Инфекции пациентов, получающих даратумумаб по недавно диагностированному миеломе: объединенный анализ MAIA и ALCYONE.

Introduction

Daratumumab is a human immunoglobulin Gκ monoclonal antibody targeting CD38 with direct on-tumor 1 , 2 , 3 , 4 and immunomodulatory mechanisms of action, 5 , 6 , 7 demonstrating greater cytotoxicity toward multiple myeloma (MM) cells ex vivo compared with analogs of other CD38 antibodies. 8 The addition of daratumumab to standard-of-care MM therapies has consistently demonstrated favorable clinical efficacy and manageable safety profiles in large phase 3 studies, 9 , 10 , 11 , 12 , 13 subsequently leading to the approval of daratumumab-based regimens for the treatment of newly diagnosed MM (NDMM). 14

Both the phase 3 MAIA and ALCYONE studies have reported significant clinical benefit with daratumumab-based regimens in transplant-ineligible patients with NDMM. In a long-term analysis of MAIA, with a median follow-up of 64.5 months, progression-free survival (PFS) was improved with the addition of daratumumab to standard-of-care Rd (lenalidomide and dexamethasone; D-Rd) vs Rd alone (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; P < .0001). 15 Median overall survival (OS) was not reached with D-Rd vs 65.5 months with Rd (HR, 0.66; 95% CI, 0.53-0.83; P = .0003), with estimated 60-month OS rates of 66.6% and 53.6%, respectively. In the final analysis of ALCYONE, with a median follow-up of 86.7 months, median OS was 83.0 months when daratumumab was combined with VMP (bortezomib, melphalan, and prednisone; D-VMP) vs 53.6 months with VMP alone (HR, 0.65; 95% CI, 0.53-0.80; P < .0001). 16 Although clinical outcomes favored the addition of daratumumab, the rates of grade 3/4 infections were more common with D-Rd and D-VMP (43% and 31%, respectively) compared with Rd and VMP (30% and 15%, respectively). 15 , 16 A subsequent post hoc analysis of pooled MAIA/ALCYONE data from daratumumab-treated patients identified several predictive markers of grade ≥3 or serious infections during the first 6 months of treatment, including age, and lactate dehydrogenase, albumin, and elevated baseline alanine aminotransferase levels. 17

Patients with NDMM have a high susceptibility to infection due, in part, to a combination of intrinsic immune dysfunction and therapy-related immunosuppression. 18 , 19 Moreover, infection is a leading cause of morbidity and mortality among patients with NDMM. 20 , 21 In a Swedish population-based study, patients with MM had a significant sevenfold higher risk of developing infection than matched controls, with 22.2% of deaths occurring within the first 2 months of diagnosis due to infections. 20 Notably, the incidence of infections in patients with MM is frequently reported to be at its highest within the first few months of treatment initiation, 22 , 23 emphasizing the need for early and effective prophylaxis and management. Given the recognized impact of infections on patients with MM, the International Myeloma Working Group (IMWG) published new consensus guidelines to provide the community with updated recommendations for optimal infection prophylaxis. 24 However, these consensus guidelines were published after full enrollment of the MAIA and ALCYONE studies.

Gaining a better understanding of infection indicators may help identify patients at risk of early infection, thereby assisting in the individualization of infection prophylaxis. 22 , 23 Here, we report a pooled analysis of infection incidence, timing, and management strategies from the MAIA and ALCYONE studies among transplant-ineligible patients with NDMM.

Methods

Trial design

MAIA ( ClinicalTrials.gov identifier: NCT02252172 ) and ALCYONE ( ClinicalTrials.gov identifier: NCT02195479 ) are multicenter, randomized, open-label, phase 3 studies in transplant-ineligible patients with NDMM. The study design and complete eligibility criteria for MAIA 25 and ALCYONE 26 have been published previously. Briefly, eligible patients had documented NDMM, had an Eastern Cooperative Oncology Group performance status score of 0 to 2, and were ineligible for high-dose chemotherapy with autologous stem cell transplant because of age (≥65 years) or the presence of comorbidities. 25 , 26

Ethics approval and consent to participate

Independent ethics committees or institutional review boards at each site approved the protocols, and both studies were conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All patients provided written informed consent prior to study participation.

Randomization and study treatment

Eligible patients were randomized 1:1 to receive either D-Rd or Rd in the MAIA study or D-VMP or VMP in the ALCYONE study. 25 , 26 Patients in both studies were stratified by the International Staging System disease stage (I vs II vs III), geographical region (MAIA: North America vs other; ALCYONE: Europe vs other), and age (<75 years vs ≥75 years).

In the MAIA study, all patients received 28-day cycles of oral lenalidomide (25 mg [10 mg dose recommended if the patient’s creatinine clearance was 30-50 mL/min] on days 1-21) and oral dexamethasone (40 mg [20 mg if the patient was aged >75 years or had a body mass index of <18.5 kg/m 2 ] on days 1, 8, 15, and 22) until disease progression or unacceptable toxicity. Patients in the D-Rd group also received IV daratumumab (16 mg/kg) once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter. 25

In the ALCYONE study, all patients received up to 9 42-day cycles of subcutaneous bortezomib (1.3 mg/m 2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), oral melphalan (9 mg/m 2 once daily on days 1-4 of each cycle), and oral prednisone (60 mg/m 2 once daily on days 1-4 of each cycle). Patients in the D-VMP group also received IV daratumumab at 16 mg/kg once weekly in cycle 1, every 3 weeks in cycles 2 through 9, and every 4 weeks thereafter until disease progression or unacceptable toxicity. To mitigate infusion-related reactions, daratumumab was administered with 20 mg of oral or IV dexamethasone, which was substituted for prednisone on day 1 of each cycle. 26

Both study protocols recommended prophylaxis for herpes zoster reactivation during the treatment phase and suggested consideration of Pneumocystis carinii pneumonia (now commonly known as Pneumocystis jirovecii pneumonia) prophylaxis, per institutional guidelines.

End points and assessments

The primary end point in both studies was PFS, which has been reported previously. 25 , 26 Safety assessments included the evaluation of adverse events, electrocardiograms, clinical laboratory testing, physical examinations, and vital signs. The safety population in both studies included all patients who received any dose of trial treatment. In this post hoc analysis, safety data were pooled across studies and summarized for the daratumumab-containing (D-Rd/D-VMP) and non–daratumumab-containing (Rd/VMP) regimens. This analysis was descriptive in nature; therefore, no formal statistical analyses or comparisons were performed. Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 23.0. 27 Incidence of adverse events is presented through number and percentage of patients with the given event, as well as through exposure-adjusted incidence rates (EAIRs; event rate per 100 patient-months [only first incidence is counted]). Time to onset of adverse events is presented through the number and percentage of patients with the given event occurring within the indicated time period, using the number of patients treated within each time period as the denominator; the same adverse event may have occurred during various time periods and was counted at each time period in which it occurred. Median time to the first onset of adverse events was calculated using Kaplan-Meier estimates, which considers all patients in the study and censors those without an event. Competing-risk analysis of time to grade 5 infection was provided. Antibiotic, antiviral, and antifungal medications for prophylaxis or treatment were coded using the World Health Organization drug dictionary ( www.who-umc.org ; March 2017 version for the MAIA study and September 2016 version for the ALCYONE study).

Results

Patients

A total of 737 patients (D-Rd, n = 368; Rd, n = 369) were randomized in MAIA and 706 patients (D-VMP, n = 350; VMP, n = 356) were randomized in ALCYONE. The pooled safety population comprised 710 patients in the D-Rd/D-VMP group and 719 patients in the Rd/VMP group. Demographic and clinical characteristics from each study have been previously published and were well-balanced between treatment groups. 25 , 26 Pooled baseline characteristics are summarized in supplemental Table 1 . The median age for the pooled population was 72 years (range, 40-93). The median follow-up time for this pooled analysis was 64.5 months (range, 0-77.6) for MAIA and 86.7 months (0-97.9) for ALCYONE.

Overall incidence and timing of treatment-emergent infections

Overall, any-grade, grade 3/4, and grade 5 treatment-emergent infections are summarized in Table 1 . The incidence of infections was higher with D-Rd/D-VMP than with Rd/VMP, inclusive of any-grade (83.1% vs 63.4%), grade 3/4 (36.9% vs 22.4%), and grade 5 (3.0% vs 1.5%) infections. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients receiving D-Rd, D-VMP, Rd, or VMP across the MAIA and ALCYONE studies.

Within the first year of study treatment, the median number of any-grade and grade 3/4 treatment-emergent infection events per patient was 2.0 (range, 1-9) and 1.0 (1-5), respectively, in the D-Rd/D-VMP group and 2.0 (1-8) and 1.0 (1-5) in the Rd/VMP group. A total of 481 (67.7%) patients in the D-Rd/D-VMP group and 394 (54.8%) patients in the Rd/VMP group had ≥1 any-grade treatment-emergent infection with onset within the first year of study treatment; 184 (25.9%) and 174 (24.2%) patients had 1 infection, 127 (17.9%) and 111 (15.4%) had 2 infections, 80 (11.3%) and 49 (6.8%) had 3 infections, and 90 (12.7%) and 60 (8.3%) had >3 infections, respectively. A total of 157 (22.1%) patients in the D-Rd/D-VMP group and 112 (15.6%) patients in the Rd/VMP group had ≥1 grade 3/4 treatment-emergent infection with onset within the first year of study treatment; 109 (15.4%) and 80 (11.1%) patients had 1 grade 3/4 infection, 32 (4.5%) and 22 (3.1%) had 2 grade 3/4 infections, 14 (2.0%) and 8 (1.1%) had 3 grade 3/4 infections, and 2 (0.3%) and 2 (0.3%) had >3 grade 3/4 infections, respectively.

Respiratory infections were the most common type of infection across both groups. In the D-Rd/D-VMP group, pneumonia was the most common grade 3/4 and grade 5 infection (18.2% and 0.7%, respectively); in the Rd/VMP group, pneumonia was also the most common grade 3/4 infection (7.6%), whereas sepsis was the most common grade 5 infection (0.6%) in this group.

Median treatment exposure was longer in the D-Rd and D-VMP groups (47.5 [range, 0.1-77.3] and 33.0 [0-97.4] months, respectively) than in the Rd and VMP groups (22.6 [0-77.5] and 12.0 [0.1-15.7] months, respectively). To account for this, EAIRs were calculated and are summarized in supplemental Table 2 . EAIRs were slightly lower with D-Rd/D-VMP than with Rd/VMP for overall grade 3/4 infections (1.19 vs 1.41) and were similar for overall grade 5 infections (0.07 vs 0.08). More specifically, EAIRs for the most clinically relevant individual any-grade and grade 3/4 infections were generally similar between the D-Rd/D-VMP and Rd/VMP treatment groups, as shown in Figure 1 . In particular, EAIRs were also similar with D-Rd/D-VMP compared with Rd/VMP for grade 3/4 (0.49 vs 0.42) and grade 5 (0.02 vs 0.02) pneumonia.

Median time to the first onset of any-grade infections per Kaplan-Meier estimates was 4.9 (95% CI, 4.1-5.6) and 7.2 (5.7-9.0) months in the D-Rd/D-VMP and Rd/VMP groups, respectively, with a delay observed for grade 3/4 infections (83.3 [62.5 to not estimable (NE)] and NE [48.6 to NE] months) and grade 5 infections (NE [NE to NE] in both groups). The highest incidence of grade 3/4 infections occurred within the first 6-month interval of study treatment initiation in both groups ( Figure 2 A). The increase in the cumulative incidence of new-onset grade 3/4 infections was highest from 3 months to 6 months in both the D-Rd/D-VMP (3.6%) and Rd/VMP (3.1%) groups ( Figure 2 B). The cumulative incidence of grade 5 infections remained low over time and was similar between treatment groups ( supplemental Figure 1 ).

Grouped treatment-emergent neutropenia/febrile neutropenia

The incidence of grade 3/4 neutropenia was higher with D-Rd/D-VMP than with Rd/VMP (47.5% vs 38.0%), whereas the incidence of grade 3/4 febrile neutropenia was similar (2.8% vs 2.6%; Table 2 ). No grade 5 neutropenia or febrile neutropenia events were observed. The median time to first onset for grade 3/4 neutropenia/febrile neutropenia (per Kaplan-Meier estimates) was shorter in the D-Rd/D-VMP group than in the Rd/VMP group (41.0; 95% CI, 23.5 to NE vs 47.4; 28.4 to NE months, respectively). The onset of grade 3/4 neutropenia/febrile neutropenia was most frequent within ≤2 months of treatment initiation, with a higher incidence observed in the D-Rd/D-VMP group than in the Rd/VMP group during this early time period (31.1% vs 22.4%; Figure 3 ). The percentage of patients (per treatment window) with onset of grade 3/4 neutropenia/febrile neutropenia generally decreased during later time periods (>2 to ≤12 months) and was similar between treatment groups.

IV immunoglobulin therapy

More patients in the D-Rd/D-VMP group reported hypogammaglobulinemia as a treatment-emergent adverse event or a postbaseline immunoglobulin G (IgG) value of <400 mg/dL compared with patients in the Rd/VMP group (402 [56.6%] vs 174 [24.2%] patients). Median time to a postbaseline IgG value of <400 mg/dL was 4.8 (range, 0-56.4) and 2.8 (0-62.4) months in the D-Rd/D-VMP and Rd/VMP groups, respectively. Specifically considering the duration of IV immunoglobulin therapy received, 31 (4.4%) patients in the D-Rd/D-VMP group and 7 (1.0%) patients in the Rd/VMP group received IV immunoglobulin therapy for ≤6 months after the initiation of study treatment, with a median duration of IV immunoglobulin therapy of 0.1 (range, 0-6) and 0.1 (0-2) months, respectively, among these patients. Thirty-eight (5.4%) patients in the D-Rd/D-VMP group and 13 (1.8%) patients in the Rd/VMP group received IV immunoglobulin therapy for a duration that lasted >6 months after the initiation of study treatment, with a median duration of IV immunoglobulin therapy of 41.4 (range, 7-113) and 47.2 (11-85) months, respectively, among these patients.

Concomitant antibiotic, antiviral, and antifungal prophylaxis and treatment

A summary of the concomitant antibiotic, antiviral, and antifungal prophylaxis and treatment is provided in supplemental Table 3 . More patients in the D-Rd/D-VMP group than in the Rd/VMP group received ≥1 antibiotic for prophylaxis (192/710 [27.0%] vs 158/719 [22.0%]) or treatment (583 [82.1%] vs 486 [67.6%]); the most common antibiotic used for prophylaxis or treatment was amoxicillin. More patients in the D-Rd/D-VMP group than in the Rd/VMP group received ≥1 antiviral as prophylaxis for herpes infection (521 [73.4%] vs 445 [61.9%]) or treatment (556 [78.3%] vs 477 [66.3%]); the antivirals most commonly used were acyclovir (prophylaxis: 314 [44.2%] vs 273 [38.0%]; treatment: 331 [46.6%] vs 287 [39.9%]) and valacyclovir (prophylaxis: 224 [31.5%] vs 177 [24.6%]; treatment: 241 [33.9%] vs 192 [26.7%]). More patients in the D-Rd/D-VMP group than in the Rd/VMP group also received ≥1 antifungal treatment (142 [20.0%] vs 94 [13.1%]), most commonly fluconazole (85 [12.0%] vs 65 [9.0%]); antifungal prophylaxis was less common than antibiotic or antiviral prophylaxis and was similar between treatment groups (37 [5.2%] vs 32 [4.5%]). Supplemental Table 4 summarizes the key observations from the MAIA/ALCYONE pooled analysis in terms of the incidence of treatment-emergent infections and study-reported prophylaxis and treatment strategies relative to the recommendations for infection prevention based on the IMWG consensus guidelines, 24 which were published after the full enrollment of the MAIA and ALCYONE studies.

Discussion

In this pooled analysis of the phase 3 MAIA and ALCYONE studies, a higher incidence of any-grade, grade 3/4, and grade 5 infections were reported after treatment with D-Rd or D-VMP vs Rd or VMP among transplant-ineligible patients with NDMM; however, infections of any grade led to the discontinuation of study treatment in only ∼2% of patients across all treatment groups. These observations are generally consistent with the safety data reported in other daratumumab clinical trials across both transplant-ineligible 13 , 28 and transplant-eligible patients with NDMM. 12 , 29 , 30

When looking at the total number of infection events per patient within the first year of treatment, the median number of any-grade (2.0 and 2.0) and grade 3/4 (1.0 and 1.0) events was similar in the D-Rd/D-VMP and Rd/VMP groups, respectively. With the significant PFS and OS benefits achieved with the addition of daratumumab to Rd or VMP in MAIA and ALCYONE, respectively, and the ALCYONE study design including VMP administration for a maximum of 9 42-day cycles but daratumumab administration until progression or unacceptable toxicity, 15 , 16 the duration of treatment exposure was more than doubled in the daratumumab-containing groups (47.5 months with D-Rd and 33.0 months with D-VMP vs 22.6 months with Rd and 12.0 months with VMP). To account for this markedly longer treatment exposure in the daratumumab-containing groups, infection incidence rates were adjusted for the duration of treatment exposure. EAIRs of any-grade, grade 3/4, and grade 5 infections were generally comparable among treatment groups, with a slightly lower EAIR for grade 3/4 infections observed with D-Rd/D-VMP than with Rd/VMP (1.19 vs 1.41) and similar EAIR for grade 5 infections (0.07 vs 0.08). This observable change in incidence after exposure adjustments, compared with unadjusted rates, underscores the critical importance of considering the overall duration of treatment exposure when assessing a patient’s potential infection risk and the benefit-to-risk ratio of varying treatment strategies.

Some key observations were made following this pooled analysis, specifically regarding the timing and onset of infections. The highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups; after 6 months of treatment initiation, incidence decreased and was generally similar between groups. The median time to first onset for grade 3/4 infections (per Kaplan-Meier estimates) with D-Rd/D-VMP compared with Rd/VMP was 83.3 months vs NE. Notably, the cumulative incidence of grade 5 infections remained low over time and similar between treatment groups. Data from other MM studies are consistent with these observations, with infections occurring primarily within the first 3 to 4 months of treatment. 22 , 23 , 31

Consistent with previously published observations, 20 , 31 respiratory infections were the most common type of infection in this analysis, with pneumonia being the most frequent grade 3/4 and grade 5 infection in the D-Rd/D-VMP group. The incidence of grade 3/4 respiratory tract infections as a grouped term, as well as grade 3/4 pneumonia specifically, was more common with D-Rd/D-VMP vs Rd/VMP. However, when adjusted for treatment exposure, EAIRs for grade 3/4 respiratory tract infection, upper respiratory tract infection, lower respiratory tract infection, and pneumonia were similar among treatment groups. In addition, few deaths due to these infections were reported, which is noteworthy in this older patient population (median age of 72 years, with 37% of patients aged ≥75 years); nevertheless, this may not be representative of the typical MM experience given that patients participating in clinical trials may inherently have a better performance status than the general population. Influenza (all grades) was also more common with D-Rd/D-VMP than with Rd/VMP, but EAIRs and the incidence of grade 3/4 events were similar among treatment groups. Notably, although cross trial comparisons should be made with caution, the rates of any-grade and grade 3/4 COVID-19 infections observed with D-Rd/D-VMP in this analysis (5.2% and 1.0%, respectively) compare favorably with the rates reported in the more recent CEPHEUS trial with daratumumab-based treatment in transplant-ineligible patients with NDMM (38.1% and 11.2%, respectively), 13 which reflects the earlier timing of the MAIA and ALCYONE studies. Although the number of patients experiencing grade 3/4 sepsis in MAIA/ALCYONE was similar among treatment groups, there was a slightly higher EAIR with Rd/VMP.

The incidence of grade 3/4 neutropenia was higher with D-Rd/D-VMP than with Rd/VMP, whereas the incidence of grade 3/4 febrile neutropenia was similar among groups; no grade 5 events were observed. The median time to the first onset of grade 3/4 neutropenia/febrile neutropenia (per Kaplan-Meier estimates) was shorter with D-Rd/D-VMP than with Rd/VMP (41.0 vs 47.4 months, respectively). The incidence of hypogammaglobulinemia or a postbaseline IgG value of <400 mg/dL was also more frequent in the D-Rd/D-VMP group than in the Rd/VMP group, with more patients in the D-Rd/D-VMP group receiving IV immunoglobulin therapy. Both the increased incidence of neutropenia coupled with the increased incidence of hypogammaglobulinemia may have contributed to the higher rates of infection (not adjusted for exposure) that were observed with D-Rd/D-VMP compared with Rd/VMP. Given the impact of blood counts and immunoglobulin levels on infection risk, patients should be monitored for cytopenias frequently, with the use of IV immunoglobulin replacement being reserved for severe or life-threatening infections and/or IgG levels of <400 mg/dL with recurrent infections. 24 Such interventions have been shown to greatly reduce the risk of infections for patients with MM receiving daratumumab-based treatment. 32 , 33

At the time of MAIA and ALCYONE study design and initiation, formal guidelines surrounding optimal infection prophylaxis and management for patients with MM did not exist. However, both study protocols recommended prophylaxis for herpes zoster reactivation and suggested consideration of P carinii pneumonia (now commonly known as P jirovecii pneumonia) prophylaxis, per institutional guidelines.

In 2022, the IMWG published consensus guidelines and recommendations for prophylactic and management strategies for common infections observed in patients with MM. 24 Briefly, experts agreed on the following: periods of highest infection risk occur primarily during the first 3 months after diagnosis and when treating relapsed/refractory MM; infections in NDMM are potentially preventable and are of viral and bacterial nature; antibacterial prophylaxis with levofloxacin is recommended during periods of increased infectious risk, with the addition of trimethoprim–sulfamethoxazole for patients at risk of P jirovecii pneumonia; and acyclovir prophylaxis is recommended for patients who are seropositive for herpes simplex virus and varicella-zoster virus (if tested) and for patients receiving proteasome inhibitors or targeted monoclonal antibodies, specifically CD38-targeted monoclonal antibodies. 24 Supplemental Table 5 summarizes the key IMWG recommendations for patients with NDMM who are treated with monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors, a similar population to that enrolled in the MAIA and ALCYONE studies discussed here.

Approximately a quarter of the patients in MAIA and ALCYONE received prophylactic antibiotics, most often with amoxicillin, whereas >60% received prophylactic antivirals. Prophylactic levofloxacin and acyclovir are both recommended by the IMWG, particularly for patients at a high risk of early infection and for those receiving CD38-targeted monoclonal antibodies, 24 and both medications were reportedly used in MAIA and ALCYONE as prophylactic measures. It is important to note that these IMWG recommendations were published after the full enrollment of MAIA and ALCYONE; therefore, infection prophylaxis and management strategies may have been more tailored in these studies if the new IMWG infection prevention recommendations had been available at the time of study conception and initiation.

In conclusion, patient outcomes are significantly improved with the addition of daratumumab to standard-of-care Rd or VMP compared with Rd or VMP alone in patients with transplant-ineligible NDMM, 15 , 16 resulting in a longer duration of treatment. Although longer duration of treatment could lead to a higher number of infections over time, crude infection rates were comparable with D-Rd/D-VMP and Rd/VMP after the first 6 months and EAIRs were similar among treatment groups. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low across treatment groups (∼2%), clinicians should remain vigilant about infections throughout treatment and follow local guidelines and IMWG recommendations to minimize the risk of infection in transplant-ineligible patients with NDMM.

Conflict-of-interest disclosure: N.B. served as a consultant/on advisory boards for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GSK, Genentech, Johnson & Johnson, Karyopharm Therapeutics, Kyte, Novartis, Pfizer, Roche, Sanofi, and Takeda; and received research funding from Johnson & Johnson and Pfizer. J.S.-M. served on advisory boards for AbbVie, Amgen, Bristol Myers Squibb, Celgene, GSK, HaemaLogiX, Johnson & Johnson, Karyopharm Therapeutics, Merck Sharp & Dohme, Novartis, Regeneron, Roche, Sanofi, Secura Bio, and Takeda. S.Z.U. received research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GSK, Johnson & Johnson, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx, and Takeda; and served as a consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, EdoPharma, Genentech, Gilead, GSK, Johnson & Johnson, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, SkylineDx, Takeda, and Teneobio. M.A.D. received honoraria from Amgen, BeiGene, Bristol Myers Squibb, Johnson & Johnson, and Takeda. P.M. served as a consultant for and received honoraria from AbbVie, Amgen, Celgene, Johnson & Johnson, Pfizer, Sanofi, and Takeda. S.Z. received research funding from Johnson & Johnson (paid to the institution); participated in advisory boards for Bristol Myers Squibb, GSK, Johnson & Johnson, and Sanofi (paid to the institution); and has received no personal funding. A.P. served on advisory boards for and received honoraria from AbbVie, Adaptive, Amgen, Bristol Myers Squibb, GSK, Johnson & Johnson, Menarini, Pfizer, Sanofi, and Takeda. S.M. served as a consultant for Amgen, Bristol Myers Squibb, GSK, Johnson & Johnson, Pfizer, Regeneron, Roche, Sanofi, and Takeda. A.C. served as a consultant/on advisory boards for AbbVie, Amgen, Antengene, Celgene/Bristol Myers Squibb, Genentech, GSK, Johnson & Johnson, Karyopharm, Millennium/Takeda, Sanofi, Seattle Genetics, Secura Bio, and Shattuck Labs; and received research funding from Amgen, Celgene/Bristol Myers Squibb, Johnson & Johnson, Millennium/Takeda, and Seattle Genetics. N.R. served as a consultant for Amgen, Bristol Myers Squibb, GSK, Johnson & Johnson, and Takeda; and received research funding from bluebird bio. R.Z.O. received research funding from Asylia Therapeutics, Biotheryx, CARsgen, Celgene/Bristol Myers Squibb, Exelixis, Heidelberg Pharma, Johnson & Johnson, Sanofi-Aventis, and Takeda; received honoraria from and served as a member on a board of directors or advisory committee for AbbVie, Biotheryx, Bristol Myers Squibb, Johnson & Johnson, Karyopharm, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin, Oncopeptides, Regeneron, Sanofi-Aventis, and Takeda; and holds stock in Asylia Therapeutics. H.G. received grants and/or provision of investigational medicinal product from Bristol Myers Squibb/Celgene, Dietmar Hopp Foundation, Johnson & Johnson, and Sanofi; received research funding from Amgen, Bristol Myers Squibb, Celgene, GlycoMimetics Inc, GSK, Heidelberg Pharma, Hoffmann-La Roche, Johnson & Johnson, Millennium, Novartis, Pfizer, Oncopeptides, and Sanofi; served on advisory boards for Bristol Myers Squibb, GSK, Johnson & Johnson, and Sanofi; and received honoraria and support for attending meetings and/or travel from Amgen, Bristol Myers Squibb, GSK, Johnson & Johnson, Oncopeptides, Pfizer, and Sanofi. S.B. served as a consultant and on a speaker’s bureau for Bristol Myers Squibb, Pfizer, and Sanofi. C.H. received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Johnson & Johnson, and Takeda. K.W. received research funding from Amgen, Adaptive Biotech, AstraZeneca, Bristol Myers Squibb/Celgene, BeiGene, GSK, Johnson & Johnson, Sanofi, Stemline, and Takeda; received honoraria from AbbVie, Amgen, Adaptive Biotech, AstraZeneca, Bristol Myers Squibb/Celgene, BeiGene, GSK, Johnson & Johnson, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; and received travel support from GSK, Johnson & Johnson, and Sanofi. M.M. received grants and honoraria from Jazz Pharmaceuticals, Johnson & Johnson, and Sanofi; received honoraria from Amgen, Bristol Myers Squibb, Celgene, MaaT Pharma, Pfizer, and Takeda; and received grants from Roche. X.L. served as a consultant for and received research funding and honoraria from AbbVie, Amgen, Bristol Myers Squibb, Gilead Sciences, GSK, Harpoon Therapeutics, iTeos, Johnson & Johnson, Merck, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. A.J. served as a consultant/on advisory boards for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Gracell, GSK, Johnson & Johnson, and Sanofi-Aventis. G.C. received research funding from Bristol Myers Squibb/Celgene, Johnson & Johnson, and Takeda; and served as a consultant for and received honoraria from Amgen, Bristol Myers Squibb/Celgene, GSK, Johnson & Johnson, Millennium/Takeda, Oncopeptides, Roche, and Sanofi. H.Q. received research funding from AbbVie, Bristol Myers Squibb, and GSK; and served as a consultant/on advisory boards for AbbVie, Bristol Myers Squibb, GSK, Johnson & Johnson, Pfizer, and Roche. C.P.V. received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Forus, GSK, Johnson & Johnson, Pfizer, and Sanofi. M.C. served as a consultant/on advisory boards for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GSK, Johnson & Johnson, Menarini Stemline, Pfizer, and Sanofi. M.N. is an employee of Cytel who contracted with Johnson & Johnson. K.B., R.C., and F.B. are employees of and may hold stock or stock options in Johnson & Johnson. M.-V.M. participated in advisory boards for AbbVie, Amgen, Celgene, GSK, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; and received honoraria from AbbVie, Amgen, Celgene, GSK, Johnson & Johnson, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Seagen, and Takeda. S.K.K. has received research funding from AbbVie, Amgen, Allogene, AstraZeneca, Bristol Myers Squibb, CARsgen, GSK, Johnson & Johnson, Molecular Templates, Novartis, Regeneron, Roche-Genentech, and Takeda; served as a consultant/on advisory boards (with no personal payments) for AbbVie, Amgen, Arcellx, AstraZeneca, bluebird bio, Bristol Myers Squibb, Epizyme, Johnson & Johnson, K36, Loxo Oncology, Monte Rosa Therapeutics, Roche-Genentech, Sanofi, Secura Bio, Takeda, and Trillium; and served as a consultant/on advisory boards (with personal payments) for Antengene, BeiGene, GLH Pharma, and Oncopeptides. The remaining authors declare no competing financial interests.

Acknowledgments

The authors thank the patients who participated in the study and their families, as well as the study coinvestigators, research nurses, and coordinators at each of the clinical sites.

The studies ( ClinicalTrials.gov identifiers: NCT02252172 and NCT02195479 ) were sponsored by Johnson & Johnson. Medical writing and editorial support were provided by Lisa Shannon and Holly Clarke of Lumanity Communications Inc and were funded by Johnson & Johnson.

The study sponsor funded the studies and, in collaboration with the authors, designed the trials and collected, analyzed, and interpreted the data.

Authorship

Contribution: M.N. analyzed the data for the pooled analysis; and all authors participated in the conception and design of the study, acquisition, analysis, or interpretation of the data, drafting and revising the manuscript, approved the final version before submission, had full access to all the data in the studies, and had responsibility for the decision to submit for publication.

Footnotes

The data sharing policy of Johnson & Johnson is available at https://innovativemedicine.jnj.com/our-innovation/clinical-trials/transparency . As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access Project site at http://yoda.yale.edu .

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Tables, Figure, and References

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Associated Data

Supplementary Materials

Supplemental Tables, Figure, and References