Protocol V2, 19/02/2007: An updated Velcade Investigator Brochure (Edition 10) necessitated a change to the patient information sheet with regard to the severity of some adverse reactions to Velcade. More detailed information relating to reactions was incorporated into a revised protocol. The requirement for patients to have a bone marrow biopsy and trephine was added to the pre-study assessments. This was considered part of routine care for patients with clinical signs of disease progression, and for this reason was not included in the first version of the protocol. However, following consultation with some of the Principal Investigators, it was suggested that this should be added to the obligatory assessments. Any patient with bone marrow involvement at baseline was required to undergo further bone marrow aspiration following cycle 4, and at the end of their treatment.

Protocol V3, 19/02/2008; A revised Investigator Brochure (Edition 11) necessitated changes to the protocol to incorporate new data related to adverse reactions, overdose and drug stability. All incidences of IMP overdose to be reported as SAEs.

Protocol V4, 22/02/2010; Recruitment period extended to 30th April 2011 as accrual slower than anticipated. Also incorporated in this protocol are: Section 7.1.2 All patients randomised to this group must be prescribed acyclovir 400 mgs twice daily for the duration of the trial medication. This is to reduce the incidences of herpes zoster / simplex. Section 16 all investigator sites will receive one carton containing 10 vials of Bortezomib following the initiation meeting. Further supplies will be forwarded to the centre when a new patient is randomised into combination group at the centre. Pharmacy information: Johnson and Johnson have asked that their own protocol number for this study be added to the drug supply records and the drug container labels, therefore in addition to the EudraCT number the labels will also have Lym - 2015 added to them.

Protocol V5, 03/11/2010; Trial website (eCRFs) to close and be replaced by paper CRFs following DMC review. Protocol revised to change the methods of data capture and randomisation of new patients, and also the reporting of Serious Adverse Events and SUSARs.

Protocol V6, 26/07/2012; The Data Monitoring Committee considered the “interim” analysis (data of the first 46 participants), and a review of other trial results which were suggestive that the standard arm was significantly inferior to the research arm of the study. Consequently, the Data Monitoring Committee advised that it would be unethical to continue with the standard arm and that it should be closed to recruitment. The DMC also recommended the continuation of patient recruitment to the research arm in order to increase safety and efficacy data of CHOP + Bortezomib. A substantial amendment was therefore submitted in which the “standard” (CHOP alone) arm of the trial was to be closed, and any further patients entered would receive the research treatment (CHOP + Bortezomib). Johnson & Johnson had further developed Bortezomib with evidence to suggest that administration subcutaneously (SC) rather than intravenously (IV) offered identical efficacy, but conferred less neurotoxicity. Furthermore, there had been a widespread switch from IV to SC Bortezomib across NHS practice, where the drug had been licensed as a consequence. It was therefore planned that recruitment would continue with all patients receiving subcutaneous Bortezomib.

Protocol V7, 29/10/2012; New safety information received from J&J required the safety section of the protocol and the patient information leaflet to be updated. There had been 7 reported incidences of Progressive Multifocal Leukoencephalopathy (PML). Six of these had involved patients with Multiple Myeloma and one with Acute Myeloid Leukaemia; there had been no incidences reported in patients with MCL.