Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma: A phase III trial to compare standard and frailty-adjusted induction therapy with ixazomib, lenalidomide and dexamethasone (IRD) and maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I).

Inclusion criteria for Randomisation 1 (R1): 1. Newly diagnosed as having multiple myeloma (MM) according to the updated International Myeloma Working Group (IMWG) diagnostic criteria 2014 (see Appendix 1 in protocol for criteria) requiring treatment. 2. Not eligible for stem cell transplant. 3. Aged at least 18 years. 4. Meet all of the following blood criteria within 14 days before R1: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 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. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L, or, in the case of heavy bone marrow infiltration (> = 50%) which in the opinion of the investigator is the cause of the thrombocytopenia and provided appropriate supportive measures and patient monitoring are in place, platelet count > = 30 x 10^9/L is permitted. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN. 5. Meet the pregnancy prevention requirements: Female participants who: a) Are not of childbearing potential (Appendix 8 in protocol), OR b) If they are of childbearing potential, agree to practice 2 effective methods of contraception (Appendix 8 in protocol), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR c) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following: a) Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Contraception for female and male participants must be in accordance with (and participants must consent to) the Celgene-approved Pregnancy Prevention Programme. If female and of childbearing potential (see Appendix 8 in protocol), they must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Pregnancy Prevention Programme. 6. Able to provide written informed consent. Inclusion criteria for Randomisation 2 (R2): 1. Randomised into the FiTNEss (Myeloma XIV) trial and received induction chemotherapy with ixazomib and lenalidomide continued for 12 cycles. 2. Achieved at least MR at the end of IRD induction according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol), with no evidence of progression prior to R2. 3. Meet all of the following blood criteria within 14 days before R2: Haematological: a) Absolute neutrophil count (ANC) > = 1 x 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. The use of growth factor support is permitted. b) Platelet count > = 50 x 10^9/L. Please note: Platelet transfusions are not allowed < = 3 days prior to randomisation in order to meet these values. c) Haemoglobin > = 80 g/L. The use of red blood cell transfusions is permitted. Biochemical: d) Total bilirubin < = 3 x upper limit of normal (ULN). e) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < = 3 x ULN.

Exclusion criteria for Randomisation 1 (R1): 1. Smouldering MM, 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 160 mg dexamethasone. 3. Known resistance, intolerance or sensitivity to any component of the planned therapies. 4. Prior or concurrent invasive malignancies except the following: ‐ Adequately treated basal cell or squamous cell skin cancer; ‐ Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention; ‐ Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention; ‐ Any cancer from which the subject has been disease-free for at least 3 years. 5. Pregnant, lactating or breastfeeding female participants. 6. Major surgery within 14 days before randomisation. This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty. 7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort. 8. Any concomitant drug therapy which, in the opinion of the investigator, may lead to an unacceptable interaction with any of the agents ixazomib, lenalidomide, dexamethasone, and that cannot be safely stopped prior to trial entry. Full details of interactions can be found in the SPCs. 9. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 10. > = Grade 2 peripheral neuropathy. 11. Known HIV positive 12. Participant has current or prior hepatitis B surface antigen positive or hepatitis C antibody positive. Participants must have screening conducted within 14 days before R1. 13. Active systemic infection. 14. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study. Exclusion criteria for Randomisation 2 (R2): 1. Received any anti-myeloma therapy other than their randomised trial treatment, with the exception of local radiotherapy to relieve bone pain (in the absence of disease progression), or bisphosphonate treatment. 2. SD or disease progression according to the IMWG Uniform Response Criteria for Multiple Myeloma (see Appendix 2 in protocol). 3. Known resistance, intolerance or sensitivity to ixazomib or lenalidomide that required cessation of either agent during induction. 4. Developed any malignancy since R1 except the following: ‐ Adequately treated basal cell or squamous cell skin cancer; ‐ Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention; ‐ Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention. 5. Pregnant, lactating or breastfeeding female participants. 6. Major surgery within 14 days before randomisation. This does not include vertebroplasty or kyphoplasty. 7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort. 8. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing. 9. > = Grade 2 peripheral neuropathy, or grade 1 with pain. 10. Known HIV positive 11. Current or known hepatitis B surface antigen positive or hepatitis C antibody positive. 12. Active systemic infection. 13. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s continued participation in this study.