Risk-Adapted therapy Directed According to Response comparing treatment escalation and de-escalation strategies in newly diagnosed patients with multiple myeloma (NDMM) suitable for stem cell transplant (TE)
Multiple myeloma
Current interventions, as of 05/09/2025: Induction treatment consists of Revlimid (R), cyclophosphamide (Cy), bortezomib (Bor) and dexamethasone (D) (RCyBorD) followed by ASCT. In v4.0 of the protocol isatuximab (Isa) was added to the induction treatment for high-risk patients only. Following induction treatment and ASCT participants will be allocated to further treatment based on the participant’s genetic risk according to FISH testing (or a diagnosis of plasma cell leukaemia, V6.0 of the protocol onwards) and response to the initial treatment, measured using an MRD test. Randomisation will be completed using a computer-generated minimisation programme that incorporates a random element to ensure treatment groups are well balanced for certain patient characteristics dependent on the randomisation. Participants will receive treatment until disease progression. R1 Participants who are standard-risk and MRD-negative following induction treatment and ASCT will be allocated to R1. Initially, participants will receive 12 cycles of isatuximab, each cycle lasting 28 days. Isatuximab will be administered via IV at a dose of 10mg/kg on days 1, 8, 15 and 22 of cycle 1, then days 1 and 15 from cycle 2 onwards. After receiving 12 cycles of isatuximab, R1 participants will be randomised to one of two treatment arms on a 1:1 basis to either: 1. Receive isatuximab maintenance until intolerance (Isa) 2. To discontinue isatuximab Isa maintenance Those randomised to receive isatuximab will receive 10 mg/kg by infusion into a vein on day 1 of each 28-day cycle. R2 Participants who are standard-risk and MRD-positive following induction treatment and ASCT will be allocated to R2. R2 participants will be randomised to one of four treatment arms on a 1:1:1:1 basis, receiving either: 1. Revlimid (R) maintenance 2. Revlimid, bortezomib (Bor) and dexamethasone (D) consolidation and revlimid maintenance (RBorD+R) 3. Lenalidomide and isatuximab (RIsa) maintenance 4. Bortezomib, lenalidom
Inclusion criteria for registration: 1. Previously untreated patients with multiple myeloma requiring therapy, defined as having myeloma defining events or with biomarkers of malignancy according to IMWG diagnostic criteria 2. Eligible for stem cell transplant 3. 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); 4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN (if ALT and AST are tested, both must meet this criteria) 6. Adequate marrow function: 6.1. 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) 6.2. Haemoglobin (Hb) > = 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted 6.3. 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. 7. Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis) 8. Able to swallow oral medication 9. Aged at least 18 years 10. Agree to follow the pregnancy prevention guidelines 11. Able to provide written informed consent Inclusion criteria for starting isatuximab maintenance, R1, R2 and R3: 1. 4 cycles of RCyBorD received 2. 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); 3. Total bilirubin < 3 x upper limit of normal (ULN) 4. Alanine aminotr
Exclusion criteria for registration (and for starting isatuximab maintenance, R1, R2 and R3): 1. Smouldering MM, monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma of bone, or extramedullary plasmacytoma (without evidence of MM) 2. 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. 3. 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 4. Cardiac disorder identified according to local practice (eg left ventricular ejection fraction, LVEF; results from formal measurements acceptable within 28 days prior to registration) 5. Significant neuropathy (Grade > = 3, or Grade 2 with pain) 6. 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 7. Pregnant, lactating or breastfeeding female participants (within 28 days prior to starting isatuximab maintenance, R1, R2 and R3 8. Known resistance, intolerance or hypersensitivity to any component of the planned therapies, except in the case of hypersensitivity which is amenable to premedicatio