n = 2e n = 3 n = 3 n = 2e n = 15 n = 4 n = 2e n = 4 
Tmax, hrc 1.6 (0.3–3.0) 0.8 (0.3–1.3) 1.6 (0.3–3.0) 3.0 (2.4–72) 2.2 (0.3–3.0) 1.6 (0.3–3.0) 0.3 (0.3–3.0) 1.6 (0.3–3.0) 1.6 (0.3–3.0) 1.6 (0.3–3.0) 
Cmax, μg/mL 16.6 (13.9–19.8) 20.1 (17.3–23.4) 31.0 (29.3–32.7) 25.6 (39.9–81) 76.1 (76.4–11) 100 (98.1–102) 101 (26–104) 111 (144–53) 12.9 (13.3–29) 56.8 (64.2–56) 
AUCtau, μg·day/mL 62.4 (40.0–97.2) 46.1 (37.8–56.1) — 132 (226–105) 608j 429 (414–444) 549 (35–587)k 765 (854–52) 22.2j 174 (208–52) 
AUCinf, μg·day/mL 64.4 (36.1–115) 48.0 (39.4–58.6) — 304 (160–577)e 794j 450 (430–470) 630 (40–692)l 1130 (1230–45)d — 165 (217–74)d 
t1/2, dayi 3.07 (1.86–8.79) 8.88 (7.34–11.2) — 4.91 (3.38–8.94)e 10.6j 4.98 (4.87–5.09) 6.76 (3.08)l 6.53 (2.14)d — 3.29 (1.25)d 

Abbreviations: %CV, percentage coefficient of variation; AUCinf, area under the serum concentration-time curve from time zero to infinity; AUCtau, area under the serum concentration-time curve from time zero to day 21 (Q3W), day 14 (Q2W), or day 7 (Q1W); Cmax, maximum observed concentration; hr, hour; PK, pharmacokinetic; t1/2, terminal phase elimination half-life; Tmax, time to Cmax.

aCombined cohorts (dose escalation and dose expansion).

bCombined cohorts.

cMedian (minimum – maximum).

dN = 3.

eN = 2 reported as mean (geometric or harmonic) and individual values.

fN = 34.

gN = 5.

hN = 4.

iHarmonic mean (pseudo-SD) where available.

jN = 1.

kN = 12.

lN = 11.

Figure 1.

Mean ABBV-838 conjugate serum concentration–time profiles in cycle 1 (A) and cycle 3 (B) on linear and log-linear scales.

Figure 1.

Mean ABBV-838 conjugate serum concentration–time profiles in cycle 1 (A) and cycle 3 (B) on linear and log-linear scales.

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For 15 days following a single dose of ABBV-838 there was a trend toward increased CS1 receptor occupancy with increasing doses of ABBV-838 when bone marrow aspirate–isolated CD45dimCD138+ plasma cells were stained with fluorescently labeled, CS1-specific ABBV-838 competing and noncompeting antibodies (Fig. 2A). A comparison of the CS1-specific, ABBV-838 noncompeting antibody demonstrated that CS1 levels on the bone marrow–derived target cells appeared to decrease as early as 15 days after first dose of ABBV-838 (Fig. 2B).

Figure 2.

A, Increased levels of CS1 receptors on bone marrow plasma cells occupied by ABBV-838 during Q3W dose escalation. Individual results are shown for all patients who had successful day 15 measurements (n = 29). B, Decreased levels of CS1 receptors on bone marrow plasma cells were observed 15 days post-dosing. Individual CS1 receptor level results are shown for all patients with successful baseline and day 15 anti-CS1, ABBV-838 noncompeting antibody measurements (n = 20).

Figure 2.

A, Increased levels of CS1 receptors on bone marrow plasma cells occupied by ABBV-838 during Q3W dose escalation. Individual results are shown for all patients who had successful day 15 measurements (n = 29). B, Decreased levels of CS1 receptors on bone marrow plasma cells were observed 15 days post-dosing. Individual CS1 receptor level results are shown for all patients with successful baseline and day 15 anti-CS1, ABBV-838 noncompeting antibody measurements (n = 20).

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Preliminary efficacy

The best overall tumor response by IMWG is summarized in Table 5. All patients were evaluable for the efficacy endpoint. An ORR was achieved in 8 patients [10.7% (95% confidence interval (CI), 4.7–19.9)]; very good partial response (VGPR) and partial response (PR) was achieved by 2 (2.7%) and 6 (8.0%) patients, respectively. Fifty-two patients had a best overall response of stable disease (69.3%), and 14 (18.7%) patients had progressive disease.

Table 5.

Best overall tumor response by IMWG.

0.6 mg/kg0.9 mg/kg1.4 mg/kg2.0 mg/kg3.0 mg/kg4.0 mg/kg5.0 mg/kg6.0 mg/kg1.5 mg/kg3.0 mg/kgExpansion
Q3WQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ1WQ2W5.0 mg/kg Q3WTotal
(n = 3)(n = 3)(n = 3)(n = 4)(n = 3)(n = 4)(n = 6)(n = 6)(n = 8)(n = 6)(n = 29)(N = 75)
Best overall response, n (%) 
 Stringent complete response 
 CR 
 VGPR 1 (16.7) 1 (16.7) 2 (2.7) 
 PR 1 (25.0) 1 (16.7) 1 (16.7) 3 (10.3) 6 (8.0) 
 Minimal response 1 (3.4) 1 (1.3) 
 Stable disease 3 (100) 2 (66.7) 3 (75.0) 3 (100) 4 (100) 3(50.0) 4 (66.7) 7 (87.5) 5 (83.3) 18 (62.1) 52 (69.3) 
 Progressive disease 1 (33.3) 3 (100) 1 (16.7) 1 (16.7) 1 (12.5) 7 (24.1) 14 (18.7) 
 Clinical relapse 
 Unknown 
ORRa 1 (25.0) 2 (33.3) 1 (16.7) 1 (16.7) 3 (10.3) 8 (10.7) 
95% CIb (0.0–70.8) (0.0–70.8) (0.0–70.8) (0.6–80.6) (0.0–70.8) (0.0–60.2) (4.3–77.7) (0.4–64.1) (0.0–36.9) (0.4–64.1) (2.2–27.4) (4.7–19.9) 
0.6 mg/kg0.9 mg/kg1.4 mg/kg2.0 mg/kg3.0 mg/kg4.0 mg/kg5.0 mg/kg6.0 mg/kg1.5 mg/kg3.0 mg/kgExpansion
Q3WQ3WQ3WQ3WQ3WQ3WQ3WQ3WQ1WQ2W5.0 mg/kg Q3WTotal
(n = 3)(n = 3)(n = 3)(n = 4)(n = 3)(n = 4)(n = 6)(n = 6)(n = 8)(n = 6)(n = 29)(N = 75)
Best overall response, n (%) 
 Stringent complete response 
 CR 
 VGPR 1 (16.7) 1 (16.7) 2 (2.7) 
 PR 1 (25.0) 1 (16.7) 1 (16.7) 3 (10.3) 6 (8.0) 
 Minimal response 1 (3.4) 1 (1.3) 
 Stable disease 3 (100) 2 (66.7) 3 (75.0) 3 (100) 4 (100) 3(50.0) 4 (66.7) 7 (87.5) 5 (83.3) 18 (62.1) 52 (69.3) 
 Progressive disease 1 (33.3) 3 (100) 1 (16.7) 1 (16.7) 1 (12.5) 7 (24.1) 14 (18.7) 
 Clinical relapse 
 Unknown 
ORRa 1 (25.0) 2 (33.3) 1 (16.7) 1 (16.7) 3 (10.3) 8 (10.7) 
95% CIb (0.0–70.8) (0.0–70.8) (0.0–70.8) (0.6–80.6) (0.0–70.8) (0.0–60.2) (4.3–77.7) (0.4–64.1) (0.0–36.9) (0.4–64.1) (2.2–27.4) (4.7–19.9) 

Abbreviations: PR, partial response; sCR, stringent complete response.

aThe proportion of subjects with a confirmed sCR, CR, VGPR, or PR to the treatment.

b95% CI for ORR was constructed using the two-sided Clopper–Pearson method.

Of the 8 patients who achieved PR or more, 5 had a response duration of less than 5 months. Overall, the duration of response ranged from approximately 1 to 11 months, and the median duration of response was 4 months. In the patients who received 5.0 mg/kg ABBV-838, 1 patient achieved VGPR with response duration of 3 months, and 2 patients achieved PR with durations of 0.8 and 8.7 months, respectively.

This phase I dose-escalation study represents the first-in-human trial of the ADC ABBV-838 in patients with RRMM. The results demonstrate that ABBV-838 is generally safe and well-tolerated. The most common TEAEs were general disorders, hematologic TEAEs, and gastrointestinal TEAEs. Overall, with the exception of corneal deposits, which were experienced by 12 patients and often accompanied by a reversible loss of visual acuity, the majority of TEAEs were consistent with those expected in patients with RRMM who had received prior chemotherapies, experienced underlying disease progression, or with those events associated with MMAE exposure. The most common grade 3/4/5 TEAEs that were considered possibly related to ABBV-838 were anemia and neutropenia, which is consistent with previous reports for ADCs containing MMAE (19). Also consistent with other MMAE-containing ADCs was the rate of peripheral neuropathy, which was thought to be manageable, but could limit treatment with ABBV-838.

A TEAE of particular interest was the corneal deposits, which appeared at various times during treatment (cycle range 1–11, majority following third or fourth cycle). The deposits appeared to contain caspase 3, suggestive of keratinocyte apoptosis. Our hypothesis is that ABBV-838 induced cell death of CS1-positive macrophages in the human cornea, which then failed to clear apoptotic keratinocytes in the corneal epithelium. Debris of apoptotic keratinocytes presumably accumulated as the corneal deposits and resulted in a loss of visual acuity.

The conjugated antibody and unconjugated MMAE exposures following intravenous infusion were generally increased with increased doses; however, the data were too limited to conclude the dose proportionality.

ABBV-838 demonstrated minimal activity in patients with RRMM, with approximately 10% of patients achieving an ORR; duration of response ranged from approximately 1 to 11 months, and median duration of response was 4 months. Pharmacokinetic analysis suggests that at the recommended dose and schedule of 5.0 mg/kg Q3W, drug exposure levels are within the estimated therapeutic levels, on the basis of unpublished preclinical studies. In addition, pharmacodynamic analysis of bone marrow–derived plasma cells indirectly indicates effective engagement of ABBV-838 with the CS1 target, with receptor occupancy levels reaching ≥50%. However, it is unclear whether adequate drug exposure was attained within the target cells. Although robust target engagement was measured in the target cells, CS1 levels also appeared to diminish over time, potentially leading to loss or downregulation of drug target. Because internalization of the drug–target complex was not quantified, it also leaves open the possibility that insufficient MMAE was released within the target cells. Clinical studies with elotuzumab, the approved anti-CSC–1 mAb, did not exhibit single-agent activity (13); however, demonstrated a favorable safety profile and scientific rationale for combination studies with IMiDs. The mechanism of action of elotuzumab is antibody-dependent cellular cytotoxicity, while ABBV-838 delivers a potent cytotoxin to target cells. Combination strategies with ABBV-838 were not pursued because of the additional safety burden of ABBV-838, specifically due to the potent cytotoxin contained in the drug. Moreover, there is no clear mechanistic rationale for combining ABBV-838 with other antimyeloma agents.

Clinical studies with other ADCs targeting epitopes frequently expressed on multiple myeloma cells have shown significant antitumor activity in patients with RRMM. Notably, updated interim results from the phase I study of GSK2857916, an ADC against B-cell maturation antigen (BCMA), in patients with multiple myeloma and progressive disease after stem cell transplantation, alkylators, PIs, and immunomodulators reported promising efficacy data (20). In total, 60% of patients achieved a PR or better, with two stringent responses and three complete responses reported. The median progression-free survival was 12 months, and median duration of response was 14.3 months. It is unclear whether the difference in clinical activity of GSK2857916 versus ABBV-838 is due to a difference in target, drug exposure, or the choice of toxin. ABBV-838 incorporates MMAE, a membrane-soluble toxin, while the BCMA-targeted ADC incorporates monomethyl auristatin F (MMAF), a membrane-impermeable toxin. It is possible the membrane-impermeable property allows the MMAF toxin to accumulate within the myeloma cells, thereby exhibiting superior exposure compared with the membrane-permeable MMAE.

In summary, while ABBV-838 demonstrated some clinical activity, there are several potential reasons why this agent may be lacking in robust antitumor activity. Interpretation of data from this study to fully establish any benefit of ABBV-838 in patients with RRMM is limited by unknown factors within the mechanism of action, as well as by the small number of patients enrolled in each cohort within this study. As the defined efficacy criteria were not met, enrollment of patients in the study (and into the combination therapy arm) was discontinued.

R. Vij is a paid consultant for Takeda, Amgen, Celgene, Bristol-Myers Squibb, Janssen, Karyopharm Therapeutics, AbbVie, Shire, and Alexion Pharmaceuticals; reports receiving commercial research grants from Takeda and Amgen; and reports receiving speakers bureau honoraria from Takeda, Amgen, Celgene, Bristol-Myers Squibb, Janssen, Karyopharm, AbbVie, Shire, and Alexion Pharmaceuticals. R. Nath is a paid consultant for AbbVie. D.E.H. Afar is an employee for AbbVie. M.-V. Mateos reports receiving speakers bureau honoraria from Janssen, Celgene, Amgen, Takeda, AbbVie, GlaxoSmithKline, Adaptive, and EDOMundipharma, and is an unpaid consultant/advisory board member for Janssen, Celgene, Amgen, Takeda, AbbVie, and GlaxoSmithKline. J.G. Berdeja is a paid consultant for Takeda, Bristol-Myers Squibb, Karyopharm, CRISPR, Celgene, Kite, Servier, Janssen, Amgen, Legend, BioClinica, and Prothena, and reports receiving commercial research grants from AbbVie, Amgen, Acetylon, Bluebird, Bristol-Myers Squibb, Celgene, Constellation, CURIS, Genentech, Glenmark, Janssen, Kesios, Lilly, Novartis, Poseida, Sanofi, Takeda, Teva, and Vivolux. M.S. Raab reports receiving speakers bureau honoraria from AbbVie. J. Martínez-López reports receiving commercial research grants from Bristol-Myers Squibb and reports receiving speakers bureau honoraria from Celgene, Novartis, Janssen, and Incyte. K. Weisel is a paid advisory board member for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Sanofi, Takeda, Karyopharm, Adaptive Biotech, and GlaxoSmithKline. S. Wong is an employee for AbbVie. S. Gulbranson is an employee for and holds ownership interest (including patents) in AbbVie. J.P. Sheridan is an employee for AbbVie. A. Reddy is an employee for AbbVie. B. Paiva reports receiving commercial research grants from Celgene, Roche, and Sanofi, and reports receiving speakers bureau honoraria from Amgen, Celgene, Janssen, and Takeda. A. Singhal is an employee for AbbVie. J.F. San-Miguel is an unpaid consultant/advisory board member for Takeda, Celgene, Novartis, Amgen, Janssen-Cilag, Bristol-Myers Squibb, and MSD. P. Moreau reports receiving speakers bureau honoraria from AbbVie, Celgene, Amgen, and Janssen. No potential conflicts of interest were disclosed by the other authors.

Conception and design: R. Nath, D.E.H. Afar, X. Leleu, S. Wong, J.P. Sheridan, A. Singhal, J.F. San-Miguel

Development of methodology: R. Nath, J. Martínez-López, X. Leleu, K. Weisel, J.P. Sheridan, B. Paiva, A. Singhal, J.F. San-Miguel

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R. Nath, M.-V. Mateos, J.G. Berdeja, M.S. Raab, A. Guenther, J. Martínez-López, A.J. Jakubowiak, X. Leleu, K. Weisel, J.P. Sheridan, A. Reddy, B. Paiva, J.F. San-Miguel

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R. Nath, D.E.H. Afar, M.-V. Mateos, J.G. Berdeja, A. Guenther, A.J. Jakubowiak, X. Leleu, K. Weisel, S. Wong, S. Gulbranson, J.P. Sheridan, A. Reddy, A. Singhal, J.F. San-Miguel, P. Moreau

Writing, review, and/or revision of the manuscript: R. Vij, R. Nath, D.E.H. Afar, M.-V. Mateos, J.G. Berdeja, M.S. Raab, A. Guenther, J. Martínez-López, A.J. Jakubowiak, X. Leleu, K. Weisel, S. Wong, S. Gulbranson, J.P. Sheridan, A. Reddy, B. Paiva, J.F. San-Miguel, P. Moreau

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): X. Leleu, K. Weisel, J.P. Sheridan

Study supervision: R. Nath, X. Leleu, J.P. Sheridan, A. Singhal, J.F. San-Miguel

AbbVie provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the article. The antibody–drug conjugate technology is licensed from Seattle Genetics. AbbVie and the authors thank the patients who participated in this clinical trial, the study coordinators, and support staff. This study was funded by AbbVie Inc. Medical writing support was provided by Shilu Amin, PhD, Aptitude Health, The Hague, the Netherlands, funded by AbbVie.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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