A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma

This article is featured in Highlights of This Issue, p. 323

Multiple myeloma is a heterogeneous plasma cell malignancy that resides in the bone marrow. Even though survival rates have improved, most patients with myeloma eventually relapse, despite timely diagnosis and advances in treatment (1). The bone marrow microenvironment has been shown to be particularly important in response to treatment and dissemination of disease, and is thus an area of active investigation in drug development for multiple myeloma. CXCR4, in particular, has attracted attention for its role in disease progression and treatment response (2). CXCR4 is a chemokine receptor that is overexpressed in more than 75% of cancer cells, including myeloma (3), whereas its pathway, the CXCR4/CXCL12 (SDF-1) axis, is a known critical regulator of tumor proliferation, cell dissemination, and migration in and out of the bone marrow (4, 5). Although activating mutations in CXCR4 are not common in multiple myeloma, increased expression is achieved through external stimulation by high levels of stroma-secreted CXCL12, suggesting CXCR4 is important for myeloma growth and sustenance (6).

We, and others, have shown that CXCR4 is critical for cell dissemination in and out of the bone marrow, and constitutes a major regulator of extramedullary dissemination through the acquisition of an “epithelial–mesenchymal-like” activation phenotype (6, 7). That makes CXCR4 a unique target for therapeutic interventions in patients with extramedullary disease and end-stage relapsed/refractory multiple myeloma. In fact, we have previously demonstrated in vitro and in vivo that downregulation of CXCR4 by knockdown or therapeutic targeting can lead to the deadhesion of multiple myeloma cells from the bone marrow, which renders them more sensitive to other therapeutic agents like bortezomib (8). Those results suggest that not only is CXCR4 inhibition relevant in myeloma treatment as monotherapy, but it could also enhance the activity of other drugs, thus justifying testing its use in therapeutic combinations.

Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12 (9). It has been shown to induce apoptosis in multiple myeloma cell lines with high CXCR4 expression and has single-agent activity in vivo in multiple myeloma tumor xenograft models (9). It is thus reasonable to assume that ulocuplumab could potentially improve the overall response rate to standard therapy, through several mechanisms of action, including mobilization and apoptosis of malignant plasma cells. A prior phase I trial in relapsed/refractory acute myelogenous leukemia (AML) was conducted using ulocuplumab in combination with mitoxantrone, etoposide, and cytarabine (MEC) in patients and showed a 51% overall complete remission and complete remission with incomplete blood count recovery rate (CR/Cri; ref. 10). The adverse effects of ulocuplumab in combination with MEC was similar to MEC alone.

This study aimed to determine the safety, tolerability, and clinical activity of ulocuplumab alone and in combination with lenalidomide/low-dose dexamethasone or bortezomib/dexamethasone in subjects with relapsed/refractory multiple myeloma.

This was a phase Ib/II open-label, multicenter study with the primary objective to evaluate the safety profile, tolerability, pharmacokinetics, pharmacodynamics of ulocuplumab, either alone (first 14 days of cycle 1) or in combination with either lenalidomide and dexamethasone (Arm A) or bortezomib and dexamethasone (Arm B). From October 2011 to March 2014, patients were enrolled at Dana Faber Cancer Institute (Boston, MA), the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL), the University of Kansas Cancer Center and Medical Pavilion (Westwood, KS), and the University of Washington School of Medicine (Seattle, WA).

Patients were eligible for this trial if they were 18 years of age or older, with relapsed or relapsed/refractory multiple myeloma after having received at least two prior lines of treatment. Subjects who had previously failed lenalidomide or bortezomib were not excluded from retreatment. Other eligibility criteria included: Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and at least one of the following: IgG, IgA, IgM M-protein ≥0.5 g/dL, IgD M-protein ≥0.05 g/dL, monoclonal light chain in the urine protein electrophoresis of ≥200 mg/24 hours, abnormal serum-free light chain ratio ≥10. Patients also had to have demonstrated the following laboratory values within 28 days prior to dosing: absolute neutrophil count (ANC) ≥1,000/mm³, platelets (PLT) ≥50,000/mm³, hemoglobin (HGB) ≥8.0 gm/dL, direct bilirubin ≤2.0 × upper limit of normal (ULN), aspartate and alanine aminotransferase (AST/ALT) ≤3 × ULN, and an estimated creatinine clearance >50 mL/min/1.73 m². Patients with uncontrolled medical disorders or active infection, gastrointestinal diseases or condition that could impact the absorption of orally administered drug, inability to swallow oral medication or be administered intravenous medications, uncontrolled or significant cardiovascular diseases, clinically significant coagulation or platelet function disorder, other malignancies, acute diffuse infiltrative pulmonary and pericardial diseases, HIV, or hepatitis B or C infection were excluded. This phase Ib/II study used 3+3 design for the phase I dose-escalation portion and a two-stage outcome design to assess the efficacy and tolerability of ulocuplumab in combination with lenalidomide or bortezomib in patients with relapsed/refractory MM. The primary objectives of the phase I and the phase II studies were to ascertain the safety and MTD of the combination therapies and to determine the overall response rates of those combinations, respectively. In addition, the phase II study was also designed to determine the safety of the combination therapies at the phase II level as well as to determine the duration of response (DOR), time to progression (TTP), and progression-free survival (PFS).

There was no specific subject assignment across the two arms. The two arms were two separate studies and should not be compared with each other. In general, subjects who most recently failed lenalidomide were preferentially enrolled on the bortezomib/dexamethasone arm and subjects who most recently failed bortezomib were preferentially enrolled on the lenalidomide plus dexamethasone arm based on physician discretion. Subjects who had failed but were not refractory to lenalidomide and bortezomib were not excluded from retreatment with the same regimen.

All patients provided written informed consent. The review boards of all participating centers approved the study in accordance with the Declaration of Helsinki and the International Conference of Harmonization Guideline for Good Clinical Practice (ICH GCP).

For the dose-escalation portion of the study, patients were assigned to a dose level in the order of study entry for each of the two arms. In the dose-escalation scheme, 1, 3, or 10 mg/kg/dose of ulocuplumab was given as monotherapy on days 1 and 8 of the first 14 days of cycle 1 in both arms. For Arm A, from day 15 to 42 of the 42-day cycle 1, the assigned dose of ulocuplumab was given on days 15, 22, 29, and 36, in combination with both 25 mg of lenalidomide on days 15 to 35 and 40 mg of oral dexamethasone on days 15, 22, 29, and 36. For Arm B, from day 15 to 35 of the 35-day cycle 1, the assigned dose of ulocuplumab was given on days 15, 22, and 29, in combination with both 1.3 mg/m² of intravenous push bortezomib on days 15, 18, 22, and 25 and 20 mg of oral dexamethasone on days 15,16, 18, 19,22, 23, 25, and 26. For cycle 2 and subsequent cycles of Arm A, the assigned dose of ulocuplumab was given on days 1, 8, 15, and 22, in combination with both 25 mg of lenalidomide on days 1 to 21 and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycles. For cycle 2 and subsequent cycles of Arm B, the assigned dose of ulocuplumab was given on days 1, 8, and 15, in combination with both 1.3 mg/m² of intravenous push bortezomib on days 1, 4, 8, and 11 and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the 21-day cycles.

For the dose-expansion portion of the study, patients were enrolled to each arm at the established maximum dose of ulocuplumab of 10 mg/kg/dose given that there were no DLTs observed. For both Arm A and Arm B, cycle 1 consisted of a 28-day cycle of ulocuplumab monotherapy given at days 1, 8, 15, and 22. For cycle 2 and subsequent cycles of Arm A, ulocuplumab was given on days 1, 8, 15, and 22, in combination with both 25 mg of lenalidomide on days 1 to 21 and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycles. For further details, see consort diagrams (Supplementary Fig. S1).

In deriving the recommended phase II dose ranges and schedules, consideration was given to the rate and nature of delayed toxicities beyond cycle 1. After cycle 1 (for escalation) and cycle 2 (for expansion) of treatment, the timing, nature, and severity of the toxicities were reviewed by the sponsor/monitor and investigators.

In the dose-escalation portion of the study, cohorts of 3 patients were sequentially enrolled at each dose based on a 3+3 design on each arm. Adverse events (AE) experienced during the first cycle of treatment determined the dose-escalation proceedings. The dose was escalated if none of the first 3 patients in the cohort or 1 of the 6 patients experienced dose-limiting AEs during the first treatment cycle. If two or more patients experienced dose-limiting AEs, then dose escalation was halted. The MTD of ulocuplumab and the combination partners was defined as the highest dose at which less than one-third of the subjects experienced a dose-limiting toxicity (DLT) in the first cycle of treatment. DLTs were defined as any of the following events attributed to either ulocuplumab alone or in combination: ANC < 500 cells/mm³ for more than 5 days or febrile neutropenia, PLT < 10,000 cells/mm³ more than once, grade 3 or higher nausea, vomiting, or diarrhea despite intervention, QTcF 500 msec or greater confirmed, grade 3 or higher cardiac ischemia/infarction, LVEF decrease by >10 percentage points from baseline, grade 3 or higher total bilirubin, grade 3 or higher ALT or AST, grade 3 or higher creatinine, and any other grade 3 or higher drug-related toxicity. Dose modification of combination partners was permitted after cycle 1. After cycle 1, subjects in both the dose expansion and dose escalation were able to receive additional cycles (cycle 2 and subsequent) of combination therapy until progressive disease (PD), intolerability, unacceptable toxicity, withdrawal of consent, or achievement of complete response (CR).

To further characterize the safety and efficacy of ulocuplumab in combination with lenalidomide or bortezomib, at least 20 subjects (6 in the dose-escalation cohort + 14 in the expansion cohort) were allowed to be enrolled in each Arm at the MTD or the highest dose tested if the MTD was not identified. Given the early responses observed in Arm A more than Arm B, a decision was made to move forward with phase II expansion of Arm A only and not of Arm B.

Toxicities were monitored throughout the study and for up to 30 days after the last dose of study drug. AEs were graded according to the National Cancer Institute Common Terminology Criteria for AEs (version 3.0). In addition, neuropathy symptoms were assessed using the FACT/GOG-Neuropathy questionnaire (Version 4.0).

Pharmacokinetic and flow cytometry data were collected during the first cycle and scheduled at 0 (predose), 1.5, 2, 4, 6, 24, 48, and 72 hours after the first dose; 0 (predose) on day 8; 0 (predose), 6, 24, and 72 hours after the third dose, on day 15; 0 (predose), 1.5, 2, 4, 6, 24, 48, and 72 after the fourth dose, on day 22; and 0 (predose), 1.5, 2, 4, 6, 24, 48, 72, and 168 hours after the fifth dose, on day 29 of cycle 1. Pharmacokinetic parameters for ulocuplumab, including maximum observed serum concentration (C_max), time of maximum observed serum concentration (T_max), and the area under the concentration–time curve (AUC) were derived from plotting serum concentration over time. Actual times were used for the analyses. In addition, exploratory assessment of dose proportionality was based on a power model and a confidence interval around the slope was calculated.

Whole blood was collected and the mononuclear cell populations were measured for the specific cell types using flow cytometry. Multiple myeloma cells were enumerated with a custom validated assay using fluorescently labeled antibodies specific for CD45, CD19, CD56, CD38, and CD138 (BD Biosciences) as CD38⁺ CD138⁺CD45DIMCD19⁻CD56⁺ cells. T cells, B cells, and NK cells were enumerated using the 6-color IVD TBNK assay from BD Biosciences. CD34⁺ stem cells were enumerated using the BD stem count assay as required by the manufacturer. All samples were acquired using BD FACSCanto flow cytometers and data were analyzed using FACSvDIVA software. CXCR4 expression on multiple myeloma cells was also assessed by flow cytometry (BD Biosciences). Flow cytometry sampling was performed at 0 (predose), 2, 4, 6, 24, 48, and 72 hours after the first dose; 0 (predose), 2, 4, 5, 24 on day 8; and 0 (predose), 2, 4, 6, 24, and 72 hours after the third dose, on day 15 of cycle 1.

Study data are reported for all patients by stratification into study groups (Arms A and B) as well as for all patients combined. A summary of baseline patient characteristics was reported as number (%) of patients and median and range of values. Single-agent and combination therapy treatment responses were generated as proportions with 95% exact binomial confidence intervals. All time-to-event intervals were calculated using Kaplan–Meier estimates with 95% confidence intervals determined by Greenwood's variance estimator.

Time to response (TTR) was determined from treatment initiation to the date that the response had been originally observed. DOR was calculated from the start of the response until PD or death and was censored from analysis for patients who failed to progress using the date of the last disease assessment. TTP and PFS were determined from the start of treatment to the date of an event (PD for TTP; PD or death for PFS). Patients without an event were censored using the date of last disease assessment for both TTP and PFS. In the incident that nonprotocol therapy (excluding erythropoietin) had been added before an event, patients were censored in the time-to-event analyses at the start of that added therapy. Kaplan–Meier estimates were used to determine time to event whereas a long-rank test compared between estimates of time to event. All statistical analysis was computed using SAS software, SAS (version 9.3, SAS Institute Inc.) and R version 3.1.1. All results with P values <0.05 were considered statistically significant. Data cutoff was July 2016.

Between October 2011 and March 2014, 30 patients were enrolled in Arm A and 16 patients were enrolled in Arm B (Supplementary Fig. S1 consort diagram). The number of patients on each dose level of the phase I dose escalation are described in Supplementary Fig. S1. The median age at enrollment for Arm A was 60 years (range, 55–69). The median number of prior therapies was 3 (range, 1–9), including prior bortezomib in 28 patients (93.3%). The median age at enrollment for Arm B was 60 years (range, 50–66) and the median number of prior therapies was 4 (range, 2–11), including prior bortezomib in 14 patients (87.5%). The median duration of treatment was 7.2 months (range, 0.7–48.8 months). Cytogenetics were available in all patients; of them, 40.0% patients in Arm A and 25.0% patients in Arm B had high-risk cytogenetics defined as patients with 17p deletion, t(4;14), t(14;16), and +1q amplification. The baseline characteristics of patients who were enrolled in Arms A and B are listed in Table 1.

Ulocuplumab was administered at three dose levels (1, 3, and 10 mg/kg/dose). No DLT or MTD was identified. Therefore, the ulocuplumab dose level up to 10 mg/kg/dose was used for the expansion cohort. The median time to maximum serum concentration was 2 (range 1–24) hours following ulocuplumab administration. Patients who received 10 mg of ulocuplumab achieved higher concentration peak and larger dose-corrected area under curve (both P < 0.001). Pharmacokinetics analyses are listed in Supplementary Table S10 and Supplementary Fig. S2.

Treatment-related AEs with ≥10% frequency are summarized in Table 2 and Fig. 1. In Arm A, the most common treatment-related AEs of any grade were neutropenia (13 patients, 43.3%), diarrhea (10 patients, 33.3%), thrombocytopenia (10 patients, 33.3%), and fatigue (7 patients, 23.3%). Fifteen patients (50.0%) had ≥ grade 3 toxicities. The most common grade 3 AEs were neutropenia (6 patients, 20.0%) and thrombocytopenia (4 patients, 13.3%). Neutropenia (3 patients, 10.0%) was the most common AE in grade 4, followed by lymphopenia (1 patient, 3.3%), and thrombocytopenia (1 patient, 3.3%). In Arm B, the most common treatment-related AEs of any grade were thrombocytopenia (6 patients, 37.5%), fatigue (4 patients, 25.0%), and anemia (4 patients, 25.0%). Seven patients (37.5%) had ≥ grade 3 toxicities and four (25.0%) had grade 4 toxicities. No deaths related to study drugs occurred. The most common grade 3 or 4 AEs were thrombocytopenia (3 patients, 18.8%) and increased lipase (2 patients, 12.5%). Sensory peripheral neuropathy was reported in 2 patients, one in Arm A with grade 1 neuropathy and one in Arm B with grade 2. Two patients (6.7%) in Arm A encountered grade 2 infusion reaction; one patient (6.3%) in Arm A had grade 1 infusion reaction. All the reactions were limited in the first two cycles. Grade 3 or 4 sensory peripheral neuropathy was not observed. Twenty-five (83.3%) patients required dose modifications in Arm A, and 15 (93.8%) patients required dose modifications in Arm B. Four patients in Arm A discontinued treatment due to treatment-related toxicities, whereas none discontinued in Arm B for treatment-related toxicities.

Response assessment is summarized in Table 3 and Figs. 2 and 3. One patient in Arm A withdrew consent before completing the first cycle of treatment so that the total number of evaluable patients was 45 (29 in Arm A and 16 in Arm B). For Arm A patients, the overall response rate (PR or better) was 55.2% (n = 16) and the clinical benefit rate was 72.4% (21/29), with 1 patient (3.5%) achieving complete response (CR), 4 patients (13.8%) achieving very good partial response (VGPR), 11 patients (37.9%) achieving partial response (PR), 5 patients (17.2%) achieving minimal response (MR), and 6 patients (20.7%) maintaining stable disease (SD). There was no difference in the overall response rate when we assessed response only in patients who received the 10 mg/kg dose, n = 21 patients at the MTD dose, with 3 of 21 (14%) achieving VGPR, 8 of 21 (38%) achieving PR and 4 of 21 (19%) achieving MR. The overall clinical benefit rate was 15 (71%) and the overall response rate was observed in 11 (52%). For Arm B patients, the overall response rate was 25.0% (n = 4) and the clinical benefit rate was 50.0%, with 2 patients (12.5%) achieving VGPR, two patients achieving PR, 4 patients achieving MR, and 7 patients (43.8%) maintaining SD. Only 5 patients received the 10 mg/kg dose and again, there was no difference observed in the overall response rate in those patients compared with all patients treated on Arm B, with 1/5 (20%) achieving PR or better in these 5 patients.

Of the patients who responded, the median time to response to PR or better (min and max) was 1.5 months (range, 0.4–7.8 months) for Arm A and 1.0 month (range, 0.5–3.7 months) for Arm B. The number of prior lines of therapy did not affect response in these patients (P = 0.131). Figure 2 demonstrates the time and depth of response for patients who achieved at least PR. The maximum change in M-protein levels from baseline is shown in Fig. 3.

Patients received a median of 5 cycles in Arm A (range, 1–50) and 9 cycles in Arm B (range, 1–65).

The median PFS were 22.31 (95% CI, 9.17–not reached) months and 9.63 (95% CI, 2.56–not reached) months in Arms A and B, respectively. The Kaplan–Meier curve of PFS is shown in Fig. 4.

In a post hoc analysis, we evaluated PFS in patients who had previously received bortezomib and lenalidomide therapy. The median PFS was 9.2 (95% CI, 4.1–22.3) months for patients who were refractory to bortezomib, and 20.1 (13.6–not reached) months for those who were not (P = 0.103). The median (95% CI) PFS of patients who were refractory to lenalidomide was 8.0 (95% CI, 2.6–14.5) months, while it was 22.3 (9.2–not reached) months for those who were not (P = 0.045).

To assess the effect of CXCR4 inhibition by ulocuplumab on cell mobilization, we performed flow cytometry on peripheral blood samples drawn during cycle 1. Flow cytometry showed that ulocuplumab administration lead to a successful mobilization of hematopoietic stem cells and to high variability in numbers of circulating plasma cells (Supplementary Fig. S3A–S3D). Interestingly, whereas the fluctuating levels of circulating plasma cells persisted during cycle 1 in nonresponding group, a slight trend to more robust mobilization of plasma cells after day 8 was observed in the responding group (Supplementary Fig. S3D). Moreover, we found significantly increased numbers of circulating B cells, CD3⁺ T cells and CD14-expressing monocytes in peripheral blood following ulocuplumab administration (Supplementary Fig. S4), demonstrating an efficient mobilization of microenvironmental cells from the bone marrow environment upon CXCR4 inhibition. Patient response or adverse effects were not significantly correlated to the reported changes in the numbers of circulating plasma or immune cells in the peripheral blood.

The bone marrow microenvironment is suspected to play a role in response to treatment and disease dissemination in many cancers (11–14). Particularly, CXCR4, a chemokine receptor related to homing of tumor cells to the bone marrow, has been shown to be associated with metastasis and poor prognosis in cancers like AML, breast, colorectal, ovarian, pancreatic and non–small cell lung cancer (15–20). In multiple myeloma, an incurable malignancy where most patients eventually relapse, the role of the bone marrow microenvironment and especially CXCR4 is an area of active investigation, with preclinical data supporting a role for CXCR4 in disease dissemination and response to treatment. Specifically, CXCR4 expression was found to be increased in patients with multiple myeloma with extramedullary plasmacytoma, linking CXCR4 to extramedullary dissemination of disease (21), whereas CXCR4 blockade was shown to inhibit tumor growth and dissemination of multiple myeloma cells in vivo (6). We have previously shown that ulocuplumab, a first-in-kind monoclonal anti-CXCR4 antibody, can inhibit CXCR4-mediated cell migration and dissemination, including EMT-like transcriptional regulation, as well as inhibit intracellular signaling pathways that regulate drug resistance like the Akt/mTOR pathway, therefore, rendering the cells more sensitive to drugs (8). This phase Ib/II study was designed to evaluate the safety and efficacy of a three-drug combination of the first fully human monoclonal anti-CXCR4 antibody with lenalidomide plus dexamethasone or bortezomib plus dexamethasone in relapsed/refractory multiple myeloma.

The study proved the combination to be safe, with no DLTs observed with full dosing of the combination in patients with relapsed/refractory multiple myeloma. The major grade 3 and 4 hematologic toxicities were thrombocytopenia and neutropenia, which were expected and are related to bortezomib or lenalidomide. With minimal infusion reactions, the safety profile of this antibody makes it ideal for therapeutic combinations in myeloma, even for patients with significant cytopenias and end-stage disease.

In terms of efficacy, our study demonstrated a high response rate, with an overall response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4% in the combination arm of ulocuplumab/lenalidomide/dexamethasone, even in patients who had been previously treated with immunomodulatory agents (IMiD). This led to a prolonged PFS of over 22 months in this relapsed/refractory population. This could indicate that the antibody synergizes with IMiDs. Although we cannot compare across trials, recent studies using lenalidomide and dexamethasone such as in the ELOQUENT-2 study had a median PFS of 14.9 months in the control arm and 19.4 months in the elotuzumab, lenalidomide, and dexamethasone arm (22). The response rate was 66% in the lenalidomide arm (22). Our study showed a median PFS of 22.31 months in the lenalidomide arm, indicating that this combination is active and further considerations of larger studies should be evaluated. Although the role of ulocuplumab in immune cell regulation in multiple myeloma has not been studied, CXCR4 is expressed on the surface of many immune cells (23, 24), indicating that ulocuplumab could be involved in immune cell activation. Indeed, in our study, we observed mobilization of some immune cells, including T cells, B cells and monocytes, following ulocuplumab administration. Previous in vivo and in vitro data showed that blockade of CXCR4 mitigates CD4⁺ T-cell exhaustion (25), reverts the suppressive activity of T-regulatory cells (26), modulate immunotherapy with anti-PD-1 (27) and activates cytotoxicity of immune cells (23), emphasizing the immunomodulatory function of ulocuplumab. Blocking CXCR4 attenuates differentiation of CD14-expressing monocytes to the tumor-supportive M2-polarized macrophages, which are known to be increased in multiple myeloma bone marrow microenvironment (28). Moreover, higher levels of CD19 B cells have been correlated with longer event-free and overall survival in multiple myeloma (29), thus implicating the potential antimyeloma response of mobilized B cells in our study. Further studies are warranted to better define the mechanisms of synergy between CXCR4 regulation and immune cell activation as a potential mechanism of antimyeloma activity.

To conclude, this study demonstrated that ulocuplumab in combination with lenalidomide and dexamethasone led to a high response rate even in heavily pretreated relapsed/refractory patients. Although further studies to explore the synergy between ulocuplumab and lenalidomide are warranted, combinations of ulocuplumab with novel agents, like mAbs against CD38, SLAMF7, and BCMA could also be investigated, especially in the treatment of extramedullary multiple myeloma, an area of unmet clinical need in multiple myeloma therapeutics.

I.M. Ghobrial is a paid consultant/advisory board member of GSK, Sanofi, Janssen, Takeda, Celgene, Karyopharm, AbbVie, GNS, Cellectar, Medscape, Genetech, Adaptive, BMS, Aptitude, Curio Science, Magenta, and Oncopeptides. R. Baz reports receiving commercial research grants from Bristol-Myers Squibb, Karyopharm, Celgene, AbbVie, Janssen, and Merck. P.G. Richardson is an employee/paid consultant for Karyopharm, Oncopeptides, Celgene, Takeda, Amgen, Janssen, and Sanofi and reports receiving commercial research grants from Oncopeptides, Celgene, Takeda, and Bristol-Myers Squibb. K.C. Anderson is an employee/paid consultant for Bristol-Myers Squibb, Celgene, Millennium Takeda, Janssen, Sanofi-Aventis, and Gilead and holds ownership interest as scientific founder of C4 Therapeutics and Oncopep. M.D. Robbins is an employee/paid consultant for Bristol-Myers Squibb. P.S. Becker is an employee/paid consultant for Accordant Health Services/Caremark and McKesson. No potential conflicts of interest were disclosed by the other authors.

Conception and design: I.M. Ghobrial, R. Baz, P.G. Richardson, K.C. Anderson, P.S. Becker

Development of methodology: I.M. Ghobrial, R. Baz, P.G. Richardson, P.S. Becker

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R.P. Perez, R. Baz, O. Zavidij, P.G. Richardson, K.C. Anderson, P. Henrick, A. Savell, K. Reyes, S. Chuma, M.D. Robbins, P.S. Becker

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): I.M. Ghobrial, C.-J. Liu, R.A. Redd, R.P. Perez, R. Baz, O. Zavidij, J. Laubach, A. Savell, K. Reyes, M.D. Robbins, P.S. Becker

Writing, review, and/or revision of the manuscript: I.M. Ghobrial, C.-J. Liu, R.A. Redd, R.P. Perez, R. Baz, O. Zavidij, R. Sklavenitis-Pistofidis, P.G. Richardson, K.C. Anderson, J. Laubach, P. Henrick, K. Reyes, K. Hornburg, P. Sabbatini, M.D. Robbins, P.S. Becker

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): P. Henrick, K. Reyes, S. Chuma, P.S. Becker

Study supervision: I.M. Ghobrial, R.P. Perez, R. Baz, K. Reyes

This work was supported in part by Bristol-Myers Squibb and NIH R01 CA181683-01A1, Leukemia and Lymphoma Society, and Multiple Myeloma Research Foundation (MMRF).

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.