Version number 4 Version date 04 26FEB2015 Summary of changes compared to previous version 3 - Patient exclusion criterion changed: Significant hepatic dysfunction (total bilirubin ≥ 1.5 x ULN or transaminases ≥ 3 times normal level) except patient’s with Gilbert’s syndrome as defined by > 80% unconjugated bilirubin - Changed timing patient’s physical evaluation during maintenance: physical evaluation during maintenance is now every 2 months (previous protocol version every month) - Dose modification instructions for Grade 2 Bullous Rash and Grade 3 Stevens –Johnson Syndrome added - Additional information FDG-PET-CT sub study.

Version number 5 Version date 17FEB2016 Summary of changes compared to previous version 4 - Ixazomib is shipped refrigerated to the sites - Patient exclusion criterion added: Patient gives consent for extra bone marrow and blood sampling - Induction therapy should start within 4 weeks after patient registration; - PB cryopreservation: Should be performed at entry and at progressive disease only; - Randomization for the maintenance therapy should be done after the response evaluation of the last given induction cycle. In randomized patients maintenance therapy should start within 12 weeks after start last induction therapy (The process of randomization should only be started after the response evaluation of the last ixazomib citrate -thalidomide-low dose dexamethasone cycle is known. For this reason it is not possible, to start maintenance within 4 weeks after start of the last ixazomib induction cycle) - Herpes Zoster prophylaxis: All patients will receive valacyclovir during the induction and maintenance therapy until one month after administration of the last administration of Ixazomib citrate - Updated criteria for symptomatic MM