Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design.
The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009–010956–93, and has completed recruitment.
Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0–43·5), median progression-free survival was 30 months (95% CI 25–36) with CVD and 20 months (15–28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48–0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0–83·5) in the CVD group and 78·5% (72·3–84·6) in the no CVD group (HR 0·98, 95% CI 0·67–1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related.
Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK.
Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.
Tumour cell diversity increases as genetic lesions accumulate, and the disease progresses from monoclonal gammopathy of undetermined significance to myeloma, leading to substantial subclonal heterogeneity at the time of diagnosis. Applying induction treatment designed to eliminate susceptible clones might provide selective pressure for the expansion of resistant clones, resulting in early or late relapse. Combination chemotherapies designed to maximise tumour cell death and eliminate resistant clones can improve clinical outcomes compared with single-agent chemotherapies. Depth of response has been identified as an independent prognostic factor, making the eradication of minimal residual disease an important therapeutic endpoint.
patients with complete response before transplantation had better progression-free survival and overall survival than patients without complete response, supporting an argument for early achievement of deep responses and the use of pre-transplant intensification rather that post-transplant consolidation.
This association raises the question as to whether monitoring response during induction therapy and switching to an alternative chemotherapy regimen in poor responders could increase the rate and depth of response and improve clinical outcomes. This study is the first to prospectively evaluate such a response-adapted approach to induction therapy for patients with newly diagnosed multiple myeloma. The purpose of the trial was to determine whether treatment intensification with a bortezomib-based regimen improves progression-free survival and overall survival in patients with suboptimal response after immunomodulatory-drug–based induction therapy, which was standard of care in the UK at time of trial design.
Evidence before this study
Potential strategies to deepen response after induction therapy for patients with myeloma include the use of autologous haemopoietic stem cell transplantation (in those eligible) and the use of post-transplant consolidation. Although the optimal timing for achieving maximum response is unclear, we found in our previous study, Myeloma IX, that patients with a complete response before autologous haemopoietic stem cell transplantation had better progression-free and overall survival than patients with a less than complete response. This supports an argument for early achievement of deep responses and the use of pre-transplant intensification rather than post-transplant consolidation. Little data is available concerning strategies for deepening response in transplantation-ineligible patients. We searched PubMed (July 15, 2019) for trials examining a response-adapted intensification strategy, using the search terms “myeloma” and “intensification”, without language restrictions, for clinical trials published before 2019 and excluding those relating to the introduction of autologous haemopoietic stem cell transplantation or those lacking response adaptation. We identified one previous phase 2 study reporting the use of cyclophosphamide, bortezomib and dexamethasone intensification administered to eight patients who failed to achieve more than a partial response to two cycles of cyclophosphamide, thalidomide and dexamethasone induction therapy. Five (63%) of eight deepened their response. To our knowledge the strategy of early response-adapted therapy has not been previously studied in a randomised trial and we sought to investigate this in Myeloma XI.
Added value of this study
We found a significant improvement in response and progression-free survival associated with the use of proteasome inhibitor-based intensification therapy for patients who achieved only a minimal or partial response to immunomodulatory triplet induction for newly diagnosed myeloma patients, although no difference in overall survival occurred.
Implications of all the available evidence
Our results support the concept that resistance to initial therapy is based on the specific therapy used and can be overcome by switching to a chemotherapy regimen with an alternate mechanism of action. In the event of a suboptimal response to immunomodulatory agent-based induction therapy, switching to a proteasome inhibitor-based combination improved response and progression-free survival. Taken together our data suggest that if agents of several different classes are available and can be tolerated in combination they should be used together upfront as is now the standard of care in the UK. If not, agent class should be switched rapidly in the absence of a deep response with the aim of response intensification to prolong progression-free survival.
Study design and participants
or will, be presented elsewhere. The trial recruited from 110 National Health Service hospitals in England, Wales, and Scotland (ppendix p 1).
Randomisation and masking
Patients with a suboptimal response to induction treatment were randomly assigned (1:1) to cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD. A minimisation algorithm with a random element was used to avoid chance imbalances in three variables: allocated induction treatment (CTD vs CRD vs attenuated CTD vs attenuated CRD), response to induction treatment (minimal or partial response), and centre. Patients allocated to KCRD induction treatment were ineligible for this randomisation.
Patients completing induction and intensification treatment (where applicable) and eligible were randomly assigned (1:1) to lenalidomide maintenance or observation. A minimisation algorithm with a random element was used to avoid chance imbalances in three variables: allocated induction treatment (CTD vs CRD vs attenuated CTD vs attenuated CRD), allocated intensification treatment (no CVD vs CVD vs not randomly assigned at intensification randomisation), and centre. Following a protocol amendment on Sep 14, 2011, and after recruitment of 442 patients under protocol versions 2.0 to 4.0, patients were randomly assigned (1:1:1) to lenalidomide, lenalidomide plus vorinostat, or observation. A similar minimisation algorithm with a random element was used to avoid chance imbalances in the same three variables with the same categories. Following a protocol amendment on June 28, 2013, and after recruitment of 615 further patients under protocol version 5.0, patients were randomly assigned (2:1) to lenalidomide or observation. A similar minimisation algorithm with a random element was used to avoid chance imbalances in the same three variables with the same categories but with the addition of KCRD to the induction treatment options. These changes were made to add and remove research questions in maintenance in this adaptive design study and were approved by the independent Data Monitoring and Ethics Committee and Trial Steering Committee.
All randomisations were done at the Clinical Trials Research Unit (Leeds, UK) by authorised members of staff with a centralised automated 24-h telephone system according to a validated minimisation algorithm produced under the supervision of WMG. Because of the nature of the intervention, the study was open label and the allocated treatment was not masked from study investigators or patients. The funders remained masked to treatment results until data cutoff.
Transplantation-eligible patients receiving KCRD proceeded to high-dose melphalan and autologous haemopoietic stem cell transplantation. Patients receiving immunomodulatory-based triplets (CTD vs CRD) followed a response-adapted approach with induction treatment intensification: those with complete response or very good partial response (assessed according to International Myeloma Working Group criteria) proceeded to transplantation in the transplantation-eligible pathway, whereas transplantation-ineligible patients proceeded directly to maintenance randomisation.
For maintenance therapy, 100 days after autologous haemopoietic stem cell transplantation or once a maximum response was achieved for transplantation-ineligible patients, patients initially received lenalidomide or were observed without lenalidomide therapy. Following a protocol amendment on Sep 14, 2011, and after recruitment of 442 patients, patients were allocated (1:1:1) to receive lenalidomide, lenalidomide plus vorinostat, or observation. After recruitment of 615 more patients, a further protocol amendment on June 28, 2013, allocated patients to receive lenalidomide or observation in a 2:1 ratio, and the lenalidomide plus vorinostat group was discontinued. Maintenance treatment continued until progressive disease in the absence of toxicity.
and reviewed centrally by an expert panel masked to treatment allocation. Adverse events were graded according to the US National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Adverse reactions were assessed at the start of each treatment cycle in patients receiving induction intensification. Comparisons between randomised groups were not made as adverse reactions could not be collected for those allocated to no CVD. Serious adverse events were reported for all patients from the date of randomisation until 30 days after the date of disease progression except in the case of serious adverse reactions or second primary malignancies, which were collected for the duration of the trial. Comparisons of these events were made for induction and maintenance comparisons only. Paraprotein, serum-free light chain, and urinary light chain excretion were assessed at least every 2 months for the first 2 years and then at least every 3 months until disease progression.
Patients were classified into three cytogenetic risk groups for the preplanned analysis of outcomes: standard risk (no adverse cytogenetic abnormalities), high risk (one adverse cytogenetic abnormality), or ultra-high risk (two or more adverse cytogenetic abnormalities). Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p).
The co-primary endpoints of the induction intensification evaluation of the trial were progression-free and overall survival. Progression-free survival was defined as the time from induction intensification randomisation to progressive disease or death from any cause. Overall survival was defined as the time from induction intensification to death from any cause or last follow-up.
Secondary endpoints were response (including the proportion of conversions from minimal or partial response to very good partial response or better in patients allocated to CVD), progression-free survival 2 (defined as the time from induction intensification randomisation to the date of second progressive disease, start of third antimyeloma treatment, or death from any cause), and toxicity.
Exploratory analyses of progression-free survival, overall survival, and response by cytogenetic risk group were prespecified in the protocol and by induction treatment were prespecified in the statistical analysis plan within each pathway. Other exploratory endpoints will be reported elsewhere.
The data cutoff date for this analysis was Jul 28, 2016. The hypothesis of the induction intensification randomisation was that CVD treatment could improve progression-free survival and overall survival compared with no CVD in adult patients with newly multiple myeloma. The overall study includes PFS and overall survival as co-primary endpoints for each randomisation. However, for the intensification element of the study only PFS was powered.
Efficacy analyses were done by intention to treat, including all patients randomly assigned to either CVD or no CVD. The safety population included all patients who received at least one dose of CVD therapy or those assigned to no CVD. For the co-primary endpoints, we estimated summaries of time to event per treatment group using the Kaplan-Meier method. We made comparisons between the allocated groups using the Cox proportional hazards model adjusted for the minimisation stratification factors, excluding centre, and stratified by treatment pathway, to estimate HRs and 95% CIs. Subgroup analysis was prespecified for the presence or absence of individual adverse cytogenetic abnormalities, cytogenetic risk status, and induction treatment. We did a likelihood ratio test for heterogeneity of treatment effect using Cox models identical to those used for the main analysis, with the inclusion of terms for the subgroup in question and the appropriate interaction terms. The reported test for heterogeneity for subgroup analysis corresponds to a one degree of freedom test for two category subgroups and a two degrees of freedom test for three category subgroups, etc. The number and proportion of participants in each response category was summarised descriptively and exact 95% CIs calculated using the Clopper-Pearson method. We summarised toxicity, in terms of adverse events, descriptively.
were used to check the adequacy of the Cox regression model. Evidence was found to support a violation of the proportional hazards assumption in the progression-free survival comparison. Post-hoc exploratory analysis using restricted mean survival time methods
was used to compare PFS times in the transplantation-eligible pathway. The parameter t* (ie, the area under the survival curve up to a time horizon) in the restricted mean survival time estimation, the expected progression-free period in this study, was chosen to be 64 months, because this was the maximum follow-up for all patients in the study. Other values of t* were investigated for the transplantation-ineligible pathway.
Additionally, at the last of these interim analyses, the possibility of an exceptionally large early effect of CVD on outcomes was evaluated using prespecified criteria of a 50% conversion or an increase in median progression-free survival of 24 months compared with no CVD (45 vs 21 months; HR 0·47). To ensure an overall significance level of 0·05 was maintained, the O’Brien and Fleming alpha-spending function was used with prespecified bounds of 0·005 for interim and 0·047 for final analysis.
The interim analysis was done and presented to the data monitoring and ethics committee on Nov 14, 2014, and the study continued without reporting the interim analysis. All reported p values are two sided and considered significant at an overall significance level of 5%.
We used SAS (version 9.4), Stata/IC (version 14.2), and R (version 3.2.3) for statistical analyses. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Of 3894 patients enrolled in the triplet induction element of the trial, 1217 achieved partial response or minimal response after induction therapy, of whom 583 (48%) were randomly assigned to CVD or no CVD in the intensification randomisation. Reasons for exclusion before intensification randomisation included withdrawn consent (n=302), ineligibility (n=37), proceeded directly to autologous haemopoietic stem cell transplantation (n=62), proceeded directly to maintenance therapy (n=25), progressive disease (n=78), and death (n=130). Slightly higher attrition occurred in the transplantation-ineligible pathway than transplantation-eligible but no difference in attrition between patients treated with lenalidomide or thalidomide-based induction was observed. The number of patients achieving partial or minimal response to each induction triplet entering the CVD randomisation were 200 (60%) of 333 in the CTD group, 167 (61%) of 276 in the CRD group, 118 (34%) of 345 in the attenuated CTD group, and 98 (37%) of 263 in the attenuated CRD group.
Table 1Baseline characteristics
Data are median (IQR) or n (%). C=cyclophosphamide. D=dexamethasone. R=lenalidomide. T=thalidomide. V=bortezomib.
Table 2Response by central review
Data are n (%). CVD=cyclophosphamide, bortezomib, and dexamethasone.
Table 3Adverse events
This study showed that additional therapy with CVD improved the depth of response for patients with newly diagnosed multiple myeloma with a suboptimal response to an immunomodulatory drug triplet combination, leading to marked improvements in progression-free survival compared with patients not receiving CVD intensification but without any difference in overall survival. The depth of response was very good partial response or better in 42·6% (95% CI 36·8–48·4) of patients treated with CVD. Median progression-free survival improved by 20 months in transplantation-eligible patients (HR 0·50, 95% CI 0·36–0·68) and 12 months in transplantation-ineligible patients (HR 0·73, 95% CI 0·52–1·02). Overall survival did not differ; however, median overall survival was not reached in either group at the time of analysis and after additional follow-up this endpoint will be reanalysed.
Statistically, evidence suggested that the hazard for not receiving CVD was not constant over time and, therefore, that the proportional hazards assumption was violated. This effect appeared more marked in the transplantation-ineligible pathway. Therefore, as prespecified in the statistical analysis plan, the restricted mean survival time method was used to confirm the results from the Cox regression analysis. This analysis confirmed the progression-free survival benefit associated with early exposure to CVD in transplantation-ineligible patients, possibly reflecting the effects of subsequent and later-line therapies in this patient subgroup.
From a biological perspective, our results are consistent with the concept that resistance to initial therapy is based on the specific therapy used. This resistance can be overcome by switching to a chemotherapy regimen with an alternate mechanism of action. We found that the adverse prognostic effect of poor initial response can be overcome and is not an inherent feature of the cancer itself but rather of the therapy administered. Analysis of patients within the trial achieving stable disease or progressive disease to immunomodulatory triplet induction who all received CVD intensification will explore this concept further and will be published separately. Additionally, in long-term follow-up, we plan to investigate the differences between achieving complete response or very good partial response to initial induction in contrast to only achieving it after CVD intensification. Minimal residual disease analysis was also done and this data will be presented separately.
patients were treated with initial therapy at investigators discretion followed by randomisation before autologous haemopoietic stem cell transplantation to one of three strategies: transplantation followed by lenalidomide maintenance, two autologous stem cell transplants followed by lenalidomide maintenance, or transplantation followed by post-transplant consolidation with bortezomib, lenalidomide, and dexamethasone (VRD) and then by lenalidomide maintenance. No difference in progression-free survival or overall survival was identified between randomisation groups. In the EMN02 study,
patients were enrolled before commencing treatment and treated with four cycles of CVD induction before being randomly assigned to autologous haemopoietic stem cell transplantation (one or two transplants depending on centre) or four cycles of bortezomib, melphalan, and prednisolone. There was a subsequent randomisation between two cycles of VRD or no consolidation. All patients received lenalidomide maintenance. In this study, post-transplant VRD consolidation before lenalidomide maintenance improved progression-free survival compared with maintenance alone (HR 0·78; p=0·045). The preliminary overall survival results indicated comparable 3-year overall survival with (86%) and without consolidation (87%). One of the key differences between studies was the initial induction therapy administered. In Stamina BMT CTN 0702, maximum response to induction therapy was more likely to have been achieved before autologous haemopoietic stem cell transplantation due to a lack of fixed duration of induction therapy. Similar to our study, patients had a median of 5 months (range 2–14 months) between initial therapy and registration and around 15% of patients had received more than one previous regimen, suggesting therapy changes in patients with a suboptimal initial response. In contrast, patients in EMN02 received a fixed four cycles of CVD given in 21-day cycles, equating to 3 months of therapy. Taken together, these two studies support the conclusions of our study and suggest that maximising treatment response, either before or after transplant, is an important endpoint of therapy.
700 transplantation-eligible patients were randomly assigned to either three cycles of VRD followed by autologous haemopoietic stem cell transplantation and two cycles of VRD or VRD for eight cycles without autologous haemopoietic stem cell transplantation. The study
supported the use of upfront autologous haemopoietic stem cell transplantation, with the median progression-free survival being longer for patients who received RVD and transplantation compared with those who received RVD alone (50 vs 36 months, HR 0·65, 95% CI 0·53–0·80, pppendix p ). VRD is not widely reimbursed outside of the USA, where the combinations used in this study remain pertinent. Furthermore, even in the setting of VRD, a proportion of patients do not respond well and so the findings of Myeloma XI would support personalising therapy by adding additional agents of a different class to induction in the absence of a deep initial response. About half of the patients in the Myeloma XI trial with partial or minimal response after induction therapy discontinued the study before intensification randomisation for various reasons and are, therefore, not included in the analysis presented here. These reasons included progressive disease and death, but also off-study treatment. Although further details for each individual patient withdrawing consent were not collected, we believe these withdrawals might have been driven by investigator and patient discomfort with delivering intensification to patients with responses very close to very good partial response but not quite meeting it or, conversely, not delivering intensification to patients with a response of only minimal response to initial induction. The substantial number of patients not reaching trial randomisation supports the use of combination therapies upfront to maximise response and improve outcomes, and these are now standard of care in the UK with the combination bortezomib, thalidomide, and dexamethasone.
these data support the maximisation of response before transplantation, given that the depth of response is associated with improved outcomes.
GHJ, FED, NHR, and GJM were chief investigators. GHJ, FED, NHR, WMG, and GJM conceived and designed the study. DAC, AS, and WMG designed the statistical analysis. GHJ, FED, CP, JRJ, BK, MG, CDW, KK, JL, JW, MWJ, GC, MFK, RGO, NHR, and GJM recruited participants. MFK, MTD, RGO, and GJM did central laboratory investigations. CC and AW collected data and prepared regulatory and governance requirements. GHJ, FED, CP, DAC, AS, MFK, MTD, RGO, WMG, and GJM analysed and interpreted data. GHJ, FED, CP, DAC, AS, and GJM wrote the manuscript. All authors reviewed and approved the manuscript.
Declaration of interests
FED reports personal fees from AbbVie, personal fees and non-financial support from Amgen and Takeda, and grants, personal fees, and non-financial support from Celgene and Janssen, outside the submitted work. CP reports personal fees and non-financial support from Amgen, Takeda Oncology, Janssen, and Celgene and personal fees from Oncopeptides, outside the submitted work. DAC reports grants and non-financial support from Celgene, Merck Sharpe & Dohme, Amgen, and Takeda, during the conduct of the study. CC reports grants and non-financial support from Celgene, Merck Sharpe & Dohme, Amgen, and Takeda, during the conduct of the study. AW reports grants and non-financial support from Celgene Corporation, Merck Sharpe & Dohme, Amgen, and Takeda, during the conduct of the study. BK reports speaker fees from Celgene, Takeda, and Jannsen and travel grants from Celgene, Jazz, and Takeda. CDW reports personal fees from Amgen and Novartis and personal fees and non-financial support from Takeda Oncology, Janssen, and Celgene, outside the submitted work. KK reports grants from Celgene Corporation and Janssen, outside the submitted work. JL reports personal fees and non-financial support from Celgene, Takeda, and Amgen, outside the submitted work. MWJ reports personal fees, consulting or advisory fees, and non-financial support from Amgen, Celgene, Janssen, Novartis, Takeda, Sanofi Genzyme, and Abbvie, outside the submitted work. GC reports grants and non-financial support from Celgene, Amgen, and Merck Sharp and Dohme, during the conduct of the study, and grants and personal fees from Takeda, Glycomimetics, Sanofi, Celgene, Janssen, Bristol-Myers Squibb, and Amgen, outside the submitted work. MFK reports grants and personal fees from Celgene, Amgen, Janssen, and Chugai and personal fees and non-financial support from Bristol-Myers Squibb and Takeda, outside the submitted work. MTD reports personal fees from and shares in Abingdon Health, outside the submitted work. RGO reports personal fees from Amgen and Celgene and personal fees and non-financial support from Takeda Oncology and Janssen, outside the submitted work. WMG reports grants from Celgene, Amgen, and Merck, during the conduct of the study, and personal fees from Celgene and Janssen, outside the submitted work. GJM reports personal fees from Janssen and Celgene, outside the submitted work. All other authors declare no competing interests.
De-identified participant data will be made available when all primary and secondary endpoints have been met. Any requests for trial data and supporting material (data dictionary, protocol, and statistical-analysis plan) will be reviewed by the trial-management group in the first instance. Only requests that have a methodologically sound proposal and whose proposed use of the data has been approved by the independent trial steering committee will be considered. Proposals should be directed to the corresponding author in the first instance. To gain access, data requestors will need to sign a data access agreement.
Primary financial support was from Cancer Research UK (C1298/A10410). Unrestricted educational grants from Celgene Corporation, Amgen, and Merck Sharp and Dohme and funding from Myeloma UK supported trial coordination and laboratory studies. We thank all the patients at centres throughout the UK whose willingness to participate made this study possible. We are grateful to the UK National Cancer Research Institute Haematological Oncology Clinical Studies Group, UK Myeloma Research Alliance, and to all principal investigators, sub-investigators, and local centre staff for their dedication and commitment to recruiting patients to the study. We thank the members of the Myeloma XI Trial Steering Committee and Data Monitoring and Ethics Committee. The support of the Clinical Trials Research Unit at The University of Leeds was essential to the successful running of the study; we thank all their staff who have contributed, past and present. Central laboratory analysis was done at the Institute of Immunology and Immunotherapy, The University of Birmingham; The Institute of Cancer Research, London; and The Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds. We are very grateful to the laboratory teams for their contribution to the study. We also acknowledge support from the National Institute of Health Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. The authors received editorial support from Excerpta Medica, funded by the University of Leeds.
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Published: October 14, 2019
© 2019 The Author(s). Published by Elsevier Ltd.