Amendment 1 Protocol Update of the current approved protocol regarding incorrect dexamethasone dosages. Instruction texts added and/or adjusted. ABR form Changes in local investigators and/or independent physicians.

Amendment 2 The reason for this amendment is: Daratumumab labels: Adjustment of Daratumumab text labels from 100 mg/5 ml injection vial to 400 mg/20 ml injection vial. Patient information: Examples of patient information available at www.kanker.nl. Test subjects There are no consequences of this amendment for the test subjects. The number of test subjects has not changed. Summary of changes: Daratumumab text label data has been adjusted. Patient information available at www.kanker.nl has been updated.

Amendment 4 Adjustment of ICF and Pre-ICF The number of evaluations during treatment now matches the protocol. Text paragraph “Additional imaging research” has been adjusted. The amount of extra blood for scientific research has been adjusted (now matches the protocol). Paragraph on patient data access has been adjusted. Treatment schedule has been adjusted (now matches the protocol). Risk language for Daratumumab and Ixazomib possible side effects has been adjusted. Changes in local investigator and/or independent physician Haga Hospital: independent physician [Name] replaces [Name]. Tergooi Hospital Hilversum: local investigator [Name] replaces [Name].

Amendment 3 Reason for the amendment The reason for this amendment is a change in participating hospitals: Red Cross Hospital in Beverwijk; Local investigator [Name] replaces Capelle aan de IJssel; Local investigator [Name] Test subjects There are no consequences of this amendment for the test subjects. The number of test subjects has not changed compared to the original number. Summary of changes A hospital has been added: Red Cross Hospital in Beverwijk; Local investigator [Name] and independent physician [Name] A hospital has been removed: IJsselland Hospital in Capelle aan de IJssel; Local investigator [Name] and independent physician [Name] The amendment also includes changes in the ABR form: Section C9: Red Cross Hospital added

Amendment 5 Reason for the amendment The reason for this amendment is a change in participating hospitals: Deventer Hospital in Deventer; Local investigator [Name] replaces UMCG in Groningen; Local investigator [Name] Test subjects There are no consequences of this amendment for the test subjects. The number of test subjects has not changed compared to the original number. Summary of changes A hospital has been added: Deventer Hospital in Deventer; Local investigator [Name] and independent physician [Name] A hospital has been removed: UMCG in Groningen; Local investigator [Name] and independent physician [Name] The amendment also includes changes in the ABR form: Section C9: Deventer Hospital replaces UMCG

Amendment 6 Protocol Summary of changes: Inclusion criteria “Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/l and platelet count ≥ 75x10⁹/l” adjusted. Time points for certain lab samples in PET-CT have been changed to (s)CR instead of “VGPR or better”. Table 10.2 and legend adjusted. Text in protocol clarified in several places. ABR / EudraCT Summary of changes: Riverland Hospital: independent physician [Name] replaces [Name]. Treat Zorggroep: independent physician [Name] replaces [Name]. Streekziekenhuis Koningin Beatrix: independent physician [Name] replaces [Name]. Groene Hart Hospital: local investigator [Name] replaces [Name]. Inclusion criteria “Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/l and platelet count ≥ 75x10⁹/l” adjusted. Time points for certain lab samples in PET-CT have been changed to (s)CR instead of “VGPR or better”.

Amendment 7 Summary of changes Treant Zorggroep: Local investigator [Name] replaces [Name].

Amendment 8 Summary of changes Deventer Hospital: Local investigator [Name] replaces [Name].

Amendment 9 Reason for the amendment Submission of Daratumumab Investigator’s Brochure version 15 and Addendum 1 ICF addendum: possible side effects of daratumumab; storage conditions for ixazomib Changes in protocol: Update of exclusion criteria Mandatory HBV test during screening and follow-up Instruction on HBV reactivation policy Storage conditions for ixazomib Additional clarification in some protocol sections Changes in sponsor contact details Changes in ixazomib and daratumumab labels Summary of changes New version of Daratumumab Investigator’s Brochure and addendum: IB Daratumumab Ed 15 dated 14 Dec 2018 and Addendum 1 dated 24 Jan 2019 Changes / ICF addendum Ixazomib storage temperature between 2–30°C Update Appendix 5 possible side effects of daratumumab: Very common side effects: high blood pressure Common side effects: herpes zoster and ingrown toenail Uncommon side effects: HBV reactivation in patients with prior hepatitis B infection; interference with pre-transfusion blood tests Changes in protocol Exclusion criteria (section 8.1.2): Patients seropositive for hepatitis B Patients seropositive for hepatitis C (except in cases of persistent virological response) HBV test during screening and follow-up (section 10.2) Screening: HBV test mandatory for all patients Follow-up: HBV test mandatory for patients with active or serological evidence of past HBV infection Instruction HBV reactivation policy (Appendix J5) Antiviral therapy must be started for patients with active HBV infection Storage conditions and label for ixazomib Ixazomib capsules must be stored at room temperature, between 2–30°C Changes in sponsor contact details [Name] is the current contact person for the HOVON Foundation The HOVON Data Center has moved; address updated accordingly Changes in ixazomib and daratumumab labels Ixazomib labels: storage temperature updated to 2–30°C

Amendment 10 Reason for the amendment Submission of Daratumumab IB Ed15 Addendum 02 dated 01 May 2019 Submission of ICF Addendum version 02 dated 23 July 2019 Summary of changes Changes / ICF Addendum Entire Appendix 5 (possible side effects of daratumumab) added to the Addendum. Appendix 5 rewritten for better clarity and readability for patients. Newly observed side effects added: Very common side effects: bronchitis, constipation, back pain Common side effects: dizziness, high blood glucose levels, low calcium levels in blood, fluid loss (dehydration), chills

Amendment 11 Reason for the amendment Addition of TMA as a newly identified ixazomib safety risk via ICF Addendum version 03 Submission of new IB ixazomib Ed 12 dated 19 June 2019 Submission of correction to IB Ed 12 SCO Table dated 25 June 2019 Test subjects The consequences of this amendment for the test subjects are as follows: Patients still being treated with ixazomib must be informed about the newly identified safety risk TMA and re-sign for voluntary participation in the study. Summary of changes TMA added as a newly identified safety risk to Appendix 5 of HO143 ICF (ixazomib citrate side effects).

Amendment 12 Reason for the amendment Addendum ICF version 04 Adjustment of possible side effects of daratumumab via ICF Addendum Submission of new IB Daratumumab Ed16 dated 20 December 2019 Test subjects The consequences of this amendment for the test subjects are as follows: Patients still being treated with daratumumab must be informed about the newly identified possible side effects and re-sign for voluntary participation in the study. With this submission, I declare that all relevant documents from the aforementioned research file have been signed by the authorized persons. The signed documents are/will be submitted for review to the ethics committee as stated in question 11 of the ABR form.

Amendment 13 Reason for the amendment Addendum ICF version 05 and protocol version 5.1 Submission of protocol v5.1 dated 16 July 2020 Submission of Addendum ICF v05 Submission of updated labels for Daratumumab Subcutaneous Submission of Cross Reference Letter for IMPD Daratumumab SQ dated Dec 2019 Submission of patient questionnaire survey Dara SC versus Dara IV Test subjects The consequences of this amendment for the test subjects are as follows: Patients currently treated with Daratumumab can switch from intravenous administration to subcutaneous injection. Additionally: Daratumumab will now be administered as a standard injection instead of infusion. These changes significantly reduce the time patients spend in the hospital for study treatment. All patients must re-sign the addendum for voluntary participation in the study. Patients switching from intravenous to subcutaneous Daratumumab must complete three time points and an additional questionnaire (patient preference survey).

Amendment 14 Reason for the amendment IB Daratumumab JNJ-54767414 Ed17 dated 17 Dec 2020 IB Ixazomib Ed13 dated 27 May 2020 ICF Addendum version 06

Amendment 15 Summary of changes Streekziekenhuis Koningin Beatrix Winterswijk: Local investigator [Name] replaces [Name]. Treant Zorggroep: Local investigator [Name] replaces [Name].

Amendment 16 Summary of changes Elisabeth-TweeSteden Hospital: Local investigator [Name] replaces [Name].

Amendment 17 Summary of changes Maasstad Hospital: Local investigator [Name] replaces [Name].

Amendment 18 Summary and motivation for the changes Treant Zorggroep: Local investigator [Name] replaces [Name]. The EudraCT application form (Annex I) has been updated. This amendment also includes changes in the ABR form.