A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma

PURPOSE

ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study.

METHODS

Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion.

RESULTS

As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively.

CONCLUSION

ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

INTRODUCTION

Multiple myeloma (MM) is the second most prevalent hematologic malignancy globally.¹ Treatment options for MM have improved substantially over the past 20 years, with many new drug classes, such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), being introduced that have increased life expectancy.² Despite these advances, patients will ultimately develop drug-resistant disease and progress to relapsed/refractory multiple myeloma (RRMM). Thus, patients with RRMM represent a significant treatment challenge, as they have a poor prognosis.³

CONTEXT

• Key Objective

• There remains an unmet clinical need for novel therapies that can overcome treatment resistance and improve overall outcomes for patients with relapsed/refractory multiple myeloma. B-cell maturation antigen has emerged as a promising therapeutic target in multiple myeloma. This trial describes outcomes with ABBV-383, an anti B-cell maturation antigen × CD3 bispecific monoclonal antibody in patients with relapsed/refractory multiple myeloma (≥ three prior lines of therapy: proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody).

• Knowledge Generated

• ABBV-383 was well tolerated in the overall population (N = 124), with cytokine release syndrome (57%) the most common treatment-emergent adverse event; majority of events were grades 1/2 (55%). An objective response rate of 68% and ≥ very good partial response rate of 54% were reported at the therapeutic doses of ≥ 40 mg. Median duration of response and progression-free survival were not reached (median follow-up: 10.8 months).

• Relevance

• The promising preliminary antitumor activity in heavily pretreated patients supports further exploration of ABBV-383 in patients with multiple myeloma in larger clinical trials.

Survival is limited in patients with RRMM with a median overall survival (OS) of 5.6-11.2 months in patients refractory to CD38-targeted mAbs⁴ and a median OS of 5.1-11.5 months in patients who are double or triple/quadruple refractory to PIs and IMiDs.^3,5 Drug resistance, which represents an important challenge for the treatment of RRMM, is due to a number of possible mechanisms including changes in the tumor microenvironment, clonal evolution, P-glycoprotein overexpression in MM cells, and multidrug resistance gene polymorphism.⁶ Therefore, there is still a need to develop new therapies with novel mechanisms of action to target RRMM cells effectively and improve treatment outcomes and overall quality of life for patients.

B-cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily member 17 or CD269, is a type III transmembrane glycoprotein that is highly expressed on MM cells, but not on other normal tissues aside from normal plasma cells.^7,8 BCMA is involved in the regulation of B-cell proliferation, survival, maturation, and differentiation into plasma cells.⁷ Thus, BCMA has emerged as a novel treatment target for MM because of its highly selective expression on malignant plasma cells.^8,9 A number of BCMA-targeted therapies are being developed, including chimeric antigen receptor–modified T-cell (CAR-T) therapies, antibody-drug conjugates (ADCs), and T-cell engaging bispecific mAbs (T-BsAbs),^7-9 and some have received approval (accelerated and/or full approval) by the US Food and Drug Administration and the European Medicines Agency. Approved agents include belantamab mafodotin (first-in-class anti-BCMA immunoglobulin [Ig]G1 ADC), idecabtagene vicleucel, and ciltacabtagene autoleucel (BCMA-targeted CAR-T therapies).^10-15

ABBV-383 (formerly known as TNB-383B), is a next-generation, fully human, monoclonal, IgG4 T-BsAb, BCMA-targeted therapy, which incorporates a low-activating CD3 that preclinically decouples T-cell activation from cytokine release and preferentially activates effector over regulatory T cells.^16-18 ABBV-383 consists of two heavy chains and one light chain: heavy chain 1 and the kappa light chain form the antigen-binding site that recognizes and binds to human CD3 with low affinity (1.3 μM), whereas heavy chain 2 targets BCMA with high affinity and avidity.^16,18 The unique design of ABBV-383 maximizes MM target-cell killing while potentially minimizing off-target toxicity and cytokine release, as demonstrated in preclinical studies. These results may translate to the improved tolerability and efficacy in vivo.¹⁸ ABBV-383 has demonstrated antitumor cell activity with minimal cytokine release in preclinical studies.^16,17 Ex vivo efficacy was also demonstrated against bone marrow mononuclear cells freshly isolated from patients with relapsed MM, with only a mild increase of cytokines associated with cytokine release syndrome (CRS).¹⁸

Herein, we report interim results from the first-in-human phase I trial that is currently ongoing to investigate the safety, clinical pharmacology, and clinical activity of ABBV-383 in patients with RRMM.

METHODS

Study Design

To our knowledge, this study was the first-in-human, phase I, multicenter, open-label clinical trial of ABBV-383 that consisted of a dose escalation phase followed by dose-expansion phase. The primary objectives of the study evaluated the safety and tolerability, determined the maximum tolerated dose (MTD) or recommended phase II dose, and evaluated clinical pharmacology of ABBV-383 monotherapy. The secondary objective evaluated the clinical activity of ABBV-383 monotherapy according to the 2016 International Myeloma Working Group (IMWG) criteria.¹⁹

All patients provided written informed consent before study entry. The study was approved by the relevant institutional review boards and/or independent ethics committees, and was conducted according to the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. This study is registered with ClinicalTrials.gov (identifier: NCT03933735).

Patient Eligibility

Full eligibility criteria are listed in the Appendix Table A1 (online only). Briefly, patients (age ≥ 18 years) with RRMM (≥ three prior lines of therapy that included a PI, an IMiD, and an anti-CD38 mAb), estimated glomerular filtration rate ≥ 30 mL/min as calculated by the Modification of Diet in Renal Disease formula, and Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤ 2 were enrolled. Prior treatment with a BCMA-targeted therapy was prohibited, and patients were not candidates for treatment regimens known to provide clinical benefit in MM.

Dose Escalation and Dose Expansion Phases

Patients received ABBV-383 intravenously (IV) over 1-2 hours at a fixed dose once every 3 weeks in the dose escalation phase (Appendix Fig A1, online only). No step or priming doses were implemented. Patients were premedicated with dexamethasone 10 mg IV (once on day 1) or equivalent prior to the administration of ABBV-383 for cycle 1. Subsequently, the dose frequency would be prior to the administration of ABBV-383 only (once every 3 weeks) and it could be tapered off as stated in the Protocol (online only) for subsequent cycles. If a patient did not experience an infusion-related reaction or immune-mediated toxicity in a given cycle, the dexamethasone premedication dose could be reduced to 5 mg IV (once on day 1) thereafter prior to the administration of ABBV-383 (once every 3 weeks). If a patient did not experience an infusion-related reaction or immune-mediated toxicity in a cycle where they received 5 mg dexamethasone IV (once on day 1) as premedication, dexamethasone could subsequently be omitted from the premedication regimen prior to the administration of ABBV-383 (once every 3 weeks). Additional administration details are provided in the Appendix 1 (online only). Fourteen dose levels were evaluated: 0.025 mg, 0.075 mg, 0.2 mg, 0.6 mg, 1.8 mg, 5.4 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 90 mg, and 120 mg. Patients received ABBV-383 until progressive disease (PD), unacceptable toxicity, or up to 3 years after the last patient's first dose.

The study used a 3 + 3 design with backfilling for selected doses and permitted intrapatient escalation to highest safe dose. In the dose escalation phase, cohorts 1-3 planned to enroll single patients, and beginning at cohort 4, a standard 3 + 3 dose escalation design was planned. Single-patient cohorts were planned to be converted to 3 + 3 cohorts if grade ≥ 2 toxicity was observed or if deemed appropriate by the safety monitoring group (eg, medical monitors and principal investigators or designated subinvestigators). Upon completion of the first cycle of the prior dose level, patients were able to intrapatient dose escalate to the next dose level following a review of the safety data from the higher dose by the safety monitoring group. Escalation-dose decisions were based on clinically significant toxicity, dose-limiting toxicity (DLT) events, and pharmacokinetic (PK) and pharmacodynamic findings. DLTs were determined during the first 21-day cycle and defined as a treatment-emergent adverse event (TEAE) not reasonably attributed to the patient's underlying disease, other medical conditions, or concomitant medications or procedures. The MTD was defined as the highest dose level at which < two of six evaluable patients experience a DLT.

At the time of the data cutoff, enrollment of the 60 mg expansion cohort had been completed, and the protocol was in process of being amended to investigate a lower dose (40 mg once every 3 weeks) in an additional expansion cohort (Appendix Fig A1). Patients were allowed to receive ABBV-383 as long as they did not meet discontinuation criteria or complete the study.

Assessments

Safety was assessed during the study through the evaluation of TEAEs, laboratory profiles, physical examinations, and vital signs. TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. TEAEs were captured from the time of consent until 90 days after discontinuation of ABBV-383. Serious TEAEs met the following criteria: death of patient, life-threatening, involved hospitalization, significant disability/incapacity, or required medical/surgical intervention to prevent serious outcome.

Blood samples for ABBV-383 PK analysis and antidrug antibody (ADA) analysis were collected at designated time points throughout the study and analyzed using the validated assays. PK parameters of ABBV-383 were determined using noncompartmental methods. Immunogenicity of ABBV-383 was summarized on the basis of the available ADA data.

Efficacy was assessed using 2016 IMWG uniform response criteria,¹⁹ including the objective response rate (ORR; defined as confirmed stringent complete response [sCR] plus complete response [CR] plus very good partial response [VGPR] plus partial response [PR]), OS, progression-free survival (PFS), time-to-progression, time-to-response, and duration of response (DoR). IMWG laboratory assessments (serum protein electrophoresis, urine protein electrophoresis, serum and urine immunofixation, serum free light chains, and serum quantitative immunoglobulins) were performed by a central laboratory. Imaging assessments were performed locally. All response categories required two consecutive assessments for confirmation. Minimal residual disease (MRD) was assessed by immunoglobulin gene rearrangement sequencing (Adaptive Biotechnologies, Seattle, WA) on bone marrow aspirate DNA at the time of suspected CR/sCR. PFS was defined as the time from the first dose of ABBV-383 to PD or death, whichever occurred first. OS was defined as the time from the first dose of ABBV-383 to death due to any cause. Patients were censored at the last known alive date on or before the data cutoff or snapshot date if no death occurred. Time-to-progression was defined as the duration from start of treatment to PD. Time-to-response was defined as the time of start of study treatment to first confirmed response (≥ PR). The DoR was defined as the time from the initial objective response to PD or death, whichever occurred first; patients were censored at the date of last tumor assessment if neither event occurred.

Statistical Analysis

The safety population included all patients who received ≥ 1 dose of ABBV-383. The efficacy-evaluable population was defined as patients who received ≥ 1 dose of ABBV-383 and have ≥ 1 postdose disease assessment. The PK population included patients who received ≥ 1 dose of ABBV-383 and had ≥ 1 PK sample drawn.

Frequency distributions were used for categorical variables and appropriate summary statistics (mean, median, and range) for quantitative/continuous variables. The two-sided 80% exact binomial CIs of the ORR are summarized using the Clopper-Pearson method together with the best overall response (CR, PR, stable disease, and PD). The Kaplan-Meier method was used to estimate PFS, OS, and DoR. Descriptive statistics for continuous safety variables and frequencies/percentages for discrete safety variables were used. The safety population allowed for detection of serious TEAEs occurring in as few as 21% of patients with 80% confidence.

RESULTS

Patient Demographics and Baseline Characteristics

As of January 8, 2022, 124 patients were enrolled (escalation phase, n = 73; expansion phase, n = 51). Demographics and baseline characteristics of treated patients (N = 124) are shown in Table 1 and includes patients treated in the ≥ 40 mg escalation- plus expansion-phase cohorts (n = 81) and 60 mg expansion cohort (n = 51). In the overall population, the median age was 68 years (range, 35-92 years), 55% were male, and 57% had an ECOG PS score of 1. The median number of prior lines of therapy was 5 (range, 3-15 lines), and 87% of patients were refractory to the last prior therapy. Patient disposition is shown in Table 2. Treatment is ongoing in 45 (36%) patients, and 79 (64%) patients discontinued treatment, mostly because of PD (n = 60/79; 76%). Fifty-five (44%) patients discontinued study participation; reasons included death (n = 33; 27%), withdrawal of consent (n = 15; 12%), and lost to follow-up (n = 1; 1%). Of the 33 (27%) reported deaths, 30 occurred > 30 days from the last dose of ABBV-383 and three occurred ≤ 30 days from the last dose; 12 occurred > 90 days from last ABBV-383 dose and 21 occurred ≤ 90 days from last dose.

TABLE 1.

Patient Characteristics

TABLE 2.

Patient Disposition

Safety

TEAEs (all grades, grade ≥ 3) in the overall population (N = 124), ≥ 40 mg escalation plus expansion (n = 81), and 60 mg expansion cohorts (n = 51) are shown in Table 3. The proportion of patients experiencing a TEAE (all grades) was similar in the overall population (98%), ≥ 40 mg escalation plus expansion (99%), and 60 mg expansion cohorts (98%); 72%, 77%, and 78%, respectively, experienced a grade ≥ 3 TEAE. The most common hematologic TEAEs (all grades [≥ 25% total patients]/grade ≥ 3) in the overall population were neutropenia (37%/34%) and anemia (29%/16%); similar results were reported for the ≥ 40 mg escalation plus expansion and 60 mg expansion cohorts. The most common nonhematologic TEAEs (all grades [≥ 25% total patients]) in the overall population were CRS (57%), fatigue (30%), nausea (29%), and diarrhea (27%); and in the ≥ 40 mg escalation plus expansion/60 mg expansion (all grades [≥ 30% of patients]) were CRS (73%/71%), nausea (35%/31%), diarrhea (32%/29%), and fatigue (30%/29%). Hypogammaglobulinemia occurred in 17 (14%) patients in the overall population. Twenty-nine (23%) patients in the overall population required administration of immunoglobulins (intravenous, n = 15 [12%]; not otherwise specified, n = 14 [11%]; preferred terms have the potential for overlapping).

TABLE 3.

TEAEs

In the overall population, serious TEAEs occurred in 66 (53%) patients, of whom 48 (59%) patients received ≥ 40 mg doses of ABBV-383 (escalation plus expansion cohorts, n = 81) and 31 (61%) patients received 60 mg (expansion cohort, n = 51). TEAEs of infection occurred in 51 (41%) patients overall (≥ 40 mg escalation plus expansion cohorts: n = 36/51, 44%; 60 mg expansion cohort: n = 24/51, 47%); 31 (25%) patients reported serious events. Grade ≥ 3 events of infections (≥ 5% total patients) in the overall population were pneumonia, sepsis, COVID-19 disease (6% each), and urinary tract infections (5%).

In the overall population, TEAEs leading to discontinuation, interruption, or dose reduction of ABBV-383 occurred in 12 (10%), 46 (37%), and six (5%) patients, respectively; neutrophil count decrease was the most common TEAE (n = 15; 12%) leading to interruption of ABBV-383, and CRS was the most common TEAE (n = 3; 2%) leading to dose reduction. Three patients experienced DLTs (DLT population: N = 73), all within the escalation cohorts (platelet count decreased [grade 4; 60 mg] and CRS [grade 3; 90 mg and 120 mg]). The MTD for ABBV-383 was not reached during the dose escalation phase, and dose-expansion was initiated with the 60 mg dose of ABBV-383 once every 3 weeks on the basis of CRS, plateauing ORR, and PK.

TEAEs leading to death occurred in seven (6%) patients due to COVID-19 disease (n = 3; 0.025 mg, 0.2 mg, and 60 mg), sepsis (n = 1; 5.4 mg), liver injury (n = 1; 50 mg), subdural hematoma (n = 1; 90 mg), and plasma cell myeloma (n = 1; 60 mg expansion cohort). All deaths were considered to be unrelated to ABBV-383 by the investigator.

Overview: AE of Interest

Details of CRS are shown in Table 4 and Appendix Figure A2 (online only). All events of CRS were considered to be related to ABBV-383 by the investigator. The onset of CRS typically occurred on the same day or the day following the first dose of ABBV-383, with a median time to onset of 1 day (overall population: range, 1-7 days; ≥ 40 mg escalation plus expansion cohorts: range, 1-2 days). The median time to resolution was 1 day (range, 1-8 days) in both the overall population and ≥ 40 mg escalation plus expansion cohorts; patients recovered quickly with standard supportive care measures and/or administration of tocilizumab. Most CRS events were grade 1 or 2 in all dose groups (Table 4). CRS grade ≥ 3 occurred in three (3%) patients at doses ≥ 60 mg (one each at 60 mg [expansion], and 90 mg and 120 mg [escalation]). Serious CRS events occurred in 22 (18%) patients in the overall population, 21 (26%) of which were in the ≥ 40 mg escalation plus expansion cohorts. A single patient in the study (at 40 mg) experienced recurrent CRS after cycle 1 (first event: grade 1, cycle 1 day 1-3; recurrent event: day 70 [cycle 4], 40 mg dose level). In total, 17 (14%) patients, all within the ≥ 40 mg escalation plus expansion cohorts, received tocilizumab.

TABLE 4.

CRS: Rate and Grade

Serious TEAEs considered to be neurotoxic, as evidenced by the preferred term immune effector cell-associated neurotoxicity, were reported in two patients (60 mg each).

PK and Immunogenicity

The preliminary PK analysis included data from 99 patients. ABBV-383 demonstrated dose-proportional PK at doses between 5.4 mg and 120 mg (Appendix Fig A3, online only). ABBV-383 concentrations from 0.025 mg and 0.075 mg were below the limits of quantification. The half-life (t_1/2) was approximately 12 days for doses between 5.4 mg and 120 mg, supporting the once every 3 weeks dosing schedule. Preliminary immunogenicity assessment of ABBV-383 indicates a relatively low incidence of immunogenicity with only four out of 76 (5%) evaluable patients treated with ABBV-383 having low-titer ADAs.

Efficacy

Response rates by dose group are shown in Table 5. The ORR and VGPR or better (≥ VGPR) rates for all efficacy-evaluable patients (n = 122) were 57% and 43%, respectively. In the 60 mg expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg escalation plus expansion cohorts (n = 79) were 68% and 54%, respectively. Of the 11 MRD-evaluable patients with CR or sCR, eight (73%) were MRD-negative (≤ 10^–5). All five MRD-evaluable patients treated in the ≥ 40 mg escalation plus expansion cohorts achieved MRD-negative CR at ≤ 10^–6 sensitivity threshold by next-generation sequencing. In triple-class refractory patients (defined as refractory to an IMiD, a PI, and an anti-CD38 mAb) overall (n = 100), the ≥ 40 mg escalation plus expansion cohorts (n = 64), and 60 mg expansion cohort (n = 41), the ORRs were 51%, 63%, and 54%, respectively. In patients with high-risk cytogenetics in the ≥ 40 mg escalation plus expansion cohorts (n = 11), the ORR, ≥ CR (sCR), VGPR, and PR rates were 82%, 27% (18%), 73%, and 9%, respectively. DoR for patients who achieved ≥ PR (n = 69) is shown in Figure 1A. At the time of the data cutoff, the median DoR had not been reached in the 60 mg expansion (n = 29) or the ≥ 40 mg escalation plus expansion cohorts (n = 54). The Kaplan-Meier estimate for the 6- and 12-month DoR rate was 79.9% (95% CI, 53.8 to 92.2) and 79.9% (95% CI, 53.8 to 92.2), respectively, for the 60 mg expansion cohort, and 74.8% (95% CI, 59.0 to 85.2) and 72.2% (95% CI, 56.1 to 83.2), respectively, for the ≥ 40 mg escalation plus expansion cohorts. Response over time for patients who achieved ≥ PR (n = 69) is shown in Appendix Figure A4 (online only). Median PFS was not reached in the ≥ 40 mg escalation plus expansion (n = 81) and 60 mg expansion (n = 51) cohorts (Fig 1B), and was 10.4 months (range, 5-19.2 months) on the overall population (N = 124). Overall, the median duration of follow-up was 10.8 months (range, 0.6-28.2 months) for all treated patients (N = 124), 8.2 months (range, 0.6-11.5 months) in the 60 mg expansion cohort (n = 51), and 9.6 months (range, 0.6-18.2 months) in the ≥ 40 mg escalation plus expansion cohorts (n = 81; Table 2).

TABLE 5.

Response Rates by IMWG Criteria

FIG 1.

DoR by IMWG criteria and PFS. DoR is for ≥ PR. DoR, duration of response; ESC, dose escalation; EXP, dose expansion; IMWG, International Myeloma Working Group; KM, Kaplan-Meier; LL, lower limit; NR, not reached; PFS, progression-free survival; UL, upper limit.

DISCUSSION

The results of this first-in-human, phase I study in patients with RRMM demonstrated that the T-BsAb BCMA-targeted therapy ABBV-383 was well tolerated at all doses administered, with a low incidence of grade ≥ 3 hematologic and nonhematologic TEAEs. ABBV-383 was associated with predictable and manageable CRS, without the need to implement step-dosing, and resolution occurred quickly with standard supportive care measures including the administration of tocilizumab if needed; only 14% of patients received tocilizumab. The majority of CRS events were grade 1 or 2 and resolved in 1 day. PK data indicated a t_½ of approximately 12 days, supporting the extended once every 3 weeks dosing. ABBV-383 also demonstrated a low level of immunogenicity, with ADA formation reported in only 5% of patients. In addition, ABBV-383 showed promising efficacy in the treatment of RRMM with an ORR of 59% observed at 60 mg in the expansion cohort (median follow-up: 8.2 months) and an ORR of 68% observed in the ≥ 40 mg escalation plus expansion cohorts (with a longer median follow-up of 9.6 months). The median 6- and 12-month DoR estimates were > 72% for both the 60 mg expansion cohort and the ≥ 40 mg escalation plus expansion cohort. The MTD was not reached, and the 60 mg once every 3 weeks dose was selected for dose-expansion on the basis of CRS, plateauing ORR, and PK.

BCMA is an important target for the treatment of RRMM, and several BCMA-targeted therapies have been approved or are in clinical development. These include belantamab mafodotin, CAR-T therapies (eg, idecabtagene vicleucel, and ciltacabtagene autoleucel), as well as the BsAbs CC-93269, REGN5458, teclistamab, and elranatamab. ABBV-383 has similar or improved efficacy in terms of ORRs (59% [60 mg expansion] and 68% [≥ 40 mg escalation plus expansion]) compared with the ADC belantamab mafodotin (32%),²⁰ the CAR-T therapies (61.5%-97%),^21-24 and the aforementioned BsAbs (44%-75%).^25-28 The tolerability profile of ABBV-383 demonstrated a 57% overall incidence of CRS (73% at ≥ 40 mg) without implementation of priming. CAR-T therapies have reported the following CRS rates: idecabtagene vicleucel, 84%²⁴; ciltacabtagene autoleucel, 95%.²² For BsAbs, overall CRS rate is approximately 70 (eg, CC-93269, 77%²⁶; teclistamab, 72%²⁷; elranatamab, 73%²⁵), which includes lower doses. In addition, this study allowed for the inclusion of patients with diminished renal function as well as patients who received allogenic transplant in comparison with CAR-T therapy clinical studies. The once every 3 weeks schedule of ABBV-383 was also viewed as convenient in that it may lead to improved compliance from patients as well as minimize the use of hospital resources. Finally, ABBV-383 has off-the-shelf availability, unlike CAR-T therapies, as well as shorter hospitalization time (first 48 hours after initial administration) versus other BCMAs and CAR-T therapies.

Limitations of this study involve the small number of patients enrolled in the dose escalation cohorts. Efforts are ongoing to determine the optimal dose regimen for ABBV-383 with lower doses being explored. ABBV-383 doses of 60 mg once every 3 weeks as well as 40 mg once every 3 weeks have been selected for further dose exploration and optimal-dose selection. The safety and efficacy of ABBV-383 will be investigated further in this ongoing phase I study.

APPENDIX 1. Methods

Study Treatment

ABBV-383 is administered by intravenous (IV) infusion over 1-2 hours at a fixed dose once every 3 weeks. If no infusion reactions occur during the first dose, the duration of the infusion for subsequent doses can be reduced to 1 hour. ABBV-383 cannot be administered over a period < 1 hour. Patients are also routinely premedicated with diphenhydramine 25-50 mg IV (once on day 1) or equivalent, oral acetaminophen 650-1,000 mg (once on day 1), and ranitidine 150 mg oral/IV (once on day 1) or equivalent, 15-60 minutes before the ABBV-383 infusion (once every 3 weeks) to reduce the risk and severity of hypersensitivity reactions commonly observed with monoclonal antibody therapy. Patients can also be premedicated with tocilizumab 8 mg/kg IV (once on day 1) at the discretion of the investigator or according to the institution's guidelines prior to the administration of ABBV-383 (once every 3 weeks).

FIG A1.

Study design and dose-expansion cohorts. Dose escalation study using a 3 + 3 design with backfilling. EXP, dose expansion.

FIG A2.

CRS overview: grade and dose. CRS, cytokine release syndrome; ESC, dose escalation; EXP, dose expansion.

FIG A3.

Clinical pharmacokinetics. Serum concentrations for 0.025 mg (n = 3) and 0.075 mg (n = 3) were below the limit of quantitation at all time points.

FIG A4.

Response over time in patients with ≥ PR. CR, complete response; MR, minor response; NE, not evaluable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

TABLE A1.

Eligibility Criteria

DATA SHARING STATEMENT

AbbVie Inc is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, 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.

These 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 (SAP) and execution of a Data Sharing Agreement (DSA). 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.

AUTHOR CONTRIBUTIONS

Conception and design: Nina Shah, Cesar Rodriguez, Peter M. Voorhees, Katja Weisel, Rajvineeth K. Pothacamury, Kevin J. Freise, Akshanth R. Polepally, Chetasi Talati, Ziyi Jin, Ben Buelow, Shaji Kumar

Administrative support: Ben Buelow

Provision of study materials or patients: Anita D'Souza, Peter M. Voorhees, Katja Weisel, Orlando F. Bueno

Collection and assembly of data: Anita D'Souza, Nina Shah, Cesar Rodriguez, Peter M. Voorhees, Katja Weisel, Orlando F. Bueno, Rajvineeth K. Pothacamury, Kevin J. Freise, Jeremy A. Ross, Akshanth R. Polepally, Chetasi Talati, Ziyi Jin, Ben Buelow, Shaji Kumar

Data analysis and interpretation: Anita D'Souza, Nina Shah, Cesar Rodriguez, Peter M. Voorhees, Katja Weisel, Orlando F. Bueno, Rajvineeth K. Pothacamury, Kevin J. Freise, Susan Yue, Jeremy A. Ross, Akshanth R. Polepally, Chetasi Talati, Shane Lee, Ziyi Jin, Ben Buelow, Ravi Vij, Shaji Kumar

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

A Phase I First-In-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma

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