Multiple myeloma is a plasma cell malignancy that accounts for 1%–2% of newly diagnosed cancers.At diagnosis, approximately 20% of patients can be identified, using cytogenetics, to have inferior survival (high-risk). Additionally, standard-risk patients, with detectable disease -positive) postautologus stem cell transplant (ASCT), fare worse compared with those who do not (MRD-negative). Research is required to determine whether a risk-adapted approach post-ASCT could further improve patient outcomes.RADAR is a UK, multicentre, risk-adapted, response-guided, open-label, randomised controlled trial for transplant-eligible newly diagnosed multiple myeloma patients, using combinations of lenalidomide (R), cyclophosphamide (Cy), bortezomib (Bor), dexamethasone (D) and isatuximab (Isa).Participants receive RCyBorD(x4) induction therapy, followed by high-dose melphalan and ASCT. Post-ASCT, there are three pathways as follows:A phase III discontinuation design to assess de-escalating therapy in standard-risk MRD-negative patients. Participants receive 12 cycles of Isa maintenance. Those who remain MRD-negative are randomised to either continue or stop treatment.A phase II/III multiarm multistage design to test treatment strategies for treatment escalation in standard-risk MRD-positive patients. Participants are randomised to either; R, RBorD(x4) +R, RIsa, or RBorIsaD(x4) + RIsa.A phase II design to assess the activity of intensive treatment strategies in high-risk patients. Participants are randomised to RBorD(x4) +R or RBorIsaD(x4) + RIsa.1400 participants will be registered to allow for 500, 450 and 172 participants in each pathway. Randomisations are equal and treatment is given until disease progression or intolerance.Ethical approval was granted by the London–Central Research Ethics Committee (20/LO/0238) and capacity and capability confirmed by the appropriate local research and development department for each participating centre prior to opening recruitment. Participant informed consent is required before trial registration and reconfirmed post-ASCT. Results will be disseminated by conference presentations and peer-reviewed publications.ISCRTN46841867. RADAR trial treatment is personalised through the utilisation of baseline cytogenetic and dynamic minimal residual disease-based stratification within its design, which includes a de-escalation strategy to determine whether patients responding to treatment need to continue treatment until progression.RADAR is adaptive, new experimental treatment arms are expected to be added as new evidence emerges.Patients achieving <PR to induction therapy will not proceed with on-study autologus stem cell transplant and will be treated off -trial, there is no trial pathway for these participants.RADAR excludes patients with impaired renal impairment (defined as CrCl <30 mL/min).Multiple myeloma (MM) is the second most common haematological malignancy with over 5500 patients diagnosed in the UK each year.1 2These advances have been made possible due to the now standard use of ‘novel agents’ including proteasome inhibitors and immunomodulatory agents (IMiD agents) in conjunction with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT). While MM is predominantly a disease of older people, around 40% of patients are young and fit enough at diagnosis to be eligible for ASCT, a strategy shown in several randomised controlled trials (RCTs) to extend progression-free survival (PFS).2–4Improved response rates and increased survival poses challenges for the evaluation of new regimens in a timely manner. Recent studies re-evaluating the role of ASCT in the era of novel agents have confirmed superior PFS in patients allocated to ASCT compared with those allocated to chemotherapy with deferred ASCT.Treatment with lenalidomide (R), cyclophosophamide (Cy), bortezomib (Bor) and dexamethasone (D) (RCyBorD) was studied as first-line therapy in the phase 2 EVOLUTION study, where it produced high response rates and deep responses compared with CyBorD or LenBorD.9At diagnosis, a small subgroup of patients (approximately 20%) can be identified on the basis of genetic features to have inferior survival regardless of treatment regimen (high-risk patients).23With increasingly effective multidrug regimens being used for induction treatment, and responses further deepened following high-dose therapy and ASCT, the major challenge for standard-risk participants is how to maintain their disease control for as long as possible. The benefit of post-ASCT consolidation approaches remains controversial, with inconsistent evidence identifying both appropriate patient groups and treatment strategies.Maintenance lenalidomide (R) has been studied within several large studies and has consistently been shown to increase PFS, confimed within a recent meta-analysis.MRD status is a clinically relevant biomarker, and an emerging clinical trial endpoint with recent guidance published by the International Myeloma Working Group (IMWG).19 24Several studies have shown that patients who have detectable disease in their bone marrow (MRD-positive) following ASCT suffer earlier relapses and shorter survival when compared with those who are MRD-negative.Patients without detectable disease in their bone marrow (MRD-negative), have longer PFS and OS.RADAR aims to address the most important contemporary therapeutic questions for newly diagnosed MM transplant eligible (NDMM TE) patients post-ASCT by considering three different post-ASCT treatment pathways:A de-escalation treatment strategy is used to determine whether ceasing Isa maintenance treatment, after 12 cycles of continuous treatment, is non-inferior to long-term Isa treatment, in terms of PFS in participants who are standard-risk at diagnosis (participants who have ≤1 high-risk cytogenetic lesion) and are MRD-negative at 100 days post-ASCT and 12 months (cycles) after.A treatment escalation strategy is used for participants who are standard-risk at diagnosis (participants who have ≤1 high-risk cytogenetic lesion) and MRD-positive at 100 days post ASCT. The trial aims to compare the activity and efficacy of post-ASCT consolidation and maintenance treatment between combinations of R, Bor D and Isa to R alone in terms of conversion to MRD-negativity.Dose-intensive consolidation and maintenance strategies will be studied for participants who are high-risk at diagnosis (participants who have >1 high-risk cytogenetic lesion). The activity of post-ASCT strategies containing R, Bor, D and Isa will be assessed in terms of PFS rate.RADAR is a national, multicentre, risk-adapted, response-guided open-label, RCT for NDMM TE patients: phase II/III for standard-risk, MRD-Positive participants, phase III randomised discontinuation design for standard-risk, MRD-Negative participants, phase II randomised for high-risk participants. The following report details the trial protocol and follows the structure of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement.10.1136/bmjopen-2022-063037.supp1Supplementary dataThe RADAR trial will be conducted at 70 centres in the UK see , as idenPotential participants will be identified by the research team at the time they are referred to the haematology outpatient department with suspected MM. A smaller number of participants may be identified during inpatient admissions. Invitation to participate in the trial and provision of information will be made either during their first consultation, when routine diagnostic tests will be performed and potential treatment options discussed, or at the time they receive their diagnostic test results.Adults (18 years and older) with previously untreated MM requiring therapy, as defined by IMWG diagnostic criteria, who are eligible for stem cell transplant and capable of giving informed consent will be assessed for eligibility. Eligibility will be confirmed prior to; registration, the start of isatuximab maintenance treatment in the Randomisation 1 pathway and each randomisation by the principal investigator (PI) or an appropriately authorised medically trained delegate and will be recorded in the participants’ medical records and on the relevant electronic case report form (eCRF).To be eligible for each point in the trial the participants must meet all the inclusion criteria and none of the exclusion criteria presented in Box 1Previously untreated patients with multiple myeloma (MM) requiring therapy, defined as having myeloma defining events or with biomarkers of malignancy according to International Myeloma Working Group diagnostic criteria.Eligible for stem cell transplant.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 ;Total bilirubin ≤1.5 x upper limit of normal (ULN).Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤3 x ULN .Adequate marrow function:9/L  ≥0.75 x 109/L is allowed).Neutrophils ≥1.0 × 10Haemaglobin ≥80 g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted.9/L (in the case of heavy bone marrow infiltration (>50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of ≥50 × 109/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted.Platelets ≥75 × 10Creatinine clearance ≥30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes .Able to swallow oral medication.Aged at least 18 years.Agree to follow the pregnancy prevention guidelines:Female participants who:Are not of childbearing potential, ORIf they are of childbearing potential, agree to practise two effective methods of contraception, at the same time, from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception.)Agree to not donate oocytes during the entire study treatment period and until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Male participants, even if surgically sterilised , must agree to one of the following:Agree to practise effective barrier contraception during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject, during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception).Agree to not donate sperm during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Contraception for female and male participants must be in accordance with (and participants must consent to) the Celgene Pregnancy Prevention Plan.If female and of childbearing potential, they must have a negative pregnancy test performed by a healthcare professional within 14 days prior to registration.Able to provide written informed consent.Asymptomatic (smouldering) MM, monoclonal gammopathy of undetermined significance, solitary plasmacytoma of bone or extramedullary plasmacytoma (without evidence of MM).Received previous treatment for MM, with the exception of local radiotherapy to relieve bone pain or spinal cord compression, prior bisphosphonate treatment, or corticosteroids as long as the total dose does not exceed the equivalent of 160mg dexamethasone. This criteria is not applicable at R1, R2 and R3 when participants will have received previous treatment for MM as part of this trial.Unstable angina or myocardial infarction within 4 months prior to registration , New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischaemia or grade 3 conduction system abnormalities unless subject has a pacemaker.Cardiac disorder identified according to local practice .Significant neuropathy (grade ≥3 or grade 2 with pain).Prior malignancy that required treatment or has shown evidence of recurrence  during the 5 years prior to registration. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed.Pregnant, lactating or breastfeeding female participants.Known resistance, intolerance or hypersensitivity to any component of the planned therapies, except in the case of hypersensitivity which is amenable to premedication with steroids or H2 blocker. Intolerance includes hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.Major surgery within 14 days before registration . This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing.Active systemic infection.Participant is hepatitis B surface antigen positive, hepatitis C antibody positive or HIV positive . Participants must have hepatitis and HIV screening conducted within 28 days prior to registration.Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study.Receipt of live vaccination within 30 days prior to registration, for the duration of the study and for 3 months after the last dose of study drug.Participant has risk factors for thromboembolism including the use of agents which may increase their risk of thrombosis, such as hormone replacement therapy (this exclusion criteria is applicable only at registration and when starting R2 or R3 pathway).Participant has risk factors for seizures (this exclusion criteria is applicable only at registration and when starting R2 or R3 pathway).Box 2not confirmed to have at least two of these genetically adverse lesions: t, t, t, del(17p), gain(1q)), as confirmed by the Clinical Trials Research Unit.Standard-risk -negative  central lab) at 100 days postautologus stem cell transplant (ASCT).2 high-dose melphalan and ASCT.Received ≥100 mg/mEastern Cooperative Oncology Group (ECOG) performance status 0–2 .Total bilirubin ≤1.5 x upper limit of normal (ULN).Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)≤3 x ULN .Adequate marrow function:9/L .neutrophils ≥1.0 × 10Hb ≥80 g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted.9/L . Platelet transfusions within 3 days prior to eligibility assessments are not permitted.Platelets ≥75 × 10Creatinine clearance ≥30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes .Agree to follow the pregnancy prevention guidelines:Female participants who:Are not of childbearing potential.If they are of childbearing potential, agree to practise two effective methods of contraception, at the same time, from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or until 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or until 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception.)Agree to not donate oocytes during the entire study treatment period until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Male participants, even if surgically sterilised , must agree to one of the following:Agree to practise effective barrier contraception during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or until 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or until 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception).Agree to not donate sperm during the entire study treatment period until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Signed the informed consent document for the R1 treatment pathway.Disease progression .MRD-positive  at 100 days post-ASCT.Registration exclusion criteria .Box 3not confirmed to have at least two of these genetically adverse lesions: t, t, t, del(17p), gain(1q)), as confirmed by the Clinical Trials Research Unit.Standard-risk -negative  at 100 days postautologus stem cell transplant (ASCT).MRD-negative  after 12 cycles of isatuximab.2 high-dose melphalan and ASCT.Received ≥100 mg/mEastern Cooperative Oncology Group (ECOG) performance status 0–2 .Total bilirubin ≤1.5 × upper limit of normal (ULN).Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)≤3 x ULN .Adequate marrow function:9/L ,Neutrophils ≥1.0 × 10Hb≥80 g/L. Blood transfusions within 3 days days prior to eligibility assessments are not permitted.9/L . Platelet transfusions within 3 days days prior to eligibility assessments are not permitted.Platelets ≥75 × 10Creatinine clearance ≥30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes .Agree to follow the pregnancy prevention guidelines:Female participants who:Are not of childbearing potential.If they are of childbearing potential, agree to practise two effective methods of contraception, at the same time, from the time of signing the informed consent form until 5 months after the last dose of study drug.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent form until 5 months after the last dose of study drug.  and withdrawal are not acceptable methods of contraception.)Agree to not donate oocytes during the entire study treatment period and until 5 months after the last dose of study drug.Male participants, even if surgically sterilised , must agree to one of the following:Agree to practise effective barrier contraception during the entire study treatment period and until 5 months after the last dose of study drug.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject during the entire study treatment period and until 5 months after the last dose of study drug.  and withdrawal are not acceptable methods of contraception).Agree to not donate sperm during the entire study treatment period and until 5 months after the last dose of study drug.Signed the informed consent document for the R1 treatment pathway.Disease progression .MRD-positive  at 100 days post-ASCT or after 12 cycles of isatuximab.Registration exclusion criteria .Box 4not confirmed to have at least two of these genetically adverse lesions: t, t, t, del(17p), gain(1q)) as confirmed by Clinical Trials Research Unit.Standard-risk  at 100 days postautologus stem cell transplant (ASCT).2 high-dose melphalan and ASCT.Received ≥100 mg/mEastern Cooperative Oncology Group (ECOG) performance status 0–2 .Total bilirubin ≤1.5 × upper limit of normal (ULN).Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤3 × ULN .Adequate marrow function:9/L .Neutrophils≥1.0 × 10Hb≥80 g/L.9/L . Platelet transfusions within 3 days days prior to eligibility assessments are not permitted.Platelets ≥75 × 10Creatinine clearance ≥30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes .Agree to follow the pregnancy prevention guidelines:Female participants who:Are not of childbearing potential.If they are of childbearing potential, agree to practise two effective methods of contraception, at the same time, from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception).Agree to not donate oocytes during the entire study treatment period and until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Male participants, even if surgically sterilised , must agree to one of the following:Agree to practise effective barrier contraception during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception).Agree to not donate sperm during the entire study treatment period and until until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Signed the informed consent document for the R2 treatment pathway.Disease progression .Registration exclusion criteria .Box 5is confirmed to have at least two of these genetically adverse lesions: t, t, t, del(17p), gain(1q)) as confirmed by Clinical Trials Research Unit.High-risk  performance status 0–2 .Total bilirubin ≤1.5 × upper limit of normal (ULN)Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)≤3 x ULN .Adequate marrow function:9/L .Neutrophils≥1.0 × 10Hb≥80 g/L.9/L. Platelet transfusions within 3 days days prior to eligibility assessments are not permitted.Platelets ≥75 × 10Creatinine clearance (CrCl) ≥30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes .CrCl≥30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes .Agree to follow the pregnancy prevention guidelines:Female participants who:Are not of childbearing potential.If they are of childbearing potential, agree to practise two effective methods of contraception, at the same time, from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject from the time of signing the informed consent form until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception).Agree to not donate oocytes during the entire study treatment period and until 12 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Male participants, even if surgically sterilised , must agree to one of the following:Agree to practise effective barrier contraception during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Agree to practise true abstinence when this is in line with the preferred and usual lifestyle of the subject during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.  and withdrawal are not acceptable methods of contraception).Agree to not donate sperm during the entire study treatment period and until 6 months after the last dose of cyclophosphamide or 5 months after the last dose of study drug, whichever is longest.Signed the informed consent document for the R3 treatment pathway.Disease progression .Registration exclusion criteria .All participants will receive 4, 21 days, cycles of induction treatment with RCyBorD. During this time, the genetics risk status of the participant will be analysed and determined from bone marrow samples prior induction treatment . Participants will either be allocated as high-risk , t, t, del(17p) or gain(1q)) or standard risk. At the end of the induction cycle, participants will be assessed for response In the absence of disease progression or intolerance, participants with at least a partial response (PR) to will proceed to HDM and ASCT, which will be carried out according to local practice. At 100 days post-ASCT participants will be assessed for MRD and response and will follow one of three pathways of post ASCT treatment, provided they meet the eligibility criteria:Participants identified as standard-risk and who are MRD-negative post-ASCT will be treated according to the R1 pathway. All participants will receive 12 cycles of Isa maintenance treatment. Those who remain MRD-negative following cycle 12, will be randomised to continue or stop Isa maintenance treatment.Participants identified as standard-risk and who are MRD-positive post-ASCT and have at least a minimal response (MR) at 100 days post ASCT, will proceed to R2. Eligible participants will be randomised between: R maintenance; RBorD consolidation and R maintenance (RBorD+R); RISa maintenance; or RBorIsaD consolidation and RIsa maintenance (RBorIsaD+RIsa).Participants identified as high-risk and have at least a PR at 100 days post-ASCT will proceed to R3. These participants will be randomised to receive either RBorD consolidation, followed by R maintenance; or RBorIsaD consolidation followed by RIsa maintenance.All randomisations are balanced across the treatment arms. A computer-generated minimisation programme that incorporates a random element will be used to ensure treatment groups are well balanced for the stratification factors of each randomisation see .Throughout the trial R will be taken orally and swallowed whole at the same time on the scheduled days. D and Cy will be taken orally, while Bor will be administrated via a subcutaneous injection. Bortezomib may also be administered at home if this is in line with local policies and if appropriate procedures are in place. Isa will be given as an intravenous infusion and at a facility capable of managing hypersensitivity reactions.To monitor adherence to the oral trial medicines, participants will complete a participant diary card which will be reviewed at each trial visit. Non-compliance will be reported to the Clinical Trials Research Unit (CTRU) and any unused capsules will be returned to the pharmacy.With the exception of Isa, which can only be interrupted and resumed, dose modifications are permitted in the management of toxicities. Upfront dose modifications in response to liver and/or renal impairment are also permitted within the protocol. When the dose of any drug is reduced the dose cannot be re-escalated in this trial.If one drug in a combination is stopped, treatment with the other drugs in combination can continue.Scenarios in which the participant may remain on trial following consultation with the chief investigator (CI) are if they: discontinue two or more drugs during combination therapy; cease treatment for more than 3 weeks in between any treatment cycle or are delayed in starting maintenance of consolidation beyond 120 days post-ASCT. Note that if Bor, R or D is stopped during the pre-ASCT induction treatment due to toxicity, the participant will only be able to be treated on the standard-risk-MRD-negative pathway (assuming they meet the relevant inclusion criteria).If treatment is discontinued early, the participant will be treated off trial at the discretion of their treating clinician.Local support care protocols, including antiemetic schedules, tumour lysis syndrome prevention, venous thromboembolism prophylaxis and prophylactic antimicrobial therapy should be followed. The excluded concomitant medications and procedures while receiving trial treatment are listed in Concomitant medication, disease and other malignancies will be recorded at eligibility.PFS-R1 is defined as the time from R1 to the time of first documented evidence of disease progression or death from any cause. Individuals who are lost to follow-up or progression-free at the time of analysis will be censored at their last known date to be alive and progression-free.Attainment of MRD-negativity is defined as a binary endpoint. MRD-negativity will be determined at 6 months post-R2  according to the IMWG 2016 response criteria.The PFS rate is defined as the proportion of participants who are alive and progression-free 28 months post-R3.Disease progression is defined according to the IMWG 2016 response criteria for MM.24 29–31The secondary outcomes of this trial are to assess; PFS for R2 and R3, Time to progression, Time to second PFS event (PFS2), OS, Survival after progression, Objective response rate, Attainment of Very Good PR, Attainment of MRD negativity, Duration of MRD Negativity, Time to improved response, Time to next treatment, Treatment compliance and total amount of therapy delivered, Toxicity and Safety, including the incidence of second malignancies, QoL including EORTC-QLQ-C30 , EORTC-QLQ-MY20 (EORTC Myeloma Module) and EQ-5D-3L (EuroQol-5Dimension-3Level) and cost-effectiveness.An overview of the planned exploratory and subgroup analysis can be found in The full trial schema can be seen in Participants will enter into the trial at one of two points in their pathway, this will either be at bone marrow registration or at main trial registration.Participants who enter the trial at bone marrow registration will provide consent to have bone marrow samples taken and sent to central laboratories for analysis. If the participant does not have myeloma or decides to not take part in RADAR, they will have the option of consenting to their samples being used in future research.All participants will be required to provide written informed consent for the trial prior to trial registration  and prior to starting their post-ASCT treatment pathway once their post-ASCT assessments have been completed (for their pathway specific treatment). Optional consent regarding QoL and healthcare resource use questionnaires and the use of samples for future research will also be obtained within the first consent process.Consent forms are included in Following initial consent, participant eligibility for trial registration will be assessed. Trial samples for blood and urine will be taken for all participants and bone marrow samples will be taken for those who did not enter the trial through bone marrow registration.Bone marrow samples from diagnosis will be analysed at time of diagnosis at local cytogenetics laboratories for FISH (Fluorescence in-situ hybridisation)-defined high-risk makers. Original/copy of the FISH testing report will also be sent to CTRU where they will be reviewed by the CI/Trial management team for risk stratification. Participants will either be categorised high-risk , t, t(14:20), del(17 p) or gain(1q)) or standard-risk.Participants will commence RCyBorD treatment once a diagnosis of symptomatic myeloma has been confirmed by the treating physician, and ideally when it is known that the FISH testing has been successful.Where risk status can be determined from the first sample participants can continue on the trial. If status cannot be confirmed and the FISH report shows a full test failure that is, no information relating to adverse lesions is available, a second attempt will be made to collect a bone marrow sample prior to treatment starting. If partial results are obtained from the FISH sample, it may be possible that the CI/ trial management group (TMG) will be able to determine risk status using the assumption that translocations are mutually exclusive and that some markers are rare. If risk status can be determined a second bone marrow sample is not required. However, this must be confirmed by the CTRU.If, after two bone marrow samples, the FISH results for some or all the adverse lesions are inconclusive participants risk will be determined using a combination of the results from the two samples. The most appropriate pathway will be determined by the CI. Note this may result in the participants stratification factor being ‘unable to determine’ at randomisation. If a second bone marrow has been requested by CTRU but the collection was not attempted, the participants will be taken off the study .Following trial registration, once all central samples have been taken and risk status confirmed, participants will receive induction treatment as described in the intervention section. In the absence of disease progression or treatment intolerance participants with at least a PR to will proceed to HDM and ASCT.Consenting participants will complete QoL and resource use questionnaires at the end of RCyBorD induction treatment.All participants who go through ASCT will have a bone marrow sample taken at 100 days (±14) post-ASCT. If an MRD result cannot be obtained at the first attempt, the bone marrow will be repeated once (within 28 days after 100 days post-ASCT time point). If the second attempt fails, the participant will be considered MRD-positive.Participants who receive all 4 cycles of induction treatment followed by ASCT will be assessed for eligibility into their assigned randomisation pathways determined by genetic risk and MRD results and treated as described in the intervention schedule.Consenting participants in the R1 pathway will complete QoL and resource use questionnaires after cycle 6, 12, 24 and 36 .Similarly, consenting participants to receive R or RIsa within pathway R2 and R3 will complete QoL and resource use questionnaires after cycles 6, 12 and 24 of maintenance. Those randomised to receive RBorIsa+R or RBorIsaD+RIsa will complete QoL and resource use questionnaires after cycles 3, 9 and 21 of maintenance.Post-ASCT treatment (including observation only in the R1 pathway) is continued until disease progression, participant or clinician withdrawal or death. After treatment discontinuation, the participant is treated off trial by their local clinician and followed-up as per the trial follow-up schedule.Participants who discontinue during induction and until 100 days post-ASCT will be followed up for data pertaining to safety, details of salvage treatment, progression (including second progression) and survival at standard care visits. Follow ups will be conducted every 2 months up until disease progression, death or the end of trial. Similar follow-up will be completed for participants who discontinue their allocated trial treatment, which started post-ASCT. In addition consenting participants will still complete QoL and resource use questionnaires at appropriate time points.All types of adverse event (AEs)/reaction will be collected until 60 days after the last dose of protocol treatment.Following disease progression, all participants will be followed up annually until death, or until the end of the trial.In total 1400 participants will be recruited into the trial. Accounting for participants who will be lost to follow-up, this allows for 500, 450 and 172 participants to enter each randomisation, respectively.Data from our previous trial Myeloma XI, suggests that approximately 50 participants will lose their MRD-negative status during the first 12 cycles of Isa maintenance. In addition, Myeloma XI estimated median PFS with continuous R to be 50 months among TE participants.A power of 80% will be attained when 238 PFS events have been observed. These calculations assume that PFS follow an exponential distribution and that there will be 3 years of recruitment to R1 and 2 further years of follow-up .Global Health Status/QoL is considered a key secondary endpoint of R1 as the conclusion that the cessation of continuous treatment is non-inferior should not come at the expense of QoL. Ignoring those required to account for participants lost to follow-up, the 406 participants recruited above give >95% power to detect a difference of 10 points at 2 years post-R1, where 10 points represents an accepted medium magnitude clinically relevant difference.34R2 is a multiarm, multistage drug/drug-combination assessment platform with seamless phase II (activity) and phase III (efficacy) stages. Each experimental arm is compared with a designated control arm (R maintenance).Early data from Myeloma XI and similar data from IFM/DFCI 200933Following the strategy of Bratton and colleaguesn=2 stages (Stage 1 (activity) and Stage 2 (efficacy)).J=4 experimental arms  and a single control arm (R)Where allocation is equal across each arms (1:1:1:1:1).The power in stage 1 and stage 2 is 95% and 85%, respectively.The one-sided significance level in stage 1 and stage 2 is 25% and 1%, respectively.Ten participants per month are entered at R2, stage 1 (activity) analysis and reporting requires 1 month and 5% of participants drop-out.This equates to 40 participants in each arm at stage I and 50 further participants in each arm at stage 2. This will require a maximum of 46 months of recruitment plus a further 6 months of follow-up for the final participant. Overall, this design has a power of 83.4% and a one-sided family-wise error rate (FWER) of ~3%.Randomisation 2 has been powered assuming four experimental arms and that all experimental arms will continue to stage 2. In the case that only three experimental arms are implemented or at least one experimental arm is concluded to show a lack of activity after stage 1, the trial will have a higher power than stated above.et alEach arm of R3 will take the form of one-stage treatment design proposed by Simon In order to have an 80% power of demonstrating that the one-sided 95% CI of the PFS rate at 28 months excludes 34.7%, 81 evaluable participants are required, where a treatment arm will be deemed a ‘success’ if at least 37 out of 81 participants are progression-free at 28 months. To account for approximately 5% of participants being unevaluable at 28 months post-R3, 86 participants will be randomised to each treatment arm that is, 172 participants are required to be entered into R3.Accounting for those participants who will be lost to-follow-up R1, R2 and R3 require 500, 450 and 172 participants to enter each randomisation, respectively.Considering R1 and R2, it is assumed that 50 participants will lose their MRD-negative status during the 12 months of continuous treatment . Therefore, 550 participants are required to enter the MRD-negative part of the standard-risk pathway. It is assumed that 55% of standard-risk participants will be MRD-negative at the point of assessment therefore approximately 1000 participants are required to reach the MRD assessment stage of the standard-risk pathwayThis gives 280 participants who are expected to enter the high-risk pathway, using the same logic as in the standard-risk pathway if 90% of participants reach R3 then there will be approximately 252 participants recruited to R3. Given the calculations above it is plausible that another arm could be added to the high-risk pathway at a later date.It is planned that 1400 participants will be recruited for a total of 36 months. Once all centres are open, the recruitment target is 38 participants a month (equating to approximately 30 standard risk and 8 high-risk participants).In order to ensure the trial will meet the target sample size within the recruitment period, site set-up was prioritised while the trial was preparing to open to recruitment. In addition, the trial team are actively engaging with PIs at sites who support the trial to ensure that those sites open quickly and are maintaining regular communication with open sites to ensure that they continue to recruit to the trial.The trial opened to recruitment on 11 May 2021.Each of the registration and randomisation procedures will be conducted centrally using the University of Leeds CTRU automated 24-hour web base and telephone system.If a patient is suspected to have myeloma they will enter the trial at the time of routine diagnostic tests, through bone marrow registration. Once diagnosis is confirmed locally and the research team consider the patient potentially eligible for the trial, patients will be provided with full verbal explanation of the trial and full participant information sheet and informed consent documents to consider. Once the patient has provided informed consent to the first stage of the trial they will be registered into the trial at Bone Marrow Registration.Patients who have already had Myeloma confirmed prior to being approached for the trial, and those who decline consent at bone marrow registration, will enter at main trial registration.Data collection will primarily be via Remote Data Entry (RDE) on eCRFs, provided by the CTRU at the University of Leeds, and will be entered by staff at the research site. Access to the live RADAR database will be provided by the CTRU following sites being authorised to open to recruitment; guidance on RDE and completing eCRFs will be provided. Data regarding informed consent, QoL, Healthcare Resource Use questionnaires and in-patient stay forms will be collected via paper CRFs.QoL and Healthcare Resource Use questionnaires will be completed by the participant in clinic or at home and sealed in an envelope before handing back to the site research team who will return them to the CTRU via post.All information collected during the course of the trial will be kept strictly confidential. Information will be held securely on paper and electronically at the CTRU. The CTRU will comply with all aspects of the Data Protection Act 2018.Data will be monitored for quality and completeness by the CTRU. Missing data will be chased until it is received, confirmed as not available or the trial is at analysis. The CTRU/sponsor will reserve the right to intermittently conduct source data verification exercises on a sample of participants, which will be carried out by staff from the CTRU/Sponsor. Source data verification will involve direct access to participant notes at the participating hospital sites and the ongoing central collection of copies of informed consent documents and other relevant investigation reports.Statistical analysis is the responsibility of the CTRU statisticians, with the exception of the cost-effectiveness analysis, which will be undertaken by the health economists at the University of Leeds. A full statistical analysis plan (SAP) and Health Economics Analysis Plan will be written and approved before any analyses are undertaken.The analysis population will depend on the randomisation. Separate intention-to-treat (ITT), per-protocol (PP) and safety populations will be defined for each randomisation. In either case the ITT population will include participants according to their randomisation allocation, regardless of eligibility whether they prematurely discontinued the treatment, or did not comply with the regimen. The PP population will exclude individuals who do not receive their randomisation allocation or who are found to be ineligible following randomisation. The safety population will consist of all participants who receive at least one dose of the trial treatments and analyse participants according to what they received rather than what they were randomised to.With the exception of two interim analyses, no other formal analysis is planned until participants have attained the primary endpoint for each of the randomisations.The primary endpoint for R1 will be attained 2 years after the final participant has been randomised to R1.As R1 is a non-inferiority trial, both PP and ITT population analyses will be used as coprimary analyses and both are required to demonstrate statistical significance of non-inferiority where any discrepancies will be reported.PFS at R1 will be assessed using Cox proportional hazards regression to adjust for the stratification factors of R1 excluding centre, and presented using Kaplan-Meier estimates of the survival function. The treatment cessation strategy will be declared non-inferior to the continuous treatment strategy if the upper bound of the one-sided 95% CI for the HR is less than 1.38. Note no adjustment will be made for interim analysis due to it being a test for inferiority (see below) and not non-inferiority.The primary endpoint for R2 will be attained 6 months after the final participant has been randomised to R2. Primary analysis will be undertaken on the ITT population.An overall one-sided approximately 3% FWER will be applied accounting for each pair-wise comparison over each stage and all comparisons. This equates to a 25% and 1% one sided significance level at interim and final analysis. MRD-negative rate will be compared between each pair-wise comparison  in turn using logistic regression and adjusted for the minimisation factors of R2 excluding centre.The primary endpoint for R3 will be attained 28 months after the final participant has been randomised to R3.Primary analysis will be undertaken on the ITT population. The number of participants who are alive and progression-free at 28 months post R3 will be summarised separately within each treatment arm and exact one sided 95% CIs calculated. The null hypothesis is that the percentage of participants alive and progression-free at 28 months post R3 is 34.7%. A treatment arm is deemed a ‘success’ if the one sided 95% CIs of the PFS rate at 28 months excludes 34.71%. The treatment will then be proposed to be investigated further in a phase III trial.No multiple imputation is planned for the primary endpoints.OS and other time-to-event endpoints will be analysed using methods similar to those described for PFS. All binary endpoints will be analysed using similar methods to those described for the attainment of MRD negativity endpoint.For both R1 and R3, each experimental arm will be independently compared with historical control data using molecularly matched individual participant data (IPD) from Myeloma XI+(TE) and assessed for superiority in terms of PFS. Further details of the molecular matching of IPD will be described in the SAP, but it is anticipated that propensity score matching may be an appropriate technique. In each case a one-sided 10% significance level will be applied for each comparison with historical data.The number and proportion of participants in each response category will be summarised by allocated treatment and exact 95% two-sided confidence intervals will be calculated. The difference in proportions for each response category will be presented with corresponding 95% two-sided confidence intervals.QoL will be summarised using mean scores adjusted for baseline and two-sided 95% CI for each EORTC QLQ-C30 and EORTC QLQ-MY20 module symptom, role and functioning domain at each assessment time-point. Similar summaries will be produced for quality-adjusted life years (QALYs) as scored by the EQ-5D 3 Level (EQ-5D-3L) questionnaire. For the key secondary analysis of R1, the Global Health Status/QoL subscale at 2 years post-R1, will be compared between the arms using a multivariable linear regression model, adjusting for the R1 stratification factors.A series of subgroup and exploratory analyses will be undertaken. Subgroup analyses will follow the same structure as the main analysis of the respective endpoint. Where appropriate interaction terms will be added to the regression models to account for the subgroup being investigated. Subgroup and exploratory analyses may, by chance, generate false negative or positive results. Those carried out will be interpreted with caution.The analysis for the exploratory outcomes will be detailed in the SAP.The economic evaluation will take a decision modelling approach to assess the cost-effectiveness of treatment options for risk stratified treatment versus standard non-stratified treatment over participants’ lifetime. This will allow several research questions to be incorporated within one model. The model will be developed using best practiceReflecting the main trial analysis of effectiveness, the economic evaluation will assess the cost-effectiveness of treatment options at each of the randomisations in RADAR. For standard risk participants at R1, the cost-effectiveness analysis will compare treatment with isatuximab for 12 cycles only to long-term isatuximab treatment, continued until disease progression. For standard risk participants who are MRD-positive at 100 days post-ASCT in terms of conversion to MRD negativity at R2, the cost-effectiveness of post-ASCT consolidation and maintenance treatments in the treatment of standard-risk participants will be evaluated. For high-risk participants at R3, the cost-effectiveness of post-ASCT consolidation and maintenance treatment strategies containing lenalidomide, bortezomib, dexamethasone and isatuximab separately will be evaluated. In addition, the cost-effectiveness of stratified treatment pathways will be compared with standard non-stratified treatments.All analyses will be conducted following National Institute for Health and Care Excellence (NICE) reference case guidelines.The TMG includes the CI, CTRU team and coinvestigators that are assigned responsibility for the clinical set up, ongoing management, promotion of the trial and interpretation of the results. The trial steering committee (TSC), consisting of independent clinicians and statisticians, will provide overall supervision on the trial, including trial progress, adherence to protocol, participant safety and consideration of new information.An independent data monitoring and ethic committee (DMEC) will review the safety and ethics of the trial. Detailed reports will be prepared by the CTRU for the DMEC meetings which will take place at approximately yearly intervals. Additional reports will also be provided at intervals between these meetings. The committee will also review cumulative safety data by arm on an ongoing basis along with individual serious AE (SAE)/SAR listings. After each annual review, the DMEC will make their recommendations to the TSC about the continuation of the trial.Full interim reports will be presented to the DMEC in confidence annually and following the planned interim analyses which are expected to take place when half the number of events (119) have been observed in the treatment de-escalation pathway (R1) and at the end of the activity stage 1 treatment escalation pathway (R2), approximately 6 months after the 40th participant has been randomised.The interim analysis of R1 will be a one-sided test for inferiority conducted at the 5% significance level. PFS at R1 will be assessed using Cox proportional hazards regression to adjust for the minimisation factors (excluding centre), and presented using Kaplan-Meier estimates of the survival function.The interim analysis for R2 will be conducted at the end of Stage I (the phase II part) of the randomisation which is due 6 months following the randomisation of the 40th participant in each arm. This analysis will compare each experimental arm with the control arm in separate tests of superiority using a one-sided 25% significance level and 95% power to determine whether any of the experimental arms show lack of activity, that is, the null hypothesis in the superiority test is not rejected. Should an arm show lack of activity it will not be continued to the second stage of the randomisation (the phase III part). To account for the interim analysis and to give an overall significance level of 1% and power of 80% for each individual comparison the final analysis will be conducted using a one-sided 1% significance level and 85% power. Recruitment will continue seamlessly between activity and efficacy in these scenarios. Formal powered pair-wise comparisons are not undertaken comparing experimental arms at either stage.The DMEC committee members, in light of the interim analysis, will make their recommendations to the TSC about the continuation of the different aspects of the trial.AEs are any untoward medical occurrence in a participant or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. AEs can be defined as any unintentional, unfavourable clinical signs or symptoms; any new illness or disease, or the deterioration of existing disease or illness; or clinically relevant deterioration in any laboratory assessments or clinical test. Due to the nature of MM and its treatment, participants are likely to experience several AEs throughout the course of the disease.All AEs, both related and unrelated to myeloma treatment will be collected on the relevant eCRF from trial registration until 60 days after the last dose of protocol treatment and will be evaluated in accordance with the NCI-CTCAE V.5.0 (NCI-CTCAE). AEs and ARs should continue to be collected for participants who are randomised to ‘stop isatuximab’ at R1 , even though they will not be receiving any trial drugs during this period.An AE of special interest (serious or non-serious) is one of scientific and medical concern specific to isatuximab, for which ongoing monitoring and rapid communication by the investigator to the sponsor is considered to be appropriate. Isatuximab AEs of special interest include; ≥grade 3 infusion reactions (IRs), pregnancies, symptomatic overdoses with IMP and second primary malignancies (SPMs).SAEs are defined as any untoward medical occurrence or effect that at any dose results in death; or are life threatening (at the time of the event); or require in-patient hospitalisation or prolongation of existing hospitalisation; or result in persistent or significant disability or incapacity; or result in a congenital anomaly or birth defect; or any other important medical event. All SAEs will be reported from registration until 60 days post the last dose of the trial drug. SAEs should continue to be collected for participants who are randomised to ‘stop isatuximab’ at R1 (and until 60 days after last on-study assessment), even though they will not be receiving any study drugs during this period.Serious adverse reactions (SARs) are SAEs that are deemed possibly related to any dose administered of any trial treatment. Suspected unexpected serious adverse events (SUSARs) are SARs which are not listed in the reference safety information for that medicinal product. SARs and SUSARs will be reported from the date of first trial dose and for the duration of the trial.All new primary malignancies (SPMs) or suspected malignancies occurring from the date of trial registration and for the duration of the trial will be recorded. SPMs will be summarised and reviewed by an appointed member of the TMG who will determine whether trial treatment should continue.Participants registered into RADAR agree to follow the Celgene approved Pregnancy Prevention Programme. Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease status) in a female participant must be reported throughout the study and for 12 months after the last dose of cyclophosphamide or for 5 months following cessation of protocol treatment, whichever is longest. Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease status) in a male participant’s partner must be reported throughout the study and for 6 months after the last dose of cyclophosphamide or for 5 months following cessation of protocol treatment, whichever is longest.Safety analyses will summarise all SUSARs, SARs, SAEs, AEs and ARs, respective to where they occurred within the trial pathway . Safety data will be presented by treatment group for the safety population in addition to relationship to trial treatment.The CTRU and the trial sponsor have procedures in place to ensure that serious breaches of Good Clinical Practice (GCP) or the trial protocol are picked up and reported. A triggered monitoring plan will ensure that sites at risk are monitored accordingly.RADAR has been developed following extensive discussion with the UK myeloma community. Patients were first involved into the research at the grant application stage, and were incorporated into the development of the primary endpoint of R1, in which they confirmed a research question involving the stopping of treatment given there was no detectable myeloma would be of interest. The trial consent and participant information documents were reviewed for clarity by a patient representative. To ensure that a patient perspective is considered throughout the trial a PPI advisory group, including 4–8 members will feed into TMG meetings, and plan to host quarterly meetings to discuss urgent matters. It is envisioned that the PPI group, may help with writing summaries of results that can be published on patient forums and websites and maybe even shared directly with patients.Ethics approval has been obtained from the London–Central Research Ethics Committee (20/LO/0238). In addition capacity and capability has been confirmed by the appropriate research and development department for each participating centre prior to opening to participant recruitment into the trial. This included but was not limited to; having access to the non-trial supplied IMP , being able to conduct FISH as SoC, capacity of staff, ability to complete all protocol required assessments/investigations, and ability to archive trials documents.Participants will be required to provide informed consent before joining the trial.The trial opened to recruitment on 11 May 2021 using protocol version 2, dated 29 April 2020. This publication is written based from protocol version 3 dated July 2021. An amendment to protocol version 3 is anticipated Mid-2022, which should include the following:The cytogenetic abnormality del(1p) will be added to the definition of high risk. In addition, Isa will be added to induction regimen for high-risk patients following their first cycle of RCyBorD (while their risk status is confirmed). Furthermore, R3 will be removed and high-risk patients will receive RBorIsaD+RIsa only post-ASCT. The pathway will follow a single-arm, single stage, phase II, three outcome design, with the new primary objective to assess the activity of RCyBorD+Isa induction followed by ASCT and RBorD+Isa consolidation and RIsa maintenance in terms of PFS at 18 months post-trial registration.The removal of the phone registration and randomisation.The clarification of allowing prescribed medication to remove risks of thromboembolism before preceding onto treatment in the exclusion criteria for registration (and for starting post ASCT treatment).The allowance of blood support products, blood transfusions and platelet transfusions as per institutional guidelines at eligibility and pretreatment assessments.An update of exclusion criteria to allow for previous plasmacytomas.The PI retains overall responsibility for the informed consent of participants at their site and must ensure that any medically qualified person delegated responsibility to participate in the informed consent process is duly authorised, trained and competent to participate according to the ethically approved protocol, principles of GCP and Declaration of Helsinki. Written consent will be obtained and signed by a medically qualified member of the site research team. Informed consent must be obtained, and the participant must be registered into the trial prior to the participant undergoing procedures that are specifically for the purposes of the trial and are out-with standard routine care at the participating site. This include the confirmation of optional consent . At any stage, participants can withdraw consent without repercussion.All information collected during the course of the trial will be kept strictly confidential. Information will be held securely on paper and electronically at the CTRU. The CTRU will comply with all aspects of the Data Protection Act 2018.IPD  for all trial participants  will be made available for secondary research purposes at the end of the trial, that is, usually when all primary and secondary endpoints have been met and all key analyses are complete.Data will be shared according to a controlled access approach, based on the following principles:The value of the proposal will be considered in terms of the strategic priorities of the CTRU, chief investigator and sponsor, the scientific value of the proposed project, and the resources necessary and available to satisfy any data release request.We encourage a collaborative approach to data sharing, and believe it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets.The timing and nature of any data release must not adversely interfere with the integrity of the trial or research project objectives, including any associated secondary and exploratory research objectives detailed in the ethically approved original research protocol. On an individual trial or research project basis, a reasonable period of exclusivity will be agreed with the trial or research project team.Any data release must be lawful, in line with participants' rights and must not compromise patient confidentiality. Where the purposes of the project can be achieved by using anonymised or aggregate data this will always be used. We will release individual patient data only in a form adjusted so that recipients of the data cannot identify individual participants by any reasonably likely means. We will also only share data when there is a binding agreement in place stating that data recipients will not attempt to re-identify any individual participants.Any data release must be in line with any contractual obligations to which the CTRU is subject.The research must be carried out by a bone fide researcher with the necessary skills and resources to conduct the research project.The research project must have clear objectives and use appropriate research methods.The research must be carried out on behalf of a reputable organisation that can demonstrate appropriate IT security standards to ensure the data are protected and to minimise the risk of unauthorised disclosure.Data will only be shared for participants who have given consent to use of their data for secondary research.Requests to access trial data should be made to CTRU-DataAccess@leeds.ac.uk in the first instance. Requests will be reviewed (based on the above principles) by relevant stakeholders. No data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention requirements, which will usually stipulate that data recipients must delete their copy of the data at the end of the planned project.Participants who stop trial treatment due to progression or any point prior to the end of trial will be treated off-trial at the discretion of their treating clinician. Those who stop prior to disease progression will be followed up 2 monthly until disease progression, death or the end of the trial. Following disease progression all participants will be followed up annually until death, or until the end of the trial for post progression endpoints.Participants in the R1 pathway who are MRD-positive at 12 months post 12 cycles of isatuximab and therefore aren’t eligible for randomisation 1 will continue to receive isatuximab maintenance, these participants would continue to be monitored, and data collected, as previously but trial samples would not be collected.Authorship will be in keeping with the UK-MRA publication policy and due acknowledgement to participants, local investigators, funders and NCRI Haematological Oncology Study Group support made. The success of the trial depends on the collaboration of all participants. For this reason, credit for the main results will be given to all those who have collaborated in the trial, through authorship and contributor-ship. Uniform requirements for authorship for manuscripts submitted to medical journals will guide authorship decisions alongside the guidance of the UK Myeloma Research Alliance Authorship Policy.To maintain the scientific integrity of the trial, data will not be released prior to the end of the trial or a primary endpoint being reached, either for trial publication or oral presentation purposes, without the permission of the TSC and the (co-)chief investigators. In addition, individual collaborators must not publish data concerning their participants that is directly relevant to the questions posed in the trial until the main results of the trial have been published and following written consent from the Sponsor.The consent forms which are to be completed by the participant at Bone Marrow Registration and/or Trial Registration and prior to each randomisation pathways are included in The collection of central samples for laboratory analysis is summarised in


The emergence of highly transmissible SARS-CoV-2 variants has created a need to reassess the risk posed by increasing social contacts as countries resume pre-pandemic activities, particularly in the context of resuming large-scale events over multiple days. To examine how social contacts formed in different activity settings influences interventions required to control Delta variant outbreaks, we collected high-resolution data on contacts among passengers and crew on cruise ships and combined the data with network transmission models. We found passengers had a median of 20 (IQR 10–36) unique close contacts per day, and over 60% of their contact episodes were made in dining or sports areas where mask wearing is typically limited. In simulated outbreaks, we found that vaccination coverage and rapid antigen tests had a larger effect than mask mandates alone, indicating the importance of combined interventions against Delta to reduce event risk in the vaccine era. Here, the authors simulate COVID-19 outbreaks on an empirical contact network derived from digital contact data collected on cruise ships. They model impacts of different control measures and find that combinations of measures, particularly vaccination and rapid antigen testing, are important for mitigating outbreaks. Settings with particularly high contact rates, such as meetings, conferences, exhibitions, and cruises, are also revenue-generating sectors with high pre-pandemic visitor throughput across the world5. However, the transmission dynamics on real world networks of large-scale events are yet to be fully explored in the COVID-19 era6. Furthermore, while pre-COVID-19 studies on human contact networks for understanding the transmission of infections spread by close contacts have analysed various network properties and attempted to reconstruct the social network from contact diaries or digital sensors, they are largely focused in school, healthcare settings or the greater community, with few studies on conferences and business meetings10. Understanding the risk of outbreaks in these settings and possible outbreak control interventions would enable event planners to gauge the sustainability of their operations and for policy makers to weigh the public health cost against the economic gains. Given breakthrough infections in vaccinated individuals and the spread of the highly transmissible SARS-CoV-2 variants13, countries have employed a range of tools alongside routine vaccination to suppress disease transmission, including vaccine certifications, rapid antigen tests, mask mandates, and digital contact tracing devices15. Although there have been efforts to estimate infection risk during large events from routine testing data and contact tracing interviews16, data from contact tracing devices can enable finer-scale assessment of interactions such as the distance and duration of contact depending on the strength and continuity of the Bluetooth signals captured in these devices. Furthermore, these devices overcome the challenges of recall bias and achieve more reliable estimates of the contacts in a network17.Many countries are resuming domestic activities as vaccination coverage and population immunity against SARS-CoV-2 increasesIn Singapore, ‘cruises to nowhere’  began as a safe travelling option during the COVID-19 pandemic with a range of activities and hence setting-specific interactions onboard. We collected contact data from around 1000 crew and 1300 passengers per sailing between November 2020 and February 2021 and analysed the resulting social interaction networks. We then use these contact networks to simulate SARS-CoV-2 Delta variant outbreaks and assess how different combinations of interventions and network formulations influence transmission in a range of settings during a large-scale event.3,963,256 contact episodes with 1,846,312 unique contact pairs were recorded during 37-h data collection periods across four separate three-day sailings (see Methods). During the period studied, cruise lines were operating at 50% capacity with a passenger to crew ratio of approximately 1:1 and passengers from different travelling groups were strongly advised to maintain a physical distance of at least one metre from other groups.The four sailings had a mean of 1304 passengers range 1142–1682) with a median age of 54 (IQR 35–63) and a mean of 1050 crew (range 1003–1083) spread across eight work departments Table . If the –1682 witThe total number of contacts made by passengers with passengers from other travelling groups varied according to the type of location and the time spent at that location. The total close contacts plateaued at approximately 3 (IQR 2–5) after spending at least 1 h in a food and beverage (F&B) location Fig.  while thOver the three-day sailings, a median of 71% (IQR 64–74%) of all the close contact episodes occurring between passengers from different travelling groups occurred in F&B locations of which 23% (IQR 19–26%) and 38% (IQR 31–40%) occurred in the buffet and inclusive restaurants respectively Fig. . 16% IQ. Passeng19.To examine the spread of SARS-CoV-2 on cruise ships and implications for other large-scale multi-day events, we used the contact data to generate an undirected network with nodes and edges representing individuals and the contact between them respectively. We defined the strength of an edge as a function of the proportion of days with recorded contact over a three-day sail period and the mean daily cumulative contact duration between two individuals to approximate a scenario where the edge weight reached 95% saturation after 3 h of contact (see Methods). This meant that the propensity for transmission increased and stabilised after 3 h of contact, to mimic contacts formed in family gatherings over extended periods of time21 to simulate SAR-CoV-2 Delta variant transmission over seven days  or smoking breaks; and would be wearing a mask correctly otherwise. Furthermore, contacts between passengers and crew were assumed to occur with mask-on at all times and crew-crew contacts were assumed to occur without a mask during meals times, workouts or smoking breaks. The proportion of contacts that occurred without a mask were modelled based on the proportion of contacts occurring in F&B and sport settings  would be infected by the end of the event Fig. . Of thesWith the introduction of a one-off PCR test one day prior to the start of the cruise, the index case was isolated in 49% of the time, while 5% of the remaining simulations resulted in no transmission due to the stochastic nature of early disease transmission and the structure of the social network Fig. . As a reWe also modelled passenger-passenger interactions occurring under a mask-off setting ~60% of the time   Fig. . The expls) Fig. .Table 4PSensitivity analysis under different assumptions of the edge weights—and hence per-contact risk—showed an increase in the expected outbreak size as the duration required to be defined as a ‘maximal contact’ (i.e. weight of one) decreases .We found that the structure and intensity of contacts over a multi-day cruise have major consequences for outbreak control in different settings, particularly if there are mask-free activities and leaky testing protocols mean infectious individuals are likely to go undetected. Cruises represent an aggregation of different activities including F&B, entertainment, sports, meeting, conference, entertainment and workplace settings. The presence of multi-group passengers and crew from different departments can therefore offers insights into the potential dynamics of different actors in other large-scale multi-day events  and resulting implications for control of SARS-CoV-2.31. While the number of contacts made with other passengers are potentially lowered due to physical distancing and awareness of the pandemic in the studied Singapore setting, the number and type of activities onboard the cruise still means that each passenger forms around 20 unique close contacts per day. Compared to an average of 59 unique close contacts with more than 15 min of interaction in a UK community setting over a 14-day period32, this was five times higher, further illustrating the intensity of contacts during such events. More than 70% of the close and casual contacts on the cruises occurred in F&B locations where passengers were largely mask-off and thus posing a higher risk of infection and transmission. We observed that the number of close contacts plateaued in F&B settings as the time spent in the location increases. As such, reducing this risk potentially requires more creative use of space to increase the distance between groups of passengers, improve indoor ventilation and encourage more outdoor dining.Our social network analysis showed that passengers had a high number of contacts and their contacts typically exhibit high levels of contact with other individuals. As such, any disease transmission would likely be driven by passenger-level interactions rather than crew. In early 2020, this was evident in the sharp rise in the number of COVID-19 passengers with symptom onset before or during the early stages of quarantine onboard the Diamond Princess33. Assuming a generation time of about 5–7 days, this corresponds to a spillover from passengers to the crew after three to four generations of transmission. With about 2.6 times more passengers than crew on the Diamond Princess cruise ship, this could delay the spillover of disease transmission. Crew and event personnel play an important role in ensuring smooth operations and their wellbeing should be accounted for in the plans when reopening events. Hence, besides encouraging crew cohorting, interventions that minimise transmission in passengers would have an indirect effect of protecting the crew.With numerous work functions interfacing with passengers, and given the overlapping shifts and closely related job scope between crew , we found it only took around two generations for the infection to spread from a passenger to a crew and an additional generation of transmission to reach another crew in a different department. For SARS-CoV-2 transmission on the Diamond Princess cruise ship, the earliest onset in crew occurred about 18 days after the onset of the index case34 which improves the sensitivity of rapid antigen tests. While PCR tests have a higher sensitivity than rapid antigen tests at low viral load levels, the tests need to be conducted on land prior to the event due to the turnaround time required and for validity of lab results. This implies that cases who develop symptoms several days after the sailing may not be identified prior to the event, due to viral loads near the limits of detection, and large outbreaks could occur.When applied individually, none of the interventions analysed were capable of reducing the expected outbreak size to be lower than one; the number of initial infected cases in passengers, equivalent to a community incidence of 1 per 1000 individuals. However, a combination of rapid antigen testing at the start and halfway through the sailing with at least 25% coverage of a vaccine that confers 50% protection against infection and 50% lowered infectiousness would result in the cruise event having fewer onward transmission than the number of initial infectives. This is conditioned on the cases exhibiting Delta variant-like high viral loads with prolonged shedding29. The risk reduction from these model estimates are about five times higher than that reported in a cluster-randomised trial. However, in this trial, proper mask wearing occurred in less than half in the intervention arm, thereby limiting the multiplicative effectiveness of mask wearing in reducing both infection and transmission30.The expected outbreak size under different combinations of interventions was sensitive to the assumptions of the network edge weights. When edges are weighted by the proportion of days with recorded interaction over a three-day sail period, two individuals with transient contact in a day are assumed to have the same risk as two individuals with close contact in a day. This assumption is applicable when the dominant mode of transmission is largely independent of the duration of contact . There were five times more transient interactions than close contacts and these contacts are now equally at risk of infection. Thus, mask wearing would largely help to lower the risk of transmission and acquiring infection, and outperforms PCR testing or even twice antigen testing interventions especially when the proportion of presymptomatic transmission is high during the early stage of viral shedding. Overall, these models estimate that mask wearing with passengers practising physical distancing could reduce transmission by about 54% under these settings, ~20–30% lower than the effectiveness of wearing a surgical mask in healthcare settings or in public areas after accounting for interactions in mask-off settings when dining or engaged in sports. This findings corroborates with behavioural surveys reporting 1.3–2 times higher risk of being infected when mask wearing in enclosed spaces is not practised2. In a fully susceptible cohort, these models estimate a mask-off, rapid antigen testing intervention at the start and midway of the event would reduce the mean outbreak size by over 90% with the additional reduction largely attributed to the administration of an additional test midway through the event.Both mask-off, rapid antigen testing and mask-on, once-off PCR testing would help to reduce the risk of disease introduction and further transmission if the index cases successfully escape initial detection. While their differences in the expected outbreak size were less than 10 cases across different assumptions to the edge weights, they bring different outcomes to the passenger experience and operations planning—an extra swab test at the middle of the event versus wearing a mask at all times other than during dining and engaged in sports, logistics to check the test outcomes versus monitoring mask wearing practises, managing false positives versus passengers flouting rules. Pre-event rapid antigen testing has been widely adopted in many large-scale events lasting less than a day and accounted for about 53% reduction in transmission in settings with high levels of social contacts and about 72% reduction after accounting for physical distancing35. Furthermore, even if the threshold for close contact to be traced is lowered, the corresponding exponential increase in contacts fulfilling this criteria would make it logistically challenging to trace all individuals in a reasonable amount of time. Fully asymptomatic infections—as opposed to presymptomatic infections—were also not considered in the analysis. Should these infections exhibit lowered viral load, the testing interventions would be less likely to detect asymptomatic individuals but any potential for increase in outbreak size would be counteracted by their lowered infectiousness. Currently, there is no strong evidence to suggest that asymptomatic SARS-CoV-2 Delta infections are less infectious than symptomatic individuals37. Lastly, the accuracy of the data collected is largely dependent on the usage behaviour and the functionality of the device. Passengers are required to carry the contact tracing devices at all times except when engaged in water sports, and this was enforced by crew and external officers. Hence, interactions at the water sports areas may not be well represented but this effect to our analysis is expected to be minor as the cruise line of study required passengers to book these facilities in advance to facilitate crowd control. In a cabin, each passenger’s device may not necessarily be placed in a 2 m proximity and the frequent close contact interactions in these settings would not be recorded accurately. However, given that individuals in the cabin would largely continue to interact with each other outside the cabin while carrying the device, this would help to record a large proportion of their close interaction. Furthermore, this limitation is reduced when the probability of infection saturates after a certain level of exposure as is in the case of SARS-CoV-238. Functional issues of the contact tracing device such as drainage of batteries and incomplete data uploading can affect the extent of missing data, but these issues can be minimised with proper training on device usage. In our main analysis, the chosen sailing had more than 97% coverage in both crew and passengers to minimise the impact of missing data on the inference of the outbreak dynamics. Outbreaks were also simulated in three other sailings as part of sensitivity analysis and similar trends in the outbreak trajectory were observed .Each cruise sailing lasts for three days—departing at 7 pm on the first day and arriving at 8am on the last day, and only contacts during this period were studied. Embarking and disembarking begins and ends at approximately 12 noon on both days and devices are stored together prior to issuance or after collection. As such, data prior to departure and after arrival were not used, as the recorded data may be an artefact of devices being stored together.All individuals onboard a cruise are issued a digital contact tracing device with a unique device identification number. These devices are calibrated based on signal strength to broadcast omnidirectional Bluetooth signals to other devices within a 2 m radius every 14.9 s followed by an omnidirectional scan of nearby signals lasting for 0.1 s. Each scan record captures the timestamp of the signal exchange and the identification number of the interacted device. After every five-minute interval, the records of 30 unique devices with the highest signal strength in each device are then stored. The stored records are then uploaded to a server on land. Further data processing is required to determine the duration of contact between two individuals. If there are two or more records with consecutive difference(s) of less than five minutes, the duration of the contact is the difference between the last and first timestamp in the series of records.For each cruise sailing, we collected a de-identified manifest with the device identification number and details of the device holder , we categorised the contacts between each dyad into one of four contact groups, 41. For each individual in each type of location, we estimated the number of different types of contacts  with passengers from different travelling groups over time spent in the location. Across the sailings, for each type of contact, we estimated the proportion of contacts occurring at a type of location over all types of location.We further classified a contact episode in a location into close, casual and transient types of contact if the cumulative duration of contact was at least 15 min, at least 5 min but less than 15 min, and less than 5 min respectively in a 2 m radius42) and individuals’ eigenvector centrality  of passengers and crew in respective departments in each sailing. We performed a Welch’s t-test to evaluate each network property for passengers against that for crew and p-values < 0.05 were considered statistically significant. While the mean and interquartile range (IQR) of each estimate fluctuate across sailings, the 95% range of the estimates exhibit substantial overlap , the distribution of the clustering coefficient , I(δ) is the probability of being infected on any of the 14 days prior to the event and is fixed at 1/14, θ is the incubation period distribution with For each simulation, we assume that the disease is introduced by one passenger who could be infected up to 14 days prior to the event, with equal probability on any of the days but the onset of the index case would only occur between the start (i.e. day 1) and the end (i.e. day 7) of the event. The distribution of the symptoms onset date, i to susceptible individual j occurs based on the following probability:Δd is the modelled time step of one day, and i and susceptible individual j on day d expressed as:d. We assumed a skew normal distribution with location parameter 46, for sensitivity analysis, we considered a scenario where about 50% of transmission occurred prior to symptom onset. With a skewed normally distributed infectiousness profile centred based on the day of the symptoms onset, this ensures that the majority of the infections occurred around the time of symptoms onset48.Currently, all crew are required to be tested weekly and are largely confined to the cruise except during periods of shore leave, thereby reducing the risk of disease introduction by crew. Each day, the model searches for susceptible individuals in contact with the infected cases who are not isolated and infection from infector 49. While an edge weight has a maximum value of 1, infection between two individuals over the entire duration of infectiousness of the infected individual is not guaranteed. As such, we multiplied the force of infection with a scaling factor, 22. The viral load trajectory was modelled in relation to the Delta variant, rising above the limits of test detection three days before symptoms onset with prolonged shedding post symptoms onset24.In the testing interventions, the sensitivity of the tests were assumed to vary with viral load. We assumed PCR is 100% sensitive for cycle threshold (Ct) values  below 35 and rapid antigen tests are 94.5% sensitive for Ct values below 25 and lowered sensitivities as the Ct values increasesg occurs while wearing a mask. βv and βm,v are the relative risk of infection based on the vaccination status of the infector and infectee (Table For the mask wearing intervention, the expected weight of the contact between individuals entclass1pt{minima50.For each intervention or combination of interventions, we ran 1000 simulations. We estimated the incidence by the day of infection, the number of cases in each generation, and the expected final outbreak size. All analyses were done in R version 4.0.4Further information on research design is available in the Supplementary InformationPeer Review FileReporting Summary