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).

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 < 3 x upper limit of normal (ULN) 5.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN 6.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. 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 aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN 5.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. 6.Creatinine clearance (CrCl) > = 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis) 7.Agree to follow the pregnancy prevention guidelines Additional inclusion criteria for starting isatuximab maintenance 1.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. 2.4 cycles of RCyBorD received 3.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 4.Received > = 100mg/m^2 high-dose melphalan and ASCT 5.Signed the Informed Consent Document for the R1 treatment pathway Additional inclusion criteria for R1 1.12 cycles of isatuximab maintenance received 2.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 1.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. 2.4 cycles of RCyBorD received 3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT 4.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 5.Received > = 100mg/m^2 high-dose melphalan and ASCT 6.Signed the Informed Consent Document for the R2 treatment pathway Additional inclusion criteria for R3 1.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 2.4 cycles of RCyBord received 3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT 4.Received > = 100mg/m^2 high-dose melphalan and ASCT 5.Signed the Informed Consent Document for the R3 treatment pathway

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 premedication with steroids or H2 blocker. Intolerance includes hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 9.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. 10.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 11.Active systemic infection 12.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. 13.Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. 14.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 1.Disease progression 2.MRD-positive at 100 days post-ASCT 3.Registration exclusion criteria Exclusion criteria for R1 1.Disease progression 2.MRD-positive at 100 days post-ASCT or after 12 cycles of isatuximab 3.Registration exclusion criteria Exclusion criteria for R2 and R3 1.Disease progression 2.Registration exclusion criteria in Section