Low-dose versus High-dose Carfilzomib with Dexamethasone (S1304) in Patients with Relapsed-Refractory Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy, with more than 30,000 patients diagnosed in the United States every year (1). There have been tremendous improvements in outcomes of patients with multiple myeloma, with an estimated 5-year overall survival (OS) of 50.7%, as compared with only 34.6% less than two decades ago (2, 3), mainly due to a better understanding of disease biology and the development of novel therapeutic agents.

Proteasome inhibitors represent one such category of antimultiple myeloma therapeutic agents (4). The ubiquitin proteasome pathway is a central component of the cellular protein degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins (5). Inhibition of this pathway causes disruption of this homeostasis and intracellular accumulation of protein degradation byproducts, leading to cell death. The first proteasome inhibitor, bortezomib, was approved by the FDA for treatment of patients with multiple myeloma in 2003 (6). Since then carfilzomib, and most recently ixazomib, have gained FDA approval (7). The utilization of these agents has evolved from single agent to combination regimens, from later lines of therapy to earlier in the treatment paradigm of patients with multiple myeloma, and with changes in the dosage and mode of administration to deliver them in the safest and most efficacious manner (4, 8). Among these changes, the utilization of carfilzomib has evolved substantially over time. Carfilzomib was initially approved as a single agent for the treatment of relapsed and/or refractory multiple myeloma (RRMM) in patients who had received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent (IMiD; ref. 9). The initially approved dose of carfilzomib was 20 mg/m² i.v. administered as a single agent on days 1, 2, 8, 9, 15, and 16 every 28 days for the first cycle, followed by 27 mg/m² on the same schedule starting cycle 2 onwards for a total of 12 cycles. Since then, several clinical trials have led to significant changes in its usage, including escalating to 27 mg/m² starting on day 8 of cycle 1, increasing the subsequent doses to 36 mg/m² or 56 mg/m² twice weekly, using it in combination with other agents, and once weekly at 70 mg/m² (10–14). All these data resulted in changes to the FDA label for carfilzomib (15). The current FDA-approved clinical indications for carfilzomib are summarized in Table 1.

Despite several clinical trials evaluating various carfilzomib-containing regimens in differing doses, schedules, and clinical settings, no study has previously compared different doses of this agent on the same schedule in a randomized trial to understand their mutual safety and efficacy. The recently published randomized A.R.R.O.W. trial did compare two doses of carfilzomib, but they were administered in differing schedules, once weekly (70 mg/m²) versus twice weekly (27 mg/m²; ref. 13). Southwest Oncology Group (SWOG) undertook an intergroup randomized phase II clinical trial, S1304, to compare the safety and efficacy of low-dose (27 mg/m²) versus high-dose (56 mg/m²) carfilzomib with dexamethasone administered twice weekly for RRMM (NCT01903811). We present here the primary results from this clinical trial.

This national, multicenter, open-label phase II randomized clinical trial was approved by the Cancer Therapy Evaluation Program, relevant institutional review boards, and was conducted according to the Declaration of Helsinki. All patients provided written informed consent. Statistical analyses were conducted at the SWOG Statistics and Data Management Center in Seattle, WA.

This randomized phase II trial compared low-dose carfilzomib plus dexamethasone (arm 1) with high-dose carfilzomib plus dexamethasone (arm 2) in RRMM. Patients who had disease progression any time between cycle 3 and 12 on arm 1 could cross-over to high-dose carfilzomib. Each study cycle was 28 days long. The study schema is outlined in Fig. 1. Treatment dose and schedule on the study arms included arm 1 with carfilzomib 27 mg/m² administered as a slow intravenous push (over 2–10 minutes) on days 1, 2, 8, 9, 15, and 16 of every cycle along with dexamethasone 20 mg i.v., 30 minutes prior to every carfilzomib dose administration. Of note, on both, arm 1 and arm 2 carfilzomib was administered at a dose of 20 mg/m² i.v. (over 2–10 minutes) for the first complete cycle, consistent with the then FDA label for carfilzomib. Arm 2 and the cross-over arm had the same treatment schedule and regimen except that carfilzomib was administered at 56 mg/m² i.v. over 30 minutes. The cross-over arm was started directly at the 56 mg/m² dose. Dose calculations were based on the patient's actual body weight at baseline. Patients with a body surface area (BSA) >2.2 m² received a dose based on BSA of 2.2 m². Treating physicians were advised to administer intravenous fluid pre- and post-carfilzomib in accordance with the FDA label, with a caveat to monitor fluids along with the patient's cardiopulmonary status and symptomatology. If a patient experienced grade ≥3 nonhematologic or grade 4 hematologic toxicity considered related to the study treatment during cycle 1 on arm 1 or arm 2, the second cycle of treatment was also administered at 20 mg/m² of carfilzomib prior to escalation to the respective treatment dose for subsequent cycles. If a patient could not undergo dose escalation to the assigned treatment dose despite being at 20 mg/m² for two cycles, they were to be removed from the protocol. All patients received antiviral prophylaxis.

In addition to myeloma-related testing, all patients underwent cardiac monitoring including electrocardiography, echocardiography (ECHO), and cardiac biomarker laboratory testing (CK-MB, troponin, and pro-BNP) every 12 weeks while on study. In addition, all patients noted to have extramedullary disease on fluorodeoxyglucose PET scan at baseline were to have a repeat PET scan at the end of treatment or at the time of achieving very good partial response (VGPR) or better, whichever occurred earlier.

Eligible patients were age ≥18 years with a confirmed diagnosis of RRMM. Those with POEMS syndrome, systemic amyloidosis, or nonsecretory multiple myeloma were ineligible. Patients were required to have at least one but no more than six prior lines of antimultiple myeloma therapy (16). No prior carfilzomib treatment was permitted. A baseline PET scan was required within 28 days prior to registration on the trial. Other study requirements included adequate performance status (Zubrod performance status 0–2), lack of any other significant concomitant illnesses (with specific focus on cardiac comorbidities including, but not limited to class III or IV heart failure; ref. 17, unstable angina pectoris, myocardial infarction within the prior 6 months, or grade ≥3 cardiac arrhythmias), lack of grade >2 peripheral neuropathy and adequate organ function [total bilirubin ≤1.5 × upper limit of normal (UNL), SGOT/SGPT ≤3 × UNL, measured creatinine clearance ≥30 mL/minute, absolute neutrophil count ≥1,000 cells/mm³ without growth factor support, and platelets ≥50,000 cells/mm³]. A left ventricular ejection fraction (LVEF) of ≥45% by ECHO was required within 28 days prior to registration on the trial. Prior antimultiple myeloma therapy including radiotherapy had to be completed at least 21 days prior, although pulse steroids for a myeloma-related complication were allowed up to 7 days prior to registration.

Eligibility criteria for registration to the cross-over portion of the trial required that the patient was initially randomized to the low-dose carfilzomib treatment (arm 1) and had disease progression noted anywhere between the completion of 2–12 cycles of treatment. At least 14 but no more than 28 days were to have elapsed between the last day of treatment on arm 1 and registration on the cross-over arm. Patients must have recovered from all nonhematologic toxicities to grade ≤2 and from all hematologic toxicities to grade ≤3 prior to registration on the cross-over arm. Patients must not have required any dose reductions on arm 1 due to drug toxicity and must not have experienced a decrease in LVEF of >10% from baseline, or any LVEF decrease accompanied by clinical signs/symptoms of NYHA class III or IV heart failure, measured within 28 days prior to registration on the cross-over arm.

Patients were stratified on the two treatment arms as per whether they had received 1–3 versus 4–6 prior therapies and whether they were refractory or not, as per International Myeloma Working Group (IMWG) criteria, to prior treatment with bortezomib (18).

The primary objective was to compare progression-free survival (PFS) of two different doses of carfilzomib with dexamethasone (arm 1 and 2) in the selected patients with RRMM. A median PFS of 9 months was anticipated in arm 1 based on information from previous trials. The study was designed with 90% power to detect a HR of 1.67, which corresponded to an increase in the median PFS from 9 to 15 months in arm 2. These calculations were based on a one-sided stratified log-rank test at level (alpha) of 0.1 and on the assumption that progressions would be exponentially distributed. Secondary objectives included evaluating the response rates, safety, and median OS of patients on arms 1 and 2 and also the response rates for patients who relapsed on low-dose carfilzomib treatment and subsequently crossed over to high-dose carfilzomib. Of note, the power calculations were to satisfy the primary objective of any clinically meaningful PFS benefit of arm 2 over arm 1.

The clinical trial was activated on October 18, 2013, the first patient was randomized on February 12, 2014, and the last patient was randomized on November 6, 2015. These primary results of the clinical trial represent a median overall follow-up of 32 months (median 31 months on arm 1 and 34 months on arm 2). A total of 143 patients were enrolled on these two arms, of which 121 patients (64 on arm 1 and 57 on arm 2) were eligible and analyzable per the protocol. Twenty-one patients were deemed ineligible due to missing or untimely baseline eligibility laboratory evaluations (six on arm 1 and 11 on arm 2), not having measurable disease at baseline (one on each arm), and not completing or discontinuing prior therapy at least 28 days prior to randomization (one on each arm). Furthermore, 3 patients (two of whom were ineligible due to missing baseline eligibility laboratory evaluations) were deemed inevaluable for having withdrawn from the study prior to receiving any treatment.

Baseline patient characteristics on the two study arms are summarized in Table 2. Of note, cytogenetic analysis was not uniformly available in all patients on the study. There were no significant differences noted in any of the baseline demographics, disease, or previous treatment characteristics between arms 1 and 2. The median number of prior lines of therapy was three on both arms. Among the eligible and analyzable patients, 7 patients on arm 1 and 3 patients on arm 2 did not initiate cycle 2 and came off treatment before the end of cycle 1. Average carfilzomib dose per cycle of treatment on arm 1 was 25 mg/m² for the whole treatment and 27 mg/m² after excluding cycle 1 (20 mg/m² dose), while that on arm 2 was 44.4 mg/m² overall and 53.8 mg/m² after excluding cycle 1. The median cumulative dose (including cycle 1 dosing) was 114.5 mg in arm 1 and 244 mg in arm 2 of the trial.

The primary objective of any significant PFS difference between arms 1 and 2 was not statistically significant. Among the eligible and analyzable treatment population, 53 of the 64 patients on arm 1 and 52 of the 57 patients on arm 2 were noted to have disease progression, resulting in a median PFS of 5 months and 8 months, respectively [HR, 1.061, 80% Wald confidence interval (CI), 0.821–1.370; P = 0.384; Fig. 2A). Similarly, OS was not significantly different between arms 1 and 2. At the time of analysis, 34 of the 64 patients on arm 1 and 36 of the 57 patients on arm 2 had died, resulting in a median OS of 26 months and 22 months, respectively (HR, 1.149; 80% Wald CI, 0.841–1.571; P = 0.284; Fig. 2B). Response assessment as per IMWG criteria was available in 112 patients (59 on arm 1 and 53 on arm 2). An overall response rate (ORR = confirmed partial response; PR or better) of 42.8% was seen in all patients (39% in arm 1, 47% in arm 2). Response rate categories by treatment arm are shown in Table 3. This data did not support the hypothesis that patients receiving high-dose carfilzomib with dexamethasone will have a significantly improved ORR as compared with those treated with low-dose carfilzomib and dexamethasone, based on a Cochran–Mantel–Haenszel test (two-sided P = 0.113). The median time to best response among patients who responded on either arm was 2.1 months on arm 1 and 2.2 months for arm 2.

A sensitivity analysis was performed for patients who initiated cycle 2 [the first cycle of treatment on the assigned study dose of carfilzomib (27 mg/m² on arm 1 and 56 mg/m² on arm 2)], because carfilzomib was administered at a dose of 20 mg/m² during cycle 1 on each of the arms. Of note, current standard practice is to escalate carfilzomib to the desired dose of 27 mg/m² or 56 mg/m² starting at day 8 of cycle 1. This sensitivity analysis did not show a significant difference in PFS (median 10 months on arm 1 and 7 months on arm 2, one-sided stratified log-rank P = 0.175; HR, 1.24; 80% Wald CI, 0.924–1.652) or OS (median 32 months on arm 1 and 22 months on arm 2, one-sided stratified log-rank P = 0.197; HR, 1.30; 80% Wald CI, 0.93–1.83).

Efficacy analysis was done for the prespecified study strata as well. There was no significant difference in PFS by number of prior lines of therapy (1–3 vs. 4–6) on arms 1 or 2. Both these strata had a median PFS of 8 months on arm 2, while the less heavily pretreated patients (1–3 prior lines of treatment) on arm 1 had a median PFS of 6 months compared with only 4 months for those with 4–6 prior lines of therapy (not significant; Fig. 3A). Similarly, OS for patients on the two arms by prior lines of therapy was not significantly different, although similar to the trend for PFS, on arm 1 the median OS for patients with 1–3 prior lines of therapy was 33 months compared with only 12 months for those with 4–6 prior lines of therapy. The median OS on arm 2 was 22 months for patients with 1–3 prior lines and 28 months for those with 4–6 prior lines of therapy (Fig. 3B). The largest numerical difference in OS between arms 1 and 2 was noted for those with 4–6 prior lines of therapy (12 months and 28 months, respectively), but this was also not statistically significant (P = 0.135). Similarly, looking at the prespecified strata of disease refractory or not to prior bortezomib therapy, there were no significant differences in PFS (Fig. 4A) or OS (Fig. 4B) between arms 1 and 2.

To see whether there was any significant efficacy difference when patients were actively receiving treatment (11 months; 12 cycles), additional landmark sensitivity analyses were performed with patient data censored at 11 months from randomization. There was no significant difference for PFS (P = 0.453) or OS (P = 0.469) for this analysis as well. An analysis of OS was also done with censoring data for patients who crossed over to arm 2 at the time of disease progression on arm 1, and OS was again not significantly different (P = 0.14).

A total of 16 patients on arm 1 crossed over to high-dose carfilzomib with dexamethasone at the time of disease progression. Response assessment was available in 12 of these, with stable disease noted in 7 and disease progression in 5 patients. Median PFS from the time of cross-over was 3 months (range 2–6 months) in these patients, with 15 patients having undergone disease progression at the time of analysis. Median OS was 15 months (range 5–27 months) for these patients. Reasons for discontinuation of treatment on the cross-over arm were increasing disease in 7, toxicity in 8,and withdrawal of consent in 1 patient. We performed a sensitivity analysis by censoring patients on arm 1 at the time of cross-over to see whether there was any OS benefit of high-dose carfilzomib with dexamethasone; the results were consistent with the primary endpoint analysis, showing no evidence of a difference between treatment arms (P = 0.14).

Adverse events (AE) on both study arms were compared and the ones that were at least possibly attributable to the study treatment and noted in >10% of patients on either arm are listed in Table 4. Hematologic AEs were seen more frequently and with a higher grade than nonhematologic AEs. Grade 3 or 4 hematologic AEs that were seen in either arm included anemia, thrombocytopenia, and lymphopenia, with anemia being the most common overall hematologic AE noted in the study. The most common nonhematologic AE overall as well as grade ≥3 was fatigue. AE categories with notable differences in the frequency of grade ≥3 AEs between arms 1 and 2 that were at least possibly attributed to the study treatment were compared with Fisher exact test. There was a significantly higher number of patients with any grade ≥3 AE in arm 2 versus arm 1 (arm 2: 37 vs. arm 1: 25; P < 0.001). Of these, fatigue and thrombocytopenia were by themselves significantly more frequently seen in arm 2 as compared with arm 1. In addition, cardiopulmonary AEs were of special interest in the trial and so they were compared between the two study arms. These analyses included cardiovascular [including hypertension, acute coronary syndrome, arrhythmias, cardiac chest pain, congestive heart failure (CHF), and cardiomyopathy] and pulmonary (including cough, dyspnea, hypoxia, pulmonary edema, and respiratory failure) AEs reviewed as separate categories, as well as analyzed together as one combined category of cardiopulmonary AEs. There was no significant difference noted for these between arms 1 and 2. It was noted that 3 patients on arm 1 and 2 patients on arm 2 discontinued treatment secondary to new onset or significant worsening (defined as significant clinical deterioration in cardiac symptoms or >10% decrease in LVEF from baseline) in preexisting CHF. Any grade hypertension was seen in 16% of patients, with no significant differences between the arms.

At the time of data analysis, 34 patients on arm 1 and 36 patients on arm 2 had died. Cause of death was multiple myeloma–related in 73% (n = 24) patients on arm 1, 56% (n = 20) on arm 2, and 64% (n = 44) for the overall study population. The cause of death for 1 patient on arm 1 had not yet been classified.

Clinical development of carfilzomib has involved several reported and ongoing clinical trials utilizing varying doses and schedules of the drug in many combination regimens (19, 20). As a single agent or in combination with dexamethasone without a third antimyeloma agent, carfilzomib is FDA approved at the doses of 20/27 mg/m² and 20/56 mg/m², administered twice weekly, and 20/70 mg/m², administered once weekly (14, 21). Because of differences in the efficacy (median PFS) and clinical context (prior lines of therapy) in these trials, there had been questions regarding the optimal dose of carfilzomib, especially in combination with dexamethasone. This is highlighted by the fact that a recent randomized phase III clinical trial (ARROW) comparing twice weekly and once weekly dosing of carfilzomib, which lead to FDA approval of once weekly (70 mg/m²) carfilzomib with dexamethasone, utilized 27 mg/m² dose of this agent with dexamethasone in the twice weekly comparator arm even though it is not a currently FDA-approved regimen at this dose and schedule (13). Furthermore, the ENDEAVOR study showed that, in a 923-patient randomized clinical trial, the 56 mg/m² twice weekly dose of carfilzomib with dexamethasone demonstrated superior OS to the comparator, bortezomib and dexamethasone, suggesting that 56 mg/m² might be the optimal twice weekly dose for carfilzomib (14). S1304 is the first clinical trial to report a direct comparison of the two doses of carfilzomib on the same treatment schedule of twice weekly administration, in combination with dexamethasone.

Despite an assumption prior to initiating the trial that the higher dose of carfilzomib with dexamethasone would have higher efficacy than the lower dose, this randomized study failed to show such an effect. The higher carfilzomib dose did have slightly better VGPR rates but not significantly so, and this difference did not translate to a significantly higher PFS, the primary endpoint of the study, or OS. Of note, no confirmed complete responses were reported on either arm due to lack of confirmatory bone marrow biopsies for response assessment. It should also be noted that both treatment arms utilized 20 mg/m² carfilzomib for the whole first cycle, as was consistent with the FDA-approved label of the drug at the time of the clinical trial design (Reference ID: 3161927). Subsequently, the carfilzomib label has been updated to increase its dose to the target dose of 27 mg/m² or 56 mg/m² on day 8 of the first cycle, as long as the patient is tolerating therapy well. This may also have resulted in a slightly longer median time to best response noted in the current trial on either arm as compared with other carfilzomib-based trials, where the dose was escalated beyond 20 mg/m² starting on day 8 of cycle 1. To eliminate any lack of efficacy on either arm due to this, we recommended that patients not be removed from the trial due to disease progression prior to the end of cycle 2, as long as it was considered safe for them to stay on treatment. Furthermore, we conducted additional analyses on patients who had received at least two cycles of therapy, including at least one cycle on the assigned treatment arm carfilzomib dose of 27 mg/m² or 56 mg/m², but this also did not isolate any efficacy difference.

There was a trend that efficacy of high-dose carfilzomib was maintained irrespective of the number of prior lines of therapy while low-dose carfilzomib seemed to have more benefit in patients with fewer (1–3) prior lines of therapy, but this was not statistically significant. Curiously, the median OS for the more heavily pretreated patients (4–6 prior lines of therapy) was 28 months as compared with only 22 months for the group that had received less pretreatment (1–3 prior lines of therapy). It could be possible that a higher level of proteasome inhibition is necessary in heavily pretreated patients, a hypothesis worth further investigation. Importantly, this was a subgroup analysis and not something that the study was powered to address. The trend was not that clear looking at patients refractory to prior bortezomib treatment or not, although there seemed to be better PFS and OS among patients not refractory to prior bortezomib, especially with high-dose carfilzomib (arm 2). Again, it is important to note that the comparisons between these study strata were exploratory, and the study was adequately powered only to detect a prespecified PFS benefit of arm 2 over arm 1. Furthermore, looking at the PFS and OS of all patients on both arms, it seemed that there was some separation of the survival curves while patients were on active treatment during the first 12 months after randomization (Fig. 2A and B), but a post hoc sensitivity analysis looking at only this study period did not show any significant survival difference between the arms. Of note, the current norm is not to discontinue carfilzomib-based treatment after a fixed number of treatment cycles, but to continue the regimen at least with maintenance dosing as long as the patient is deriving adequate clinical benefit and is tolerating the regimen well.

While the study plan included a cross-over to the higher dose for those patients who had disease progression on the lower dose of carfilzomib, only 16 patients entered the cross-over treatment. There were more patients on arm 1 who had disease progression while on treatment, but they did not cross-over based on patient or physician preference. At least in this small number of patients, the higher dose of carfilzomib was not able to provide any objective incremental responses. Analysis of the genomic, imaging, and cardiac correlative study objectives is ongoing.

The safety profile from this trial was noted to be very similar to that from other studies, with no significant concern of cardiopulmonary AEs, even with the higher carfilzomib dose on this twice weekly schedule. While a majority of the AEs noted on both arms did not have grade 3 or higher events, there were some AEs including thrombocytopenia, peripheral neuropathy, and fatigue, which were significantly more evident in the high-dose carfilzomib arm. The incidence of grade ≥3 of any AE was noted to be significantly higher with 56 mg/m² carfilzomib (65%) as compared with the 27 mg/m² dose (39%; P = 0.006). This suggests that the twice weekly 56 mg/m² dose of carfilzomib with dexamethasone results in increased toxicity without necessarily additional clinical benefit as compared with the 27 mg/m² dose on the same schedule.

It is conceivable that a comparison of the outcomes from S1304 will be made with existing data on carfilzomib, especially the ENDEAVOR trial, where the 56 mg/m² dose was used as the study arm, although it was compared with bortezomib treatment. The S1304 subset which is closest to the ENDEAVOR trial includes patients who were treated on arm 2 and had 1–3 prior lines of therapy. However, the efficacy measures for this subset do not mimic the results from ENDEAVOR, and this is likely due to several factors, some of which were mentioned earlier. First, S1304 included patients with 1–6 prior lines of therapy (median of 3), while ENDEAVOR included patients with 1–3 previous treatments (median of 2). Most agents used against myeloma are more efficacious in earlier lines of therapy when the disease is less chemo-resistant. Second, ENDEAVOR excluded patients who were previously bortezomib refractory, while S1304 allowed such patients and they may have had disease with some cross-resistance to carfilzomib that reduced its efficacy. Third, S1304 continued carfilzomib dosing for up to a maximum of 12 cycles because that was the carfilzomib regimenwhich was approved at that time, while ENDEAVOR continued dosing until disease progression. Fourth, the subgroup of patients with 1–3 prior lines of therapy on the high-dose carfilzomib arm constitutes only 42 patients, and the trial was not powered to compare patients with 1–3 versus those with 4–6 prior therapies. Similarly, it was not designed or powered for cross-study comparisons, and it is possible that the small sample size of this cohort therefore contributes to the differences between S1304 and ENDEAVOR. Finally, the ENDEAVOR trial dosed carfilzomib at 20 mg/m² for days 1 and 2 of cycle 1 only, and then increased the carfilzomib dosing to 56 mg/m². In contrast, S1304 dosed carfilzomib at 20 mg/m² for all of cycle 1 because that was the approved dose and schedule at the time of study initiation, and did not increase the dose to 56 mg/m² until cycle 2.

Current and future clinical use of carfilzomib is moving toward once weekly dosing with the recent FDA approval at 70 mg/m² in combination with dexamethasone as well as ongoing clinical trials with additional agents (13, 22). Yet, this dose and schedule is not approved in any other combination and prospective data are necessary to achieve optimal utilization of carfilzomib to derive maximal clinical benefit. There is data for significant heterogeneity in carfilzomib dosing and schedule leading to possibly suboptimal clinical benefit in the real-world setting (23). In this light, S1304 provides valuable data informing our clinical decisions and practice. This study shows that in a twice weekly and fixed duration schedule in combination with dexamethasone, 56 mg/m² dosing of carfilzomib does not provide statistically significant clinical benefit as compared with the 27 mg/m² dose. However, treatment to progression in earlier patient populations with high-dose carfilzomib using different schedules should still be considered as part of the standard of care.

S. Ailawadhi is an employee/paid consultant for Celgene, Takeda, Janssen, and Amgen, and reports receiving commercial research grants from Pharmacyclics, Cellectar, BIVIS, Amgen, Medimmune, and Ascentage Pharmaceuticals. S. Lentzsch is an employee/paid consultant for Sanofi, Janssen, Celularity, Amgen, and Sorrento, reports receiving commercial research grants from Sanofi and Karyopharm, reports receiving speakers bureau honoraria from and holds ownership interest (including patents) in Caelum Bioscience. P.M. Voorhees is an advisory board member/unpaid consultant for Celgene, Adaptive Biotechnologies, Janssen, Novartis, TeneoBio, Oncopeptides, GlaxoSmithKline, and BMS. A.D. Cohen is an employee/paid consultant for Celgene, GlaxoSmithKline, BMS, Seattle Genetics, Janssen, Oncopeptides, Kite Pharma, and Takeda, reports receiving commercial research grants from and holds ownership interest (including patents) in Novartis. K. Kelly is an employee/paid consultant for Genentech and Verastem, reports receiving commercial research grants from Takeda, and reports receiving speakers bureau honoraria from Celgene, AstraZeneca, Janssen, Novartis, and Bayer. B. Durie is an advisory board member/unpaid consultant for Amgen, Janssen, Celgene, and Takeda. R.Z. Orlowski is an employee/paid consultant for Amgen, Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals North America, reports receiving commercial research grants from BioTheryX, and holds ownership interest (including patents) in Asylia Therapeutics. No potential conflicts of interest were disclosed by the other authors.

Conception and design: S. Ailawadhi, R. Sexton, S. Lentzsch, E.M. Rohren, A. Hoering, B. Durie, R.Z. Orlowski

Development of methodology: S. Ailawadhi, S. Lentzsch, E.M. Rohren, R.Z. Orlowski

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S. Ailawadhi, R. Sexton, P.M. Voorhees, A.D. Cohen, E.M. Rohren, S. Heitner, K. Kelly, D.M. Baer, B. Durie, R.Z. Orlowski

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. Ailawadhi, R. Sexton, S. Lentzsch, M.H. Abidi, E.M. Rohren, K. Kelly, N.J. Mackler, A. Hoering, R.Z. Orlowski

Writing, review, and/or revision of the manuscript: S. Ailawadhi, R. Sexton, S. Lentzsch, M.H. Abidi, P.M. Voorhees, A.D. Cohen, E.M. Rohren, S. Heitner, K. Kelly, D.M. Baer, A. Hoering, B. Durie, R.Z. Orlowski

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Ailawadhi

Study supervision: S. Ailawadhi, M.H. Abidi

This work was supported by NIH/NCI grants CA180888, CA180819, CA180820, CA180821, CA180830, CA189821, CA189971, CA180826, CA189830, CA180858, CA189858, CA189872, CA189829, CA180846, CA139519, CA189822, CA180798, CA189808, and CA189952, legacy grants CA46282 and CA13612, and in part by Onyx Pharmaceuticals, Inc. (AMGEN subsidiary). R. Z. Orlowski, the Florence Maude Thomas Cancer Research Professor, would like to acknowledge support from the National Cancer Institute (R01 CA194264, R01 CA184464), and the Leukemia & Lymphoma Society (SCOR-12206-17). Additional support came from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

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