Status: Open
Specialty: Haematology
Date Opened: 21/02/2023
Planned Close Date: 30/09/2024
Sponsor: University of Leeds
Principal Investigator: Dr Oo
Study Title: RADAR (UK-MRA Myeloma XV)
Myeloma is a cancer of the bone marrow cells. Combining stem cell transplantation (SCT) with new drug treatments has shown to improve outcomes in myeloma patients. Some patients have been found to have genetic abnormalities in the myeloma cells and these ‘high-risk’ patients do not respond well to standard treatment. Some patients without these genetic abnormalities are also known to not respond as well to initial therapy. This study will investigate different treatment combinations for these two groups of patients. It will also investigate whether a third group of patients, who do respond well to initial treatment, can receive treatment for a shorter period of time without coming to harm. This study gives access to new treatments (the unlicensed drug isatuximab) and treatment combinations.
All participants will receive the same initial induction treatment and during this time will have genetic tests to determine whether they have ‘standard-risk’ or ‘high-risk’ disease. Following this chemotherapy treatment participants will receive ASCT (A stands for autologous, meaning that the participant's own stem cells are used).
After induction treatment participants will be allocated to a second stage treatment group based on their genetic risk, high-risk or standard-risk, and on how well the myeloma has responded to the initial treatment. Each treatment group will then receive different combinations of medication to investigate their benefit. Treatment will comprise of combinations of isatuximab, bortezomib, cyclophosphamide, lenalidomide and dexamethasone.
Newly diagnosed myeloma patients, above the age of 18 who are suitable for SCT will be eligible for the study. Patients will be required to have bone marrow, blood and urine tests throughout the trial. Participants will also be asked to complete questionnaires about their quality of life. The study will be conducted in multiple hospitals throughout the UK.
RADAR study is funded by Cancer Research UK, Celgene and Sanofi.
Inclusion criteria for registration
Previously untreated patients with multiple myeloma requiring therapy, defined as having myeloma defining events or with biomarkers of malignancy according to IMWG diagnostic criteria
Eligible for stem cell transplant
Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG > 2 is due to effects of myeloma eg spinal cord compression);
Total bilirubin < 3 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN
Adequate marrow function:
•neutrophils > = 1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 109/L is allowed),
•haemaglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted,
•platelets > = 75 × 10^9/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 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted.
Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis)
Able to swallow oral medication
Aged at least 18 years
Agree to follow the pregnancy prevention guidelines
Able to provide written informed consent
Inclusion criteria for starting isatuximab maintenance, R1, R2 and R3
4 cycles of RCyBorD received
Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG > 2 is due to effects of myeloma eg spinal cord compression);
Total bilirubin < 3 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN
Adequate marrow function:
•neutrophils > = 1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC > = 0.75 x 10^9/L is allowed),
•haemaglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted,
•platelets > = 75 × 10^9/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 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted.
Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis)
Agree to follow the pregnancy prevention guidelines
Additional inclusion criteria for starting isatuximab maintenance
Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q), as confirmed by the CTRU.
4 cycles of RCyBorD received
MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT
Received > = 100mg/m^2 high-dose melphalan and ASCT
Signed the Informed Consent Document for the R1 treatment pathway
Additional inclusion criteria for R1
12 cycles of isatuximab maintenance received
MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) after 12 cycles of isatuximab
Additional inclusion criteria for R2
Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q) as confirmed by CTRU.
4 cycles of RCyBorD received
At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT
MRD-positive (proportion of malignant cells in the bone marrow is > = 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT
Received > = 100mg/m^2 high-dose melphalan and ASCT
Signed the Informed Consent Document for the R2 treatment pathway
Additional inclusion criteria for R3
High-risk (participant is confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q)) as confirmed by CTRU
4 cycles of RCyBord received
At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT
Received > = 100mg/m^2 high-dose melphalan and ASCT
Signed the Informed Consent Document for the R3 treatment pathway
Exclusion criteria for registration (and for starting isatuximab maintenance, R1, R2 and R3)
Smouldering MM, monoclonal gammopathy of undetermined significance (MGUS), 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 (or at any time since registration for participants starting isatuximab maintenance, R1, R2 and R3), 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 ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
Cardiac disorder identified according to local practice (eg left ventricular ejection fraction, LVEF; results from formal measurements acceptable within 28 days prior to registration)
Significant neuropathy (Grade > = 3, or Grade 2 with pain)
Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) 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 (within 28 days prior to starting isatuximab maintenance, R1, R2 and R3
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 (or starting isatuximab maintenance, R1, R2 and R3). 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.
Exclusion criteria for starting isatuximab
Disease progression
MRD-positive at 100 days post-ASCT
Registration exclusion criteria
Exclusion criteria for R1
Disease progression
MRD-positive at 100 days post-ASCT or after 12 cycles of isatuximab
Registration exclusion criteria
Exclusion criteria for R2 and R3
Disease progression
Registration exclusion criteria in Section
Research Nurse: Hilary Thatcher
Administrators: research.randr@mbht.nhs.uk
Link to EDGE