INTRODUCTION
Introduction of novel agents for multiple myeloma (MM) treatment has significantly improved patient outcomes, 1 , 2 with increased efficacy and tolerability with novel drugs versus chemotherapies. Despite these advances, most patients relapse and MM remains incurable. Distinct cytogenetic abnormalities characterize MM and influence disease presentation, treatment response, and outcomes. However, the impact of patient cytogenetics on treatment decisions is limited by the lack of biomarker-directed therapies.
CONTEXT
Key Objective To assess if venetoclax-dexamethasone improved independent review committee–assessed progression-free survival (PFS) compared with pomalidomide-dexamethasone in patients with t(11;14)-positive relapsed/refractory multiple myeloma (RRMM) in a phase III trial (CANOVA). Knowledge Generated The CANOVA trial primary end point was not met, with venetoclax-dexamethasone showing numerically longer median PFS of 9.9 months compared with 5.8 months with pomalidomide-dexamethasone but failing to meet statistical significance ( P = .24). As observed with previous venetoclax studies, infections were associated with venetoclax-dexamethasone, and no new safety signals were observed. Relevance (S. Lentzsch) Venetoclax-dexamethasone did not significantly improve PFS over pomalidomide-dexamethasone in t(11;14)-positive RRMM. These results do not support its routine clinical use and highlight the continued need for more effective, biomarker-driven therapies.* *Relevance section written by JCO Associate Editor Suzanne Lentzsch, MD, PhD.
Translocation between chromosomes 11 and 14 [t(11;14)] is the most frequent primary translocation, 3 with a real-world prevalence of 22.1% in MM, 4 and is associated with unique biology characterized by CCND1 overexpression and remnants of B-cell biology. 3 , 5 , 6 t(11;14)-positive MM cells demonstrate greater BCL-2 dependence and higher sensitivity to BCL-2 inhibition. 3 Venetoclax is a highly selective, potent, oral BH3 mimetic that binds to BCL-2, thereby inhibiting BCL-2 function and inducing cell death. 7 Venetoclax has demonstrated tolerability and promising efficacy in t(11;14)-positive relapsed/refractory MM (RRMM) in phase I and II studies as monotherapy and as a 2-drug combination with dexamethasone or 3-drug combinations with dexamethasone, proteasome inhibitors (PIs; bortezomib or carfilzomib), or anti-CD38 monoclonal antibodies (daratumumab). 8 - 12 Furthermore, combining venetoclax with dexamethasone and bortezomib enhances BCL-2 dependency in MM cells. 13 - 15
In the phase III BELLINI study of venetoclax plus bortezomib-dexamethasone versus placebo plus bortezomib-dexamethasone in RRMM, subgroup analysis showed patients harboring t(11;14) received the greatest clinical benefit with venetoclax versus the control arm; venetoclax was unfavorable in the overall study population because of excess mortality. 16 Here, we report the primary analysis results of the randomized phase III CANOVA study evaluating venetoclax-dexamethasone versus pomalidomide-dexamethasone in patients with t(11;14)-positive RRMM.
METHODS
Study Design and Patients
The randomized, open-label, multicenter, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled patients age 18 years and older with t(11;14)-positive RRMM diagnosed according to International Myeloma Working Group (IMWG) criteria. 17 Eligibility criteria included Eastern Cooperative Oncology Group performance status ≤2, exposure to ≥2 previous lines of therapy (LOT), progression on or within 60 days after last LOT completion, exposure to a PI, and either refractoriness to lenalidomide or relapse within 6 months of stopping lenalidomide treatment. Patients were required to have MM positive for t(11;14) as determined by the Vysis IntelliFISH CCND1/IGH XT fluorescent in situ hybridization probe kit (Abbott Molecular, Des Plaines, IL) per centralized laboratory testing. Patients were required to have measurable disease and meet predefined laboratory values within the screening period (Supplementary Methods, online only).
Eligible patients were randomly assigned (1:1) to receive either once-daily oral venetoclax 800 mg, with no dose ramp-up, or oral pomalidomide 4 mg once daily on Days 1 to 21 of each 28-day cycle. All patients also received oral dexamethasone at 40 mg (or 20 mg for patients age 75 years and older) on Days 1, 8, 15, and 22 of each 28-day cycle; intravenous dexamethasone was permitted if oral administration was not possible. Randomization was stratified by age (<65 v ≥65 years) at random assignment, previous LOTs (2-3 v ≥4), and International Staging System stage (I v II v III) at screening. Patients continued assigned treatment until progressive disease (PD), unacceptable toxicity, or treatment discontinuation. Venetoclax dose reductions were allowed (Data Supplement, Table S1, online only).
The protocol recommended anti-infective and tumor lysis syndrome (TLS) prophylaxis, which were administered per investigator discretion and local guidelines (Supplementary Methods).
Study protocol, amendments, and related documents were approved by each institution's institutional review board or independent ethics committee. All patients provided written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guideline.
End Points and Assessments
The primary end point was progression-free survival (PFS) per blinded independent review committee (IRC) assessment, defined as time from random assignment until PD (Data Supplement, Table S2) or death; PFS per investigator assessment was a supplementary analysis. Key secondary end points were overall response rate (ORR), rate of very good partial response or better (≥VGPR), overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), time to deterioration in disease symptoms (TTDDS) per European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) MM Module 20 disease symptom domain, and time to deterioration in physical functioning (TTDPF) per EORTC QLQ Core 30 physical functioning domain. Other secondary end points included duration of response (DOR) and safety. Post hoc event-free survival (EFS) analysis was conducted to determine the time from random assignment until IRC-assessed PD, death, or start of a new anti-MM therapy.
Response assessments based on IMWG 2016 criteria 17 (Data Supplement, Table S2) were performed at baseline (Cycle 1 Day 1 before first study drug dose or during screening if within 7 days of Cycle 1 Day 1) and Day 1 of every cycle starting with Cycle 2 until confirmed PD or withdrawal of consent. ORR was defined as the proportion of patients with best response of PR or better. OS was defined as the time from random assignment to death. MRD was centrally assessed in bone marrow aspirates by next-generation sequencing (ClonoSEQ assay) at <10 –5 , with <10 –6 evaluated as exploratory analysis.
Safety evaluation included treatment-emergent adverse events (TEAEs), defined as those with an onset at or after first day of study treatment, excluding those developing >30 days after last study drug dose. TEAEs were graded by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Cytopenias of neutropenia, thrombocytopenia, anemia, and lymphopenia are presented as grouped terms (Supplementary Methods).
Statistical Analysis
Approximately 244 randomly assigned patients and 147 PFS events were required to provide 90% power to detect 70% improvement in median PFS (hazard ratio [HR], 0.583) with venetoclax-dexamethasone versus pomalidomide-dexamethasone. P value for primary analysis of PFS used stratified log-rank test with two-sided type I error rate with an alpha of .05; HR for PFS and corresponding 95% CIs were estimated by stratified Cox proportional hazards model, with treatment arm as the main effect.
Key secondary end points included ORR per IRC, ≥VGPR rate per IRC, OS, MRD negativity rate, TTDDS, and TTDPF. For ORR, ≥VGPR, ≥CR, and MRD negativity rates, 95% CIs were produced by the Clopper-Pearson method. All time-to-event end point analyses used Kaplan-Meier product-limit method, with 95% CIs determined by Brookmeyer-Crowley method. HRs and corresponding 95% CIs for OS, TTDDS, and TTDPF were estimated by stratified Cox proportional hazards model.
Per protocol, the primary analysis was to occur when approximately 147 events of PD or death accrued; this was reached at the cutoff date of July 24, 2023. Two interim futility analyses for PFS were planned after approximately 50 and 80 OS events. The final OS analysis was conducted after 146 OS events, with a data cutoff date of September 30, 2024. Safety and efficacy data were reviewed by an independent data monitoring committee. Study sponsors remained blinded until after database lock when 110 OS events had occurred. Efficacy analyses were conducted in the intention-to-treat population, which consisted of all randomly assigned patients. Safety analyses were conducted in all patients who received ≥1 study drug dose.
RESULTS
Patients
There were 459 patients screened, with 263 randomly assigned across 111 sites in 20 countries. The most common reasons for screening failure were lack of t(11;14) positivity by central laboratory analysis and failure to meet laboratory values. There were 133 patients randomly assigned to venetoclax-dexamethasone with 130 patients treated; 130 patients were randomly assigned to pomalidomide-dexamethasone with 127 treated (Fig 1 ).
The median time on study was 24.9 months (range, 0.4-54.9) in the venetoclax-dexamethasone arm and 25.6 months (range, 1 day-54.1 months) in the pomalidomide-dexamethasone arm. Patients in the venetoclax-dexamethasone arm had median three previous LOTs (range, 2-8) and 79% were refractory to a PI and an immunomodulatory drug (Table 1 ). Patients in the pomalidomide-dexamethasone arm had median two previous LOTs (range, 2-8) and 72% were refractory to a PI and an immunomodulatory drug (Table 1 ). All patients had t(11;14)-positive RRMM; 21% and 23% of evaluable patients in the venetoclax-dexamethasone and pomalidomide-dexamethasone arms, respectively, concomitantly carried deletion 17p. Gain(1q) was present in 25% and 36% of evaluable patients in the venetoclax-dexamethasone and pomalidomide-dexamethasone arms, respectively.
TABLE 1.
Baseline Demographics and Disease Characteristics
Abbreviations: ECOG, Eastern Cooperative Oncology Group; IMWG, International Myeloma Working Group; ISS, International Staging System; LOT, lines of therapy; PI, proteasome inhibitor. a Randomization was stratified by age at random assignment (<65 v ≥65 years), previous LOT (2-3 v ≥4), and ISS stage at screening (I v II v III). b Percentages were based on the number of patients with nonmissing data. c High risk was defined as ISS stage II/III and del(17p) per IMWG consensus on risk stratification. 18
| Characteristic | Venetoclax-Dexamethasone Arm (n = 133) | Pomalidomide-Dexamethasone Arm (n = 130) |
| Age at random assignment, No. (%) | ||
| Median (range), years | 67 (39-85) | 66 (37-89) |
| <65 a | 56 (42) | 58 (45) |
| ≥65 a | 77 (58) | 72 (55) |
| ≥75 | 29 (22) | 23 (18) |
| Sex, No. (%) | ||
| Female | 52 (39) | 61 (47) |
| Male | 81 (61) | 69 (53) |
| Race, No. (%) b | ||
| American Indian or Alaska Native | 0 | 0 |
| Asian | 40 (31) | 40 (31) |
| Black or African American | 1 (1) | 2 (2) |
| Native Hawaiian or Other Pacific Islander | 0 | 1 (1) |
| White | 88 (68) | 85 (66) |
| Missing, No. | 4 | 2 |
| Hispanic or Latino ethnicity, No. (%) b | 6 (5) | 4 (3) |
| Geographic region, No. (%) | ||
| China | 17 (13) | 18 (14) |
| Europe | 64 (48) | 62 (48) |
| Japan | 15 (11) | 12 (9) |
| North America | 7 (5) | 7 (5) |
| Rest of the world | 30 (23) | 31 (24) |
| ECOG performance status, No. (%) | ||
| 0 | 63 (47) | 63 (48) |
| 1 | 55 (41) | 61 (47) |
| 2 | 15 (11) | 6 (5) |
| ISS stage at screening, No. (%) | ||
| I a | 67 (50) | 60 (46) |
| II a | 40 (30) | 46 (35) |
| III a | 26 (20) | 24 (18) |
| IMWG consensus risk, No. (%) b , c | ||
| Standard risk | 91 (93) | 88 (92) |
| High risk | 7 (7) | 8 (8) |
| Missing, n | 35 | 34 |
| Positive t(11;14) status, No. (%) | 133 (100) | 130 (100) |
| Concomitant cytogenetic abnormality, n/N (%) | ||
| Deletion (17p) | 14/66 (21) | 15/66 (23) |
| gain(1q) (≥3 copies) | 13/51 (25) | 17/47 (36) |
| Median number of previous LOT (range) | 3 (2-8) | 2 (2-8) |
| Previous LOT at screening, No. (%) | ||
| 2-3 a | 98 (74) | 97 (75) |
| 2 | 58 (44) | 72 (55) |
| 3 | 40 (30) | 25 (19) |
| ≥4 a | 35 (26) | 33 (25) |
| Previous stem-cell transplantation, No. (%) b | ||
| Autologous | 69 (97) | 74 (99) |
| Allogeneic | 2 (3) | 1 (1) |
| Missing, No. | 62 | 55 |
| Refractory to PI, No. (%) | 109 (82) | 95 (73) |
| Refractory to immunomodulatory drug, No. (%) | ||
| Refractory to lenalidomide | 128 (96) | 125 (96) |
| Refractory to anti-CD38 monoclonal antibody, No. (%) | 47 (35) | 50 (38) |
| Refractory to PI and immunomodulatory drug, No. (%) | 105 (79) | 94 (72) |
| Refractory to PI, immunomodulatory drug, and anti-CD38 monoclonal antibody, No. (%) | 40 (30) | 42 (32) |
At the time of the primary analysis, 36 patients still had ongoing treatment (venetoclax-dexamethasone v pomalidomide-dexamethasone: n = 25 [19%] v n = 11 [8%]). The most common reason for venetoclax or pomalidomide discontinuation was PD (n = 83 [64%] v n = 73 [57%]); other reasons included adverse events (n = 15 [12%] v n = 20 [16%]), physician decision (n = 3 [2%] v n = 12 [9%]), and other (n = 1 [1%] v n = 6 [5%]). Overall, 121 patients discontinued the study, most commonly due to death (n = 50 [38%] v n = 61 [47%]; Fig 1 ).
Primary and Key Secondary End Points
At 24.9 months of median follow-up (range, 1 day-54.9 months), IRC-assessed median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone and 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24; Fig 2 A). Investigator assessed-PFS was similar (Data Supplement, Fig S1), with 94% concordance with IRC-assessed PFS. The Data Supplement (Fig S2) presents subgroup analysis of IRC-assessed PFS.
IRC-assessed ORR was 62% (95% CI, 53 to 70) with venetoclax-dexamethasone and 35% (95% CI, 27 to 44) with pomalidomide-dexamethasone (Fig 3 A, Data Supplement, Table S3). The ≥VGPR rate was 39% (95% CI, 31 to 48) with venetoclax-dexamethasone and 14% (95% CI, 8 to 21) with pomalidomide-dexamethasone (Fig 3 A). The median DOR was comparable between treatment arms (venetoclax-dexamethasone, 13.8 months [95% CI, 10.1 to 18.4]; pomalidomide-dexamethasone, 13.0 months [95% CI, 8.3 to 23.6]).
Overall, 19 patients (venetoclax-dexamethasone, n = 18; pomalidomide-dexamethasone, n = 1) achieved stringent complete response or complete response and were included in the MRD analysis. MRD negativity rate was 8% (95% CI, 4 to 13) with venetoclax-dexamethasone and 0% (95% CI, 0 to 3) with pomalidomide-dexamethasone (Fig 3 B).
Median time to next treatment (TTNT) was 21.2 months (95% CI, 15.8 to 27.2) with venetoclax-dexamethasone and 8.3 months (95% CI, 6.3 to 10.8) with pomalidomide-dexamethasone (HR, 0.546 [95% CI, 0.385 to 0.776]; Fig 2 C). Median TTDDS was 20.3 months (95% CI, 9.2 to not estimable) with venetoclax-dexamethasone and 9.4 months (95% CI, 5.7 to 19.7) with pomalidomide-dexamethasone (Data Supplement, Fig S3A). Median TTDPF was 13.2 months (95% CI, 9.7 to 20.1) with venetoclax-dexamethasone and 5.6 months (95% CI, 3.8 to 9.5) with pomalidomide-dexamethasone (Data Supplement, Fig S3B).
At the final OS analysis, median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]; Fig 3 C).
Post Hoc EFS Analysis
Fewer patients in the venetoclax-dexamethasone (n = 8 [6%]) than the pomalidomide-dexamethasone arm (n = 29 [22%]) initiated next anti-MM therapy without IMWG-confirmed PD (Data Supplement, Table S4). Post hoc EFS analysis was conducted to account for start of new anti-MM treatment, regardless of the reason for next-line initiation or lack of confirmed PD. Median EFS was 9.4 months (95% CI, 6.8 to 11.5) with venetoclax-dexamethasone and 4.0 months (95% CI, 2.9 to 5.6) with pomalidomide-dexamethasone (HR, 0.651 [95% CI, 0.487 to 0.870]; Fig 2 B).
Safety
In the safety analysis population (venetoclax-dexamethasone, n = 130; pomalidomide-dexamethasone, n = 127), the median number of cycles was 10 cycles (range, 1-47) with venetoclax-dexamethasone versus five cycles (range, 1-30) with pomalidomide-dexamethasone (Data Supplement, Table S5); dose reductions and interruptions were similar between treatment arms (Data Supplement, Table S5). Nearly every patient experienced ≥1 any-grade TEAE (venetoclax-dexamethasone v pomalidomide-dexamethasone: 95% v 98%; Table 2 , Data Supplement, Table S6), with the most common any-grade TEAEs being GI (diarrhea: 41% v 17%) and hematologic events (neutropenia: 25% v 63%; thrombocytopenia: 18% v 39%; anemia: 18% v 35%). No clinical TLS occurred; laboratory TLS occurred in six patients (venetoclax-dexamethasone, n = 4; pomalidomide-dexamethasone, n = 2; Data Supplement, Table S7).
TABLE 2.
TEAEs Occurring in ≥15% of Patients
Abbreviations: PD, progressive disease; TEAE, treatment-emergent adverse event. a Listed are TEAEs of any grade that occurred in ≥15% of patients in either treatment arm. PD was recorded as a TEAE per protocol but was excluded here. b Includes preferred terms of neutropenia and neutrophil count decreased. c Includes preferred terms of lymphopenia and lymphocyte count decreased. d Includes preferred terms of anemia and hemoglobin decreased. e Includes preferred terms of thrombocytopenia and platelet count decreased.
| TEAE a | Venetoclax-Dexamethasone Arm (n = 130), No. (%) | Pomalidomide-Dexamethasone Arm (n = 127), No. (%) | ||
| Any Grade | Grade ≥3 | Any Grade | Grade ≥3 | |
| Any TEAE | 124 (95) | 87 (67) | 124 (98) | 105 (83) |
| Diarrhea | 53 (41) | 5 (4) | 21 (17) | 4 (3) |
| Neutropenia b | 32 (25) | 25 (19) | 80 (63) | 69 (54) |
| Lymphopenia c | 31 (24) | 23 (18) | 20 (16) | 18 (14) |
| Nausea | 28 (22) | 4 (3) | 12 (9) | 1 (1) |
| COVID-19 | 27 (21) | 3 (2) | 11 (9) | 1 (1) |
| Fatigue | 25 (19) | 1 (1) | 26 (20) | 3 (2) |
| Anemia d | 24 (18) | 17 (13) | 44 (35) | 31 (24) |
| Insomnia | 24 (18) | 1 (1) | 19 (15) | 3 (2) |
| Thrombocytopenia e | 23 (18) | 17 (13) | 49 (39) | 34 (27) |
| Hypokalemia | 19 (15) | 4 (3) | 9 (7) | 5 (4) |
| Vomiting | 19 (15) | 2 (2) | 6 (5) | 0 |
| Constipation | 14 (11) | 0 | 20 (16) | 0 |
| Back pain | 13 (10) | 1 (1) | 20 (16) | 2 (2) |
| WBC count decreased | 11 (8) | 3 (2) | 29 (23) | 20 (16) |
Grade ≥3 TEAEs occurred in 75% of patients; neutropenia was most common (venetoclax-dexamethasone, 19%; pomalidomide-dexamethasone, 54%). Serious TEAEs occurred in 38% and 40% of patients in the venetoclax-dexamethasone and pomalidomide-dexamethasone arms, respectively; pneumonia was the most common serious TEAE in both arms (Data Supplement, Table S8).
Overall rates of infections and serious infections were similar between treatment arms (Data Supplement, Table S9); fatal infections occurred with venetoclax-dexamethasone (n = 7 [5%]; Data Supplement, Fig S4 and Table S9). As an exploratory post hoc analysis, change in peripheral immune cell counts were evaluated during treatment (Data Supplement, Fig S5), including examination of baseline CD4 + T-cell counts and infections in 208 patients with baseline and longitudinal peripheral blood samples (Data Supplement, Table S10). Patients with fatal infections had low CD4 + T-cell counts at study entry, suggesting an existing immunosuppressive environment.
TEAEs led to venetoclax or pomalidomide discontinuation in 15% and 16% of patients, respectively; the most common (venetoclax-dexamethasone v pomalidomide-dexamethasone) were serious infection (5% v 1%), second primary malignancy (3% v 2%), and thrombocytopenia (2% v 2%). TEAEs led to dose reductions in 22% and 28% of patients in the venetoclax-dexamethasone and pomalidomide-dexamethasone arms, respectively (Data Supplement, Table S11).
In the safety analysis population, 109 patients (42%) died (venetoclax-dexamethasone, n = 48; pomalidomide-dexamethasone, n = 61), with 67 deaths (61%) due to PD (venetoclax-dexamethasone, n = 26; pomalidomide-dexamethasone, n = 41). Sixteen deaths (12%) in the venetoclax-dexamethasone arm and eight (6%) in the pomalidomide-dexamethasone arm were treatment-emergent (ie, occurred within 30 days of last study drug dose; Data Supplement, Table S12). Given the previous infection signal with venetoclax plus bortezomib-dexamethasone, 16 timing of anti-infective prophylaxis, infection, and disease response/progression were closely evaluated in patients with treatment-emergent deaths (Data Supplement, Fig S4); unfortunately, no correlations were observed. Three deaths (pneumonia, internal hemorrhage, Pneumocystis jirovecii infection) were considered possibly related to venetoclax, and no death was considered related to pomalidomide (Data Supplement, Fig S4).
DISCUSSION
In this randomized phase III study, venetoclax-dexamethasone resulted in numerically longer IRC-assessed PFS versus pomalidomide-dexamethasone (median, 9.9 v 5.8 months) in patients with t(11;14)-positive RRMM, but the difference was not statistically significant (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24), and so the primary end point was not met.
Athough acknowledging limitations of cross-trial comparisons, efficacy of the venetoclax-dexamethasone doublet regimen offered numerically longer PFS and OS versus pomalidomide-dexamethasone for patients with t(11;14)-positive RRMM in third-line and beyond, which are comparable with those of available therapies in this setting. 19 - 22 PFS observed with pomalidomide-dexamethasone was similar to that reported in other pomalidomide clinical studies in RRMM. 19 , 21
Informative censoring of patients leaving the study before protocol-defined PD confounds PFS interpretation. 23 In CANOVA, there was an imbalance in the number of patients who initiated next anti-MM therapy without PD based on the IMWG criteria (venetoclax-dexamethasone, n = 8; pomalidomide-dexamethasone, n = 29), and the PFS for pomalidomide-dexamethasone may have been overestimated because of this differential censoring. 24 When post hoc EFS analysis accounted for the start of new therapy as an event, EFS was longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone (median, 9.4 v 4.0 months; HR, 0.651 [95% CI, 0.487 to 0.870]).
Other efficacy measures that may be less affected by informative or differential censoring, including response rates, TTNT, and patient-reported outcomes of TTDDS and TTDPF, showed clinical benefit with venetoclax-dexamethasone. Additionally, OS was numerically longer (median, 32.4 v 26.9 months; HR, 0.856 [95% CI, 0.612 to 1.197]) and the MRD negativity rate was higher (8% v 0%) with venetoclax-dexamethasone versus pomalidomide-dexamethasone.
Although initially developed as a monotherapy, additional studies demonstrated an efficacy benefit with venetoclax in combination with other MM agents. Venetoclax-dexamethasone was originally evaluated in patients with t(11;14)-positive RRMM in a phase I/II study. The ORRs of 20 patients enrolled in the phase I portion and 31 patients enrolled in the phase II portion was 60% (≥VGPR, 30%) and 48% (≥VGPR, 36%), respectively. 12 Venetoclax plus carfilzomib-dexamethasone in an all-comer RRMM population was associated with an ORR of 80% in 49 patients (92% in 13 patients with t[11;14]; 75% in 36 patients without t[11;14] RRMM), with no unexpected safety signals reported. 10 Likewise, in a multipart phase I/II study, the ORR of 24 patients with t(11;14)-positive RRMM treated with venetoclax in combination with daratumumab-dexamethasone was 96% (all ≥VGPR), and the ORR of 24 all-comer patients with RRMM treated with venetoclax plus daratumumab, bortezomib, and dexamethasone was 92%, including five of six patients with t(11;14). 11
CANOVA confirmed initial findings with venetoclax-dexamethasone in patients with t(11;14)-positive RRMM, with an ORR of 62% (≥VGPR, 39%) at a median 24.9 months of follow-up. These ORR and ≥VGPR rates with venetoclax-dexamethasone were higher than with pomalidomide-dexamethasone (ORR, 35%; ≥VGPR, 14%). Given the heterogeneity of MM, biomarker-driven approaches with different combination partners may yield the greatest clinical benefit of venetoclax in RRMM.
The safety profile associated with venetoclax-dexamethasone was consistent with the known safety profile of each study drug. 9 , 12 The most common any-grade TEAE was diarrhea (41%; grade ≥3, 4%) in the venetoclax-dexamethasone arm and neutropenia (63%; grade ≥3, 54%) in the pomalidomide-dexamethasone arm. Diarrhea and nausea are among the most frequent nonhematologic TEAEs observed with venetoclax-based regimens, but few patients in this and other venetoclax studies experienced grade ≥3 diarrhea or nausea. 9 - 12 , 16
Overall infection rates were similar between treatment groups but there were seven fatal infections in the venetoclax-dexamethasone arm and none in the pomalidomide-dexamethasone arm. Exploratory immune profiling analysis in CANOVA revealed that patients with low CD4 + T-cell counts (<250 cells/μL) were at higher risk of fatal infections when treated with venetoclax-dexamethasone versus pomalidomide-dexamethasone. Although the exploratory nature of the analysis and small sample size limit interpretation, further investigation to understand the relationship between low CD4 + T-cell count and fatal infections is warranted. Anti-infective prophylaxis was protocol recommended, but treatment was at the investigator's discretion and may warrant further consideration with venetoclax-based regimens. The infection signal observed with venetoclax-dexamethasone in CANOVA was similar to that previously reported with the venetoclax triplet combination evaluated in the phase III BELLINI study, 16 with the exception that no OS detriment was observed in CANOVA.
In CANOVA, venetoclax was administered orally at 800 mg once daily, with no dose ramp-up. This dose was selected on the basis of phase I/II study results and supported by exposure-response analyses, which demonstrated that efficacy was maximized at 800 mg without an increase in safety events. 25 Updated exposure-response analyses, including data from CANOVA, further confirmed 800 mg as the optimal venetoclax dose combined with dexamethasone. Rates of TEAEs leading to dose interruption, reduction, and study drug discontinuation in CANOVA were similar between treatment arms.
A major limitation of CANOVA was its open-label design. The lack of double blinding along with previous knowledge by both patients and investigators regarding the effects of venetoclax in t(11;14)-positive MM likely led to unequal patient dropout between treatment arms and subsequent informative censoring in the control arm before PD criteria were met. 23 Despite these limitations and the failure to meet the primary end point, this randomized phase III study showed clinical activity of venetoclax-dexamethasone, with higher response rates and greater depth of response that translated into numerically longer survival outcomes, including PFS, EFS, and OS, with once-daily oral venetoclax-dexamethasone versus pomalidomide-dexamethasone in patients with t(11;14)-positive RRMM. These results suggest a need to further develop anti–BCL-2 agents for the treatment of t(11;14)-positive RRMM.
Supplementary Material
SUPPLEMENTARY MATERIAL
ACKNOWLEDGMENT
AbbVie and Genentech/Roche and the authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing assistance was provided by Laura Ruhge, PhD, of Bio Connections, LLC, and funded by AbbVie. A list of the study investigators and their study institutions are provided in Appendix Table A1 .
DISCLAIMER
Venetoclax is being developed in collaboration between AbbVie and Genentech/Roche. AbbVie and Genentech/Roche sponsored the study and participated in the design, study conduct, analysis, collection, and interpretation of the data, as well as the writing, review, and approval of the publication. All authors had access to the full study data and approved of the decision to submit the manuscript. The corresponding author had final responsibility for the decision to submit.
PRIOR PRESENTATION
Presented in part at the International Myeloma Society Annual Meeting, Athens, Greece, September 27-30, 2023.
CLINICAL TRIAL INFORMATION
NCT03539744 (CANOVA)
Supplementary Materials
Protocols
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-00924 .
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Use Agreement (DUA). Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home.”
AUTHOR CONTRIBUTIONS
Conception and design: Rakesh Popat, Meletios A. Dimopoulos, Maika Onishi, Nabanita Mukherjee, Jeremy A. Ross, Mohamed Ali Badawi, Emma Arriola, Orlando F. Bueno, Nizar J. Bahlis, Jason Valent, María-Victoria Mateos
Provision of study materials or patients: Meral Beksac, Meletios A. Dimopoulos, Moshe E. Gatt, Francesca Gay, K. Martin Kortüm, Silvia Ling, Chandramouli Nagarajan, Kenshi Suzuki, Orlando F. Bueno, Shinsuke Iida, Philippe Moreau, Jason Valent, María-Victoria Mateos
Collection and assembly of data: Rakesh Popat, Meral Beksac, Meletios A. Dimopoulos, Moshe E. Gatt, Jae-Cheol Jo, Prashant Kapoor, Eirini Katodritou, K. Martin Kortüm, Silvia Ling, Kenshi Suzuki, Lugui Qiu, Maika Onishi, Nabanita Mukherjee, Jeremy A. Ross, Edyta Dobkowska, Emma Arriola, Orlando F. Bueno, Shinsuke Iida, María-Victoria Mateos
Data analysis and interpretation: Rakesh Popat, Meral Beksac, Meletios A. Dimopoulos, Moshe E. Gatt, Francesca Gay, Jae-Cheol Jo, Prashant Kapoor, K. Martin Kortüm, Silvia Ling, Chandramouli Nagarajan, Maika Onishi, Grace Ku, Monique Dail, Nabanita Mukherjee, Jeremy A. Ross, Mohamed Ali Badawi, Mary Jean Fusco, Edyta Dobkowska, Emma Arriola, Orlando F. Bueno, Nizar J. Bahlis, Shinsuke Iida, Philippe Moreau, María-Victoria Mateos
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Venetoclax-Dexamethasone Versus Pomalidomide-Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma: Primary Results of the Randomized, Phase III CANOVA Study
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Rakesh Popat
Honoraria: Johnson and Johnson/Janssen, Pfizer, GlaxoSmithKline, AbbVie, Celgene, BMS
Consulting or Advisory Role: GlaxoSmithKline, Roche, Janssen, Galapagos NV, Sanofi, Regeneron
Speakers' Bureau: Pfizer
Research Funding: GlaxoSmithKline (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline
Meral Beksac
Consulting or Advisory Role: Janssen Oncology (Inst), BMS Turkey (Inst), Takeda (Inst), Oncopeptides (Inst), Sanofi (Inst), Pfizer (Inst), GlaxoSmithKline (Inst)
Speakers' Bureau: Sanofi (Inst), Takeda (Inst), Menarini (Inst), BMS Turkey (Inst)
Meletios A. Dimopoulos
Honoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeiGene, Sanofi, Regeneron, Menarini, AstraZeneca, Swixx BioPharma, GlaxoSmithKline
Consulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, BeiGene, Sanofi, Regeneron, Menarini, Swixx BioPharma, GlaxoSmithKline, AstraZeneca
Travel, Accommodations, Expenses: Amgen, Janssen, Takeda, Bristol Myers Squibb/Celgene
Francesca Gay
Honoraria: Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Sanofi
Consulting or Advisory Role: Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Oncopeptides, Pfizer, Sanofi, AstraZeneca, Kite, a Gilead company
Prashant Kapoor
Honoraria: Pharmacyclics, Sanofi (Inst), BeiGene, MustangBio, AstraZeneca, AbbVie (Inst)
Consulting or Advisory Role: Sanofi (Inst)
Research Funding: Amgen (Inst), Takeda (Inst), Sanofi (Inst), AbbVie (Inst), GlaxoSmithKline (Inst), Sorrento Therapeutics (Inst), Karyopharm Therapeutics (Inst), Regeneron (Inst), Ichnos Sciences (Inst), Bristol Myers Squibb/Celgene (Inst)
Travel, Accommodations, Expenses: GlaxoSmithKline, Janssen, Sanofi
Eirini Katodritou
Honoraria: Takeda, Janseen-Cilag, Amgen, Pfizer, GlaxoSmithKline
Consulting or Advisory Role: Johnson and Johnson/Janssen, GlaxoSmithKline, Amgen, Swixx BioPharma
Research Funding: Takeda, Amgen, Janseen-Cilag, Genesis Pharma, AbbVie, Karyopharm Therapeutics, Pfizer, Bristol Myers Squibb/Celgene
Travel, Accommodations, Expenses: Takeda, Johnson and Johnson/Janssen
K. Martin Kortüm
Honoraria: BMS, GlaxoSmithKline, AbbVie, Sanofi, Menarini, Pfizer, Johnson and Johnson/Janssen
Consulting or Advisory Role: GlaxoSmithKline, Sanofi, BMS, AbbVie, Skyline Diagnostics, Johnson and Johnson/Janssen, Pfizer
Research Funding: Janssen
Travel, Accommodations, Expenses: Janssen
Silvia Ling
Consulting or Advisory Role: GlaxoSmithKline
Travel, Accommodations, Expenses: BMS
Chandramouli Nagarajan
Honoraria: Janssen (Inst)
Consulting or Advisory Role: Janssen (Inst), Sanofi (Inst), BeiGene (Inst), AstraZeneca (Inst), Pfizer (Inst)
Speakers' Bureau: GlaxoSmithKline (Inst), BeiGene (Inst)
Research Funding: Janssen (Inst)
Travel, Accommodations, Expenses: Kite, a Gilead Company (Inst)
Lugui Qiu
Consulting or Advisory Role: BeiGene, Sanofi, Pfizer, J&J
Speakers' Bureau: BeiGene, J&J, Roche, Sanofi, Pfizer
Maika Onishi
Employment: Genentech
Stock and Other Ownership Interests: Genentech/Roche
Grace Ku
Employment: Genentech/Roche
Stock and Other Ownership Interests: Genentech/Roche
Consulting or Advisory Role: AstraZeneca (I), Elevar Therapeutics (I), Exelis (I)
Research Funding: BMS (I), Compass Therapeutics (I)
Monique Dail
Employment: Genentech/Roche
Stock and Other Ownership Interests: Roche/Genentech
Jeremy A. Ross
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Mohamed Ali Badawi
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Mary Jean Fusco
Stock and Other Ownership Interests: I have stock through mutual funds and a variety of companies and is at the discretion of my wealth management firm Fisher
Edyta Dobkowska
Employment: AbbVie/Pharmacyclics
Stock and Other Ownership Interests: AbbVie
Travel, Accommodations, Expenses: AbbVie/Pharmacyclics
Emma Arriola
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Orlando F. Bueno
Employment: AbbVie, AbbVie (I)
Stock and Other Ownership Interests: AbbVie, AbbVie (I)
Research Funding: AbbVie
Travel, Accommodations, Expenses: AbbVie, AbbVie (I)
Nizar J. Bahlis
Honoraria: Celgene, Janssen, AbbVie, Amgen, Sanofi, Takeda, Karyopharm Therapeutics, GlaxoSmithKline, Genentech/Roche
Consulting or Advisory Role: Janssen, Celgene, Amgen, Sanofi, Takeda, Pfizer, Karyopharm Therapeutics
Research Funding: Janssen (Inst), Celgene (Inst), Pfizer (Inst)
Shinsuke Iida
Honoraria: Bristol Myers Squibb, Pfizer, Sanofi, Janssen, Ono Pharmaceutical, AstraZeneca
Consulting or Advisory Role: Sanofi, Janssen, GlaxoSmithKline, AbbVie, Pfizer, Novartis, Bristol Myers Squibb Japan, Regeneron, AstraZeneca
Research Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Sanofi (Inst), Bristol Myers Squibb Japan (Inst), Janssen (Inst), AbbVie (Inst), GlaxoSmithKline (Inst), Daiichi Sankyo/UCB Japan (Inst), Celgene (Inst), Lilly (Inst), Pfizer (Inst), Shionogi (Inst), Novartis (Inst), AstraZeneca (Inst), Astellas Pharma (Inst)
Philippe Moreau
Honoraria: Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, Sanofi, Pfizer
Consulting or Advisory Role: Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVie, Pfizer
Maria-Victoria Mateos
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Honoraria: Janssen-Cilag, Celgene, Amgen, GlaxoSmithKline, AbbVie/Genentech, Sanofi, Pfizer
Consulting or Advisory Role: Takeda, Janssen-Cilag, Celgene, Amgen, AbbVie, GlaxoSmithKline, Pfizer, Regeneron, Roche/Genentech, Stemline Therapeutics, Kite, a Gilead Company
No other potential conflicts of interest were reported.
Rakesh Popat
Honoraria: Johnson and Johnson/Janssen, Pfizer, GlaxoSmithKline, AbbVie, Celgene, BMS
Consulting or Advisory Role: GlaxoSmithKline, Roche, Janssen, Galapagos NV, Sanofi, Regeneron
Speakers' Bureau: Pfizer
Research Funding: GlaxoSmithKline (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline
Meral Beksac
Consulting or Advisory Role: Janssen Oncology (Inst), BMS Turkey (Inst), Takeda (Inst), Oncopeptides (Inst), Sanofi (Inst), Pfizer (Inst), GlaxoSmithKline (Inst)
Speakers' Bureau: Sanofi (Inst), Takeda (Inst), Menarini (Inst), BMS Turkey (Inst)
Meletios A. Dimopoulos
Honoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeiGene, Sanofi, Regeneron, Menarini, AstraZeneca, Swixx BioPharma, GlaxoSmithKline
Consulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, BeiGene, Sanofi, Regeneron, Menarini, Swixx BioPharma, GlaxoSmithKline, AstraZeneca
Travel, Accommodations, Expenses: Amgen, Janssen, Takeda, Bristol Myers Squibb/Celgene
Francesca Gay
Honoraria: Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Sanofi
Consulting or Advisory Role: Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Oncopeptides, Pfizer, Sanofi, AstraZeneca, Kite, a Gilead company
Prashant Kapoor
Honoraria: Pharmacyclics, Sanofi (Inst), BeiGene, MustangBio, AstraZeneca, AbbVie (Inst)
Consulting or Advisory Role: Sanofi (Inst)
Research Funding: Amgen (Inst), Takeda (Inst), Sanofi (Inst), AbbVie (Inst), GlaxoSmithKline (Inst), Sorrento Therapeutics (Inst), Karyopharm Therapeutics (Inst), Regeneron (Inst), Ichnos Sciences (Inst), Bristol Myers Squibb/Celgene (Inst)
Travel, Accommodations, Expenses: GlaxoSmithKline, Janssen, Sanofi
Eirini Katodritou
Honoraria: Takeda, Janseen-Cilag, Amgen, Pfizer, GlaxoSmithKline
Consulting or Advisory Role: Johnson and Johnson/Janssen, GlaxoSmithKline, Amgen, Swixx BioPharma
Research Funding: Takeda, Amgen, Janseen-Cilag, Genesis Pharma, AbbVie, Karyopharm Therapeutics, Pfizer, Bristol Myers Squibb/Celgene
Travel, Accommodations, Expenses: Takeda, Johnson and Johnson/Janssen
K. Martin Kortüm
Honoraria: BMS, GlaxoSmithKline, AbbVie, Sanofi, Menarini, Pfizer, Johnson and Johnson/Janssen
Consulting or Advisory Role: GlaxoSmithKline, Sanofi, BMS, AbbVie, Skyline Diagnostics, Johnson and Johnson/Janssen, Pfizer
Research Funding: Janssen
Travel, Accommodations, Expenses: Janssen
Silvia Ling
Consulting or Advisory Role: GlaxoSmithKline
Travel, Accommodations, Expenses: BMS
Chandramouli Nagarajan
Honoraria: Janssen (Inst)
Consulting or Advisory Role: Janssen (Inst), Sanofi (Inst), BeiGene (Inst), AstraZeneca (Inst), Pfizer (Inst)
Speakers' Bureau: GlaxoSmithKline (Inst), BeiGene (Inst)
Research Funding: Janssen (Inst)
Travel, Accommodations, Expenses: Kite, a Gilead Company (Inst)
Lugui Qiu
Consulting or Advisory Role: BeiGene, Sanofi, Pfizer, J&J
Speakers' Bureau: BeiGene, J&J, Roche, Sanofi, Pfizer
Maika Onishi
Employment: Genentech
Stock and Other Ownership Interests: Genentech/Roche
Grace Ku
Employment: Genentech/Roche
Stock and Other Ownership Interests: Genentech/Roche
Consulting or Advisory Role: AstraZeneca (I), Elevar Therapeutics (I), Exelis (I)
Research Funding: BMS (I), Compass Therapeutics (I)
Monique Dail
Employment: Genentech/Roche
Stock and Other Ownership Interests: Roche/Genentech
Jeremy A. Ross
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Mohamed Ali Badawi
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Mary Jean Fusco
Stock and Other Ownership Interests: I have stock through mutual funds and a variety of companies and is at the discretion of my wealth management firm Fisher
Edyta Dobkowska
Employment: AbbVie/Pharmacyclics
Stock and Other Ownership Interests: AbbVie
Travel, Accommodations, Expenses: AbbVie/Pharmacyclics
Emma Arriola
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Orlando F. Bueno
Employment: AbbVie, AbbVie (I)
Stock and Other Ownership Interests: AbbVie, AbbVie (I)
Research Funding: AbbVie
Travel, Accommodations, Expenses: AbbVie, AbbVie (I)
Nizar J. Bahlis
Honoraria: Celgene, Janssen, AbbVie, Amgen, Sanofi, Takeda, Karyopharm Therapeutics, GlaxoSmithKline, Genentech/Roche
Consulting or Advisory Role: Janssen, Celgene, Amgen, Sanofi, Takeda, Pfizer, Karyopharm Therapeutics
Research Funding: Janssen (Inst), Celgene (Inst), Pfizer (Inst)
Shinsuke Iida
Honoraria: Bristol Myers Squibb, Pfizer, Sanofi, Janssen, Ono Pharmaceutical, AstraZeneca
Consulting or Advisory Role: Sanofi, Janssen, GlaxoSmithKline, AbbVie, Pfizer, Novartis, Bristol Myers Squibb Japan, Regeneron, AstraZeneca
Research Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Sanofi (Inst), Bristol Myers Squibb Japan (Inst), Janssen (Inst), AbbVie (Inst), GlaxoSmithKline (Inst), Daiichi Sankyo/UCB Japan (Inst), Celgene (Inst), Lilly (Inst), Pfizer (Inst), Shionogi (Inst), Novartis (Inst), AstraZeneca (Inst), Astellas Pharma (Inst)
Philippe Moreau
Honoraria: Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, Sanofi, Pfizer
Consulting or Advisory Role: Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVie, Pfizer
Maria-Victoria Mateos
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Honoraria: Janssen-Cilag, Celgene, Amgen, GlaxoSmithKline, AbbVie/Genentech, Sanofi, Pfizer
Consulting or Advisory Role: Takeda, Janssen-Cilag, Celgene, Amgen, AbbVie, GlaxoSmithKline, Pfizer, Regeneron, Roche/Genentech, Stemline Therapeutics, Kite, a Gilead Company
No other potential conflicts of interest were reported.
APPENDIX
TABLE A1.
List of CANOVA Study Principal Investigators
| Study Investigator | Study Institution |
| Henrik Gregersen | Aalborg University Hospital |
| Meletios-Athanasios Dimopoulos | Alexandra General Hospital |
| Vladimir Ivanov | Almazov National Medical Research |
| Fevzi Altuntas | Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital |
| Meral Beksac | Ankara University |
| Clotilde Cangialosi | AO Ospedali Riuniti Villa Sofia—Cervello |
| Francesca Gay | AOU Citta della Salute e della Scienza di Torino |
| Mario Boccadoro | AOU Citta della Salute e della Scienza di Torino |
| Hans Salwender | Asklepios Klinik Altona |
| Anna Marina Liberati | Azienda Ospedaliera Santa Maria Terni |
| Massimo Offidani | Azienda Ospedaliero Universitaria Ospedali |
| Omur Gokmen Sevindik | Bagcilar Medipol Mega Universite Hastanesi |
| Ciara Freeman | BC Cancer—Vancouver |
| Alina Gerrie | BC Cancer—Vancouver |
| Wenming Chen | Beijing Chaoyang Hospital, Capital Medical University |
| Tamar Tadmor | Bnai Zion Medical Center |
| Charles Crawley | Cambridge University Hospitals NHS |
| Igor Blau | Charite Universitaetsklinikum Berlin |
| Klaus Axel Nogai | Charite Universitaetsklinikum Berlin |
| Tatiana Tolstykh | City Clinical Hospital No. 52 |
| Sergey Semochkin | City Clinical Hospital No. 52 |
| Jason Valent | Cleveland Clinic |
| Chakra Chaulagain | Cleveland Clinic Florida |
| Olha Kuchkova | Communal nonprofit enterprise Regional Center |
| Jose Luis Sastre Moral | Complejo Hospitalario Universitario |
| Fahri Sahin | Ege University |
| Ludek Pour | Fakultni Nemocnice Brno |
| Vladimir Maisnar | Fakultni Nemocnice Hradec Kralove |
| Jiri Minarik | Fakultni Nemocnice Olomouc |
| Roman Hajek | Fakultni Nemocnice Ostrava |
| Luca Baldini | Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico |
| Zubeyde Ozkurt | Gazi University |
| Sosana Delimpasi | General Hospital of Athens Evaggelismos |
| Xin Du | Guangdong Provincial People's Hospital |
| Hiroshi Handa | Gunma University Hospital |
| Baijun Fang | Henan Cancer Hospital |
| Ian Irving | Icon Cancer Centre |
| Giuseppe Pietrantuono | IRCCS Crob |
| Pellegrino Musto | IRCCS Crob |
| Moshe Etzion Gatt | Hadassah Hebrew University Medical Center |
| Atsushi Shinagawa | Hitachi General Hospital |
| Salomon Manier | Hopital Claude Huriez |
| Thierry Facon | Hopital Claude Huriez |
| Philippe Moreau | Hotel Dieu-HME |
| Karim Belhadj | Hopital Henri Mondor |
| Lionel Karlin | Hopital Lyon Sud |
| Veronique Morel-Malek | Hopital Pitie Salpetriere |
| Maria Casanova Espinosa | Hospital Costa Del Sol |
| Felipe Casado | Hospital General Universitario de Toledo Comp |
| Joaquin Martinez Lopez | Hospital Universitario 12 de Octubre |
| Maria Victoria Mateos Manteca | Hospital Universitario de Sal |
| Elham Askari | Hospital Universitario Fundacion Jimenez Diaz |
| Estrella Carrillo Cruz | Hospital Universitario Virgen del Roci |
| Jesus Martin Sanchez | Hospital Universitario Virgen del Roci |
| Marta Reinoso Segura | Hospital Universitario Virgen del Roci |
| Aris Chaidos | Imperial College Healthcare NHS Trust |
| Lugui Qiu | Institute of Hematology & Blood Diseases Hospital |
| Gang An | Institute of Hematology & Blood Diseases Hospital |
| Yolanda Gonzalez | Instituto Catalan de Oncologia (ICO) Giron |
| Sevgi Besisik | Istanbul University Istanbul |
| Nobuhiro Tsukada | Japanese Red Cross Medical Center |
| Kenshi Suzuki | Japanese Red Cross Medical Center |
| Takayuki Ishikawa | Kobe City Medical Center General Hospital |
| Olga Uspenskaya | Leningrad Regional Clinical Hospital |
| Silvia Ling | Liverpool Hospital |
| Valeriy Chistyakov | LLC Novaya Klinika |
| Rachel Brown | Manchester University NHS Foundation |
| Alberto Rocci | Manchester University NHS Foundation |
| Shaji Kumar | Mayo Clinic Rochester |
| Prashant Kapoor | Mayo Clinic Rochester |
| Krina Patel | MD Anderson Cancer Center |
| Shigeki Ito | Iwate Medical University Hospital |
| Vladimir Vorobyev | Moscow State Budgetary Healthcare Institution |
| Vera Zherebtsova | Moscow State Budgetary Healthcare Institution |
| Shinsuke Iida | Nagoya City University Hospital |
| Bing Chen | Nanjing Drum Tower Hospital |
| Wee Joo Chng | National University Hospital |
| Kristian Bowles | Norfolk and Norwich University Hospital |
| Niels Abildgaard | Odense Universitets Hospital |
| Kazutaka Sunami | Okayama Medical Center |
| Hirohiko Shibayama | Osaka University Hospital |
| Michiko Ichii | Osaka University Hospital |
| Zhou Daobin | Peking Union Medical College Hospital |
| Junling Zhuang | Peking Union Medical College Hospital |
| Maan Alwan | Perth Blood Institute Ltd |
| Ross Baker | Perth Blood Institute Ltd |
| Robert Ayto | Portsmouth Hospitals University NHS |
| Edward Belsham | Portsmouth Hospitals University NHS |
| Ismail Sharif | QE II Health Sciences Centre |
| Darrell White | QE II Health Sciences Centre |
| Noa Lavi | Rambam Health Care Campus |
| Christian Bjorn Poulsen | Roskilde Hospital |
| Bo Jensen | Roskilde Hospital |
| Pratap Neelakantan | Royal Berkshire NHS Foundation |
| Jianqing Mi | Ruijin Hospital, Shanghai Jiaotong University School of Medicine |
| Sung-Soo Yoon | Seoul National University Hospital |
| Ping Li | Shanghai Tongji Hospital |
| Zhuogang Liu | Shengjing Hospital of China Medical University |
| Chandramouli Nagarajan | Singapore General Hospital |
| Ory Rouvio | Soroka University Medical Center |
| Etai Levy | Soroka University Medical Center |
| Zhongjun Xia | Sun Yat-Sen University Cancer Center |
| Jane Freeman | Sydney Adventist Hospital |
| Torben Plesner | Sygehus Lillebalt, Vejle |
| Irit Avivi | Tel Aviv Sourasky Medical Center |
| Hila Magen | The Chaim Sheba Medical Center |
| Chengcheng Fu | The First Affiliated Hospital of Soochow University |
| Chang Ki Min | The Catholic University of Korea, Seoul |
| Songfu Jiang | The First Affiliated Hospital of Wenzhou Medical University |
| Jie Jin | The First Affiliated Hospital, Zhejiang University |
| Cai Zhen | The First Affiliated Hospital, Zhejiang University |
| Yan Li | The First Hospital of China Medical University |
| Kaichi Nishiwaki | The Jikei University Kashiwa Hospital |
| Kazuhito Suzuki | The Jikei University Kashiwa Hospital |
| Huey-Shin Lee | The Queen Elizabeth Hospital |
| Eirini Katodritou | Theagenion Cancer Hospital |
| Yafei Wang | Tianjin Medical University Cancer Institute & Hospital |
| Noriko Fukuhara | Tohoku University Hospital |
| Hirokazu Miki | Tokushima University Hospital |
| Shingen Nakamura | Tokushima University Hospital |
| Nizar Bahlis | Tom Baker Cancer Centre |
| Mats Hardling | Uddevalla sjukhus |
| Jae-Cheol Jo | Ulsan University Hospital |
| Yu Hu | Union Hospital Tongji Medical College Huazhong University |
| Katja Weisel | Universitaetsklinikum Hamburg-Eppendorf (UKE) |
| Marie von Lilienfeld-Toal | Universitaetsklinikum Jena |
| Britta Besemer | Universitaetsklinikum Tuebingen |
| Hermann Einsele | Universitaetsklinikum Wuerzburg |
| Martin Kortuem | Universitaetsklinikum Wuerzburg |
| Rakesh Popat | University College London Hospitals NHS Foundation Trust |
| Mehmet Kocoglu | University of Maryland School of Medicine |
| Ivan Spicka | Vseobecna fakultni nemocnice v Praze |
| Gurdeep Parmar | Wollongong Hospital |
| Jin Seok Kim | Yonsei University Health System Severance |
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