supplementary appendixde la fuente, yolanda gonzález montes, jesus martin sanchez, maria victoria...

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Dimopoulos M A, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2018; published online Dec 10. http://dx.doi.org/10.1016/S0140-6736(18)33003-4.

TOURMALINE-MM3 supplementary appendix 1

SUPPLEMENTARY APPENDIX

Oral ixazomib maintenance following autologous stem cell transplantation: a double-

blind, randomised, placebo-controlled phase 3 trial

Professor Meletios A Dimopoulos, MD, Francesca Gay, MD, Fredrik Schjesvold, MD, Professor Meral Beksac,

MD, Professor Roman Hajek, MD, Katja Christina Weisel, MD, Professor Hartmut Goldschmidt, MD,

Professor Vladimir Maisnar, MD, Professor Philippe Moreau, MD, Chang Ki Min, MD, Agnieszka Pluta, MD,

Professor Wee-Joo Chng, MB ChB, Martin Kaiser, MD, Professor Sonja Zweegman, MD, Professor Maria-

Victoria Mateos, MD, Professor Andrew Spencer, MBBS, Shinsuke Iida, MD, Gareth Morgan, MD, Kaveri

Suryanarayan, MD, Zhaoyang Teng, PhD, Tomas Skacel, MD, Antonio Palumbo, MD, Ajeeta B Dash, PhD,

Neeraj Gupta, PhD, Richard Labotka, MD, Professor S. Vincent Rajkumar, MD, on behalf of the

TOURMALINE-MM3 study group*

This appendix has been provided by the authors to give readers additional information about their work.


Supplementary Material

Part I – TOURMALINE-MM3 investigators 3

Part II – Additional methodology

Prespecified secondary endpoints 5

Criteria for dose escalation at cycle 5 6

Local laboratory evaluation of cytogenetics/high-risk criteria 6

Central laboratory evaluation for minimal residual disease 7

Population pharmacokinetic analysis 7

Patient-reported quality of life assessments 8

Definition of analysis populations 8

Part III – Supplementary Figures

Supplementary Figure S1: Study overview 10

Supplementary Figure S2: CONSORT diagram 12

Supplementary Figure S3: Kaplan-Meier progression-free survival curves for patients who were

negative or positive for minimal residual disease at study entry in the ixazomib and placebo groups

15

Supplementary Figure S4: Patient-reported quality of life 16

Supplementary Figure S5: Ixazomib plasma concentration time-profiles in the TOURMALINE-MM3

study and the TOURMALINE-MM1 study

17

Part IV – Supplementary Tables

Supplementary Table S1: Detailed eligibility criteria 18

Supplementary Table S2: Additional adverse events (high-level terms) in the safety population 20


Part I – TOURMALINE-MM3 investigators

Patients were recruited from 227 centers across 30 countries in 6 continents. The following investigators (listed

by country) enroled patients into the study:

Argentina: Daniel Bar, Alfredo Basso, Dorotea Fantl; Australia: Simon He, Noemi Horvath, Cindy Lee,

Phillip Rowlings, Kerry Taylor, Andrew Spencer, Tara Cochrane, Fiona Kwok, Sundreswran Ramanathan;

Austria: Hermine Agis, Niklas Zojer; Belgium: Alain Kentos, Fritz Offner, Jan Van Droogenbroeck,

Ka Lung Wu; Brazil: Angelo Maiolino, Gracia Martinez, Karla Zanella, Marcelo Capra, Sérgio Araújo;

Czech Republic: Evzen Gregora, Roman Hajek, Vladimir Maisnar, Ludek Pour, Vlastimil Scudla, Ivan Spicka;

Denmark: Niels Abildgaard, Niels Andersen, Bo Amdi Jensen, Carsten Helleberg, Torben Plesner,

Morten Salomo, Asta Svirskaite; France: Richard Delarue, Philippe Moreau; Germany: Igor Blau,

Hartmut Goldschmidt, Aneta Schieferdecker, Veronica Teleanu, Markus Munder, Christoph Röllig,

Hans-Juergen Salwender, Stephan Fuhrmann, Katja Weisel, Jan Duerig, Matthias Zeis, Stefan Klein,

Peter Reimer, Christian Schmidt, Christof Scheid, Karin Mayer, Martin Hoffmann, Markus Sosada;

Greece: Athanasios Dimopoulos, Sosana Delimpasi, Mary-Christine Kyrtsonis, Achilleas Anagnostopoulos;

Hungary: Zsolt Nagy, Árpád Illés, Miklós Egyed, Zita Borbényi, Gabor Mikala; Israel: Najib Dally,

Netanel Horowitz, Odit Gutwein, Anatoly Nemets, Iuliana Vaxman, Olga Shvetz, Svetlana Trestman,

Rosa Ruchlemer, Arnon Nagler, Tamar Tadmor, Ory Rouvio, Meir Preis; Italy: Francesca Gay, Michele Cavo,

Luca De Rosa, Pellegrino Musto, Anna Cafro, Patrizia Tosi, Massimo Offidani, Alessandro Corso,

Giuseppe Rossi, Anna Marina Liberati, Alberto Bosi; Japan: Kenshi Suzuki, Shinsuke Iida, Chiaki Nakaseko,

Takayuki Ishikawa, Morio Matsumoto, Hirokazu Nagai, Kazutaka Sunami, Takaaki Chou, Koichi Akashi,

Naoki Takezako, Shotaro Hagiwara; Republic of Korea: Hyeon Seok Eom, Deog-Yeon Jo, Jin Seok Kim,

Jae Hoon Lee, Chang Ki Min, Sung Soo Yoon, Dok Hyun Yoon, Kihyun Kim; Netherlands: Sonja Zweegman,

Mark-David Levin, Edo Vellenga, Monique Minnema; Norway: Fredrik Schjesvold, Anders Waage,

Einar Haukås; Poland: Sebastian Grosicki, Andrzej Pluta, Tadeusz Robak; Portugal: Herlander Marques,

Rui Bergantim, Fernando Campilho; Singapore: Wee Joo Chng, Yeow Tee Goh;

South Africa: Andrew McDonald, Bernado Rapoport; Spain: Miguel Angel Álvarez Rivas, Felipe De Arriba

de La Fuente, Yolanda González Montes, Jesus Martin Sanchez, Maria Victoria Mateos, Albert Oriol

Rocafiguera, Laura Rosinol, Jesús San Miguel, Jaime Pérez de Oteyza, Cristina Encinas, Adrian Alegre-Amor,

Ana López-Guía; Sweden: Per Axelsson, Kristina Carlson, Olga Stromberg, Markus Hansson,

Cecilie Hveding Blimark; Switzerland: Rouven Mueller; Taiwan: Chih-Cheng Chen, Ta-Chih Liu,


Shang-Yi Huang, Po-Nan Wang; Thailand: Thanyaphong Na Nakorn, Kannadit Prayongratana;

Turkey: Meral Beksac, Ali Unal, Hakan Goker, Mehmet Sonmez; Ukraine: Sybiryna Korenkova;

United Kingdom: Aristeidis Chaidos, Heather Oakervee, Hamdi Sati, Reuben Benjamin, Ashutosh

Wechalekar, Mamta Garg, Martin Kaiser, Karthik Ramasamy, Gordon Cook, Andrew Chantry, Matthew Jenner;

United States of America: Francis Buadi, Robert Berryman, Murali Janakiram.


Part II – Additional Methodology

Prespecified secondary endpoints

The key secondary objective was:

• To determine the effect of ixazomib maintenance therapy on overall survival (OS) compared with

placebo.

The other secondary objectives were:

• To determine the effect of ixazomib maintenance therapy on improving best response for patients who

enrol in the study at partial response (PR) or very good partial response (VGPR), as well as

maintaining best overall response for patients who enrol in the study at complete response (CR).

• To determine the effect of ixazomib maintenance therapy on time to progression.

• To determine the effect of ixazomib maintenance therapy on progression-free survival 2 (PFS2),

defined as time from the date of randomisation to the date of objective disease progression on next-line

treatment or death from any cause, whichever occurs first.

• To determine the effect of ixazomib maintenance therapy on time to start of the next line of treatment,

defined as the time from the date of randomization to the date of the first dose of the next line of

antineoplastic therapy for any reason.

• To determine the effect of ixazomib maintenance therapy on time to end of the next line of treatment,

defined as the time from the date of randomisation to the date of the last dose of the next line of

antineoplastic therapy for any reason.

• To determine the effect of ixazomib maintenance therapy on duration of the next line of antineoplastic

therapy.

• To assess the incidence of new primary malignancies in patients receiving ixazomib maintenance

therapy compared with placebo following autologous stem cell transplantation (ASCT).

• To evaluate the frequency of conversion from minimal residual disease (MRD)-positive to MRD-

negative, or the maintenance of MRD negativity, after 1 and 2 years of therapy in patients treated with

ixazomib compared with placebo, using bone marrow aspirates and 8-colour flow cytometry or next-

generation sequencing.

• To assess the correlation between MRD status (assessed by 8-colour flow cytometry and next-

generation sequencing) and PFS and OS, using bone marrow aspirates.


• To determine the effects of ixazomib maintenance therapy on PFS and OS in high-risk cytogenetic

patient groups characterised by individual or multiple cytogenetic abnormalities such as chromosome

17p deletion [del(17p)], translocation between chromosomes 4 and 14 [t(4;14)], and translocation

between chromosomes 14 and 16 [t(14;16)]).

• To determine the long-term safety and tolerability of ixazomib administration to multiple myeloma

(MM) patients following ASCT.

• To assess overall health-related quality of life, as measured by the global health domain of the

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.

• To collect pharmacokinetic data to contribute to population pharmacokinetic and exposure-response

(safety/efficacy) analyses.

• To evaluate the resolution and improvement of peripheral neuropathy, if it occurred, by grading at each

subsequent monthly visit until 1) resolution of peripheral neuropathy, 2) the start of an alternative

antineoplastic treatment, or 3) 6 months after progression had occurred, whichever occurred first.

Criteria for dose escalation at cycle 5

To provide patients the opportunity to derive maximum clinical benefit from study drug maintenance therapy,

the dose of 3 mg was increased to 4 mg at cycle 5 provided that, during the previous 2 cycles (cycle 3 and 4),

there were no grade ≥2 nonhaematologic adverse events related to study drug, no dose interruptions related to

study drug toxicities, and no delays of greater than 1 week in starting a cycle due to study drug toxicities.

Patients who had a dose reductions were unable to dose escalate. If dose escalation was inadvertently missed at

cycle 5, escalation was performed with permission from the Millennium project clinician or designee.

Local laboratory evaluation of cytogenetics/high-risk criteria

Cytogenetic evaluation was performed before ASCT using fluorescence in situ hybridisation and/or

conventional cytogenetics (karyotyping). Cytogenetic assessment was performed using fluorescence in situ

hybridisation in 72% of patients (ixazomib: 281 patients; placebo: 188 patients), conventional karyotyping for

3% of patients (ixazomib: 10 patients; placebo: 9 patients), and 25% of patients (ixazomib: 104 patients;

placebo: 63 patients) were assessed by both fluorescence in situ hybridisation and conventional karyotyping.

This included testing for the presence or absence of at least 2 of the following 3 high-risk abnormalities:

del(17p), t(4;14), and t(14;16). All cytogenetic evaluations were performed locally by the site according to local


standards and were reviewed centrally by a board-certified haematopathologist. In selected regions where

cytogenetic evaluation at the time of disease diagnosis was not routinely conducted, pre-screening cytogenetic

evaluation was performed where possible. Cytogenetic characteristics were documented by the site at the time

of disease diagnosis and were not reassessed during the course of the study.

Central laboratory evaluation for minimal residual disease

Bone marrow aspirate samples were collected for MRD assessment for patients achieving CR and VGPR at

screening. In addition, bone marrow aspirates for MRD were also collected: when a patient was suspected of

having a CR and a bone marrow aspirate was performed for confirmation; in patients with VGPR or CR at cycle

13 and at end of treatment (approximately 24 months, if no treatment delays [equivalent to 26 cycles, to the

nearest complete cycle]) unless already collected within the previous 2 cycles. Bone marrow aspirates were also

obtained in patients achieving CR or VGPR who had stopped therapy before cycle 26.

Bone marrow aspirate samples for MRD analyses were collected in K2-EDTA tubes and centrally

analysed in a specialty laboratory within 72 h. A single-tube flow cytometry assay with a panel of antibodies

against CD38, CD81, CD45, CD138, CD19, CD27, CD56, and CD117 was used, and analysis was done on a

LCT RUO BD FACSCanto IITM flow cytometer. Phenotypically aberrant plasma cells were identified based on

the differential expression of these markers.1 Resulting files were centrally reviewed by a flow cytometry expert

to determine MRD status. MRD-negativity was defined as being when <20 clonal plasma cells were detected

among ≥2x106 leukocytes (<0·001%). The sensitivity of the assay was 10-5.

Minimal residual disease limit of detection was ≥10-5 in 162 (19%) and 103 (19%) of assessments in

patients in the ixazomib (870 assessments) and placebo (551 assessments) groups, ≥10-6 but <10-5 in 705 (81%)

and 447 (81%), and <10-6 in 3 (<1) and 1 (<1).

Population pharmacokinetic analysis

Blood samples for ixazomib were collected for population pharmacokinetic analysis during day 1 cycle 1, 1 h

and 4 h post-dose and within 4 h pre-dose on days 8 and 15 of cycle 1, days 1 and 8 of cycle 2, and day 1 of

cycle 3–10. Plasma samples of ixazomib were measured using a validated liquid chromatography/tandem mass

spectrometry assay.


Patient-reported quality of life assessments

Health-related quality of life was evaluated through patient self-reported instruments including the European

Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and MY-20 instruments;

healthcare resource utilisation and utility were recorded using the EQ-5D instrument and by collecting data on

all medical encounters and number of days missed from work or other activities. The health-related quality-of-

life assessments were completed by the patient at screening, at the start of every cycle (C30) or at the start of

cycles 1, 4, 7,10,13, 16, 19, 22, and 25 (MY-20), at end of treatment, and then every 4 weeks until disease

progression, and every 12 weeks following disease progression. The European Organisation for Research and

Treatment of Cancer Quality of Life Questionnaire-C30 incorporates five functional scales (physical

functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), one global

health status scale, three symptom scales (fatigue, nausea and vomiting, and pain), and six single items

(dyspnea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). The European Organisation

for Research and Treatment of Cancer Quality of Life Questionnaire-MY20 MM module has four independent

subscales, two functional subscales (body image, future perspective) and two symptoms scales (disease

symptoms and side-effects of treatment). High scores for the both global and functional domains indicate higher

quality of life or functioning, while high scores on the symptom scales represent higher levels of

symptomatology or problems. The MY20 instrument was administered subsequent to the European

Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30.

The time recall period for completion of these questionnaires was 1 week immediately preceding the

assessment. The questionnaires took approximately 15 min to administer and consisted of a total of 50 items.

These questionnaires have been validated and used in many countries. These health-related quality-of-life

assessments were completed before other assessments were performed or study drug was taken. During the

PFS2 follow-up period only, assessments were completed twice, once approximately 8 to 12 weeks following

the start of next-line therapy and then 8 to 12 weeks later.

Definition of analysis populations

The populations used for analysis included the following:

Safety population: The safety population was defined as all patients who received at least 1 dose of ixazomib

or placebo. Patients were analysed according to the treatment they actually received. One patient in the placebo


group erroneously received 3 doses of ixazomib during cycle 8 and was therefore analysed as part of the

ixazomib safety population.

Intent-to-treat population: The intent-to-treat population was defined as all patients who were randomised,

and for whom post-randomisation data were available. Patients were analysed according to the treatment they

were randomised to receive, regardless of any dosing errors.

Per-protocol population: The per-protocol population is a subset of the intent-to-treat population. The per-

protocol population consists of all patients who did not violate the terms of the protocol in a way that would

impact the study outcome significantly, as determined by the study clinician, who was blinded to study drug

assignment. All decisions to exclude patients from the per-protocol population were made before the unblinding

of the study.


Part III – Supplementary Figures

Figure S1: Study overview

ASCT=autologous stem cell transplant. IMiD=immunomodulatory drug. OS=overall survival. PD=progressive

disease. PD2=progressive disease on next-line of treatment. PFS=progression-free survival. PFS2=time from the


date of randomisation to the date of objective disease progression on next-line treatment or death from any

cause, whichever occurs first. PI=proteasome inhibitor. SOC=standard of care. VAD=vincristine, Adriamycin

(doxorubicin), and dexamethasone.

*After the first 4 cycles of treatment, eligible patients had their dose of ixazomib (or matching placebo)

escalated from 3 mg to 4 mg. The first interim analysis, which was also the primary and only analysis of PFS,

was planned when approximately 50·3% of patients experienced a PFS event (328 events) or 25 months after

the last patient was enroled, whichever occurred later. Patients were assessed during the PFS follow-up period

by the treating physician/investigator and by the independent review committee.

**If a physician chose to start next-line therapy before progressive disease, the patient skipped the progressive

disease follow-up period and entered directly into the PFS2 follow-up period.

†After the first occurrence of progressive disease, the date and characteristics of progressive disease 2, PFS2,

and disease status, were assessed by the treating physician/investigator only. All disease response and

progressive disease assessments were performed according to the International Myeloma Working Group

(IMWG) uniform response criteria, version 2011.2

‡The second interim analysis will be conducted for OS when approximately 200 death events have occurred.

This second interim analysis will determine the number of OS events required for the final analysis.


Figure S2: CONSORT diagram

*The reasons for 197 patients being ineligible were as follows:

• Absence of documented results for cytogenetics/FISH from any time before transplant or for ISS

staging at the time of diagnosis (n=40)

• Did not undergo screening and/or randomisation within specified time frame (n=30)


• No confirmed diagnosis of symptomatic multiple myeloma or too young (n=25)

• No documented response to ASCT (n=23)

• Did not receive standard-of-care induction therapy (n=22)

• Did not meet the clinical laboratory inclusion criteria (n=21)

• No voluntary written informed consent (n=7)

• Diagnosed or treated for another malignancy within 5 years before randomisation or previously

diagnosed with another malignancy with evidence of residual disease (n=6)

• Infection requiring IV antibiotic therapy or other serious infection within 14 days before randomisation

(n=6)

• Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the

investigator, made the patient inappropriate for entry into the study (n=5)

• Multiple myeloma that had relapsed following primary therapy or was not responsive to primary

therapy (n=5)

• Lack of suitable venous access for the study-required blood sampling (n=3)

• Received double (tandem) ASCT (n=2)

• ECOG performance status >2 (n=1)

• Evidence of a current uncontrolled cardiovascular condition (n=1)

†The ‘Other’ reasons for discontinuing treatment were as follows:

• In the ixazomib group (n=20):

o Patient withdrew from treatment, continued with follow-up (n=11)

o PD not meeting IMWG criteria (n=7)

o Relapse from CR (n=1)

o Suspected PD, confirmed after EOT (n=1)

• In the placebo group (n=19):

o Patient withdrew from treatment, continued with follow-up (n=10)

o PD not meeting IMWG criteria (n=8)

o Investigator decision (n=1)

‡The ‘Other’ reasons for discontinuing the study were as follows:

• In the ixazomib group (n=2):

o Patient returned to original hospital for further care (n=1)


o Patient not suitable for study treatment straight after randomization (n=1)

• In the placebo group (n=1):

o Investigator/patient decision due to adenocarcinoma treatment

§All intention-to-treat subjects who did not violate the terms of the protocol in a way that would impact the

study outcome significantly as determined by the medical monitor, prior to study unblinding


Figure S3: Kaplan-Meier progression-free survival curves for patients who were negative or positive for minimal residual disease at study entry in the ixazomib

and placebo groups

MRD=minimal residual disease.


Figure S4: Patient-reported quality of life

C=cycle. D=day. EOT=end of treatment. EOT_C=end of treatment for patients who completed the maximum number of cycles per protocol. EOT_INC=end of treatment for

patients who did not complete maximum number of cycles per protocol. SE=study entry.


Figure S5: Ixazomib Plasma Concentration Time-Profiles in the TOURMALINE-MM3 Study and the

TOURMALINE-MM1 Study.

Solid and dashed lines respectively represent median and 5th and 95th percentiles of individual model-predicted

concentrations.


Part IV – Supplementary Tables

Table S1: Detailed eligibility criteria

Inclusion criteria Exclusion criteria

• Male or female patients aged ≥18 years with a confirmed diagnosis of

symptomatic MM

• Patients with documented results available for cytogenetics/fluorescence in situ

hybridisation obtained at any time before transplant and for International Staging

System stage at the time of diagnosis

• Patients who received standard of care induction therapy (induction therapy must

have included proteasome inhibitor- and/or immunomodulatory drug-based

regimens as primary therapy for MM), followed by a single ASCT with a high-

dose melphalan (200 mg/m2) conditioning regimen, within 12 months of

diagnosis. The triplet regimen vincristine-doxorubicin-dexamethasone was not an

acceptable induction therapy for this trial

• Started screening no earlier than 75 days after transplant, completed screening

within 15 days, and was randomised no later than 115 days after transplant

• The patient must not have received post-ASCT consolidation therapy

• Documented response to ASCT (partial response [PR], very good partial response

[VGPR], complete response [CR]/stringent complete response [sCR]) according

to International Myeloma Working Group (IMWG) criteria2

• Eastern Cooperative Oncology Group performance status of 0 to 2

• Female patients who:

o If they were of childbearing potential, agreed to practice two effective

methods of contraception, at the same time, from the time of signing the

informed consent through 90 days after the last dose of ixazomib/placebo,

and

o Adhered to the guidelines of any treatment-specific pregnancy prevention

program, if applicable, or

o Agreed to practice true abstinence, when this was in line with the preferred

and usual lifestyle of the patient. Periodic abstinence (eg, calendar,

ovulation, symptothermal, postovulation methods) and withdrawal were not

acceptable methods of contraception

• Patients with MM that had relapsed following primary therapy or was not

responsive to primary therapy. For this study, stable disease following

ASCT was considered nonresponsive to primary therapy

• Patients who had received double (tandem) ASCT

• Patients who had received radiotherapy within 14 days before the first dose

of ixazomib/placebo

• Diagnosed or treated for another malignancy within 5 years before

randomisation or previously diagnosed with another malignancy with

evidence of residual disease. Patients with nonmelanoma skin cancer or

carcinoma in situ of any type were not excluded if they had undergone

complete resection

• Female patients who were lactating and breastfeeding or had a positive

serum pregnancy test during the Screening period

• Patients who had major surgery within 14 days before randomisation

• Patients who had central nervous system involvement

• Patients who had infection requiring intravenous antibiotic therapy or

other serious infection within 14 days before randomisation

• Diagnosis of Waldenstrom's macroglobulinemia, POEMS

(polyneuropathy, organomegaly, endocrinopathy, monoclonal

gammopathy, and skin changes) syndrome, plasma cell leukaemia, primary

amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome

• Evidence of current uncontrolled cardiovascular conditions, including

uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic

congestive heart failure, unstable angina, or myocardial infarction within

the past 6 months

• Patients who had received systemic treatment with strong cytochrome

P450 (CYP) 3A inducers (rifampin, rifapentine, rifabutin, carbamazepine,


• Male patients, even if surgically sterilised (ie, status postvasectomy), who:

o Agreed to practice effective barrier contraception during the entire study

treatment period and through 90 days after the last dose of

ixazomib/placebo, and

o Adhered to the guidelines of any treatment-specific pregnancy prevention

program, if applicable, or

o Agreed to practice true abstinence, when this was in line with the preferred

and usual lifestyle of the patient. Periodic abstinence (eg, calendar,

ovulation, symptothermal, postovulation methods for the female partner) and

withdrawal were not acceptable methods of contraception

• Voluntary written consent must have been given before performance of any

study-related procedure not part of standard medical care, with the understanding

that consent may have been withdrawn by the patient at any time without

prejudice to future medical care

• Suitable venous access for the study-required blood sampling

• Was willing and able to adhere to the study visit schedule and other protocol

requirements

• Met the following clinical laboratory criteria at study entry:

o Absolute neutrophil count ≥1,000/mm3 and platelet count ≥75,000/mm3.

Platelet transfusions to help patients meet eligibility criteria were not

allowed within 3 days before randomisation

o Total bilirubin ≤1.5 x the upper limit of the normal range

o Alanine aminotransferase and aspartate aminotransferase ≤3 x the upper

limit of the normal range

o Calculated creatinine clearance ≥30 mL/min

phenytoin, phenobarbital) or use of Ginkgo biloba, or St. John's wort

within 14 days before randomisation in the study

• Active hepatitis B or C virus infection, or known HIV positive

• Patients who had comorbid systemic illnesses or other severe concurrent

disease that, in the judgment of the investigator, would make the patient

inappropriate for entry into this study or interfere significantly with the

proper assessment of safety and toxicity of the prescribed regimens (eg,

peripheral neuropathy that was grade 1 with pain or grade 2 or higher of

any cause)

• Psychiatric illness/social situation that would limit compliance with study

requirements

• Known allergy to any of the study medications, their analogues, or

excipients in the various formulations of any agent

• Inability to swallow oral medication, inability or unwillingness to comply

with the drug administration requirements, or gastrointestinal procedure

that could interfere with the oral absorption or tolerance of treatment

• Treatment with any investigational products within 60 days before the first

dose of the ixazomib/placebo


Supplementary Table S2: Additional AEs (high-level terms) in the safety population

AE Ixazomib group (n=394) Placebo group n=259)

No. of patients (%)

Any

grade

Grade

3

Grade

4

Any

grade

Grade

3

Grade

4

Haematologic AEs of any cause

Blood and lymphatic system disorders (MedDRA SOC)† 85 (22) 24 (6) 8 (2) 32 (12) 8 (3) 4 (2)

Leukopenias NEC 8 (2) 0 0 3 (1) 1 (<1) 0

Lymphatic system disorders NEC 5 (1) 0 0 0 0 0

Anaemia deficiencies 1 (<1) 1 (<1) 0 0 0 0

Anaemias due to chronic disorders 1 (<1) 0 0 0 0 0

Bleeding tendencies 1 (<1) 0 0 1 (<1) 0 0

Leukocytoses NEC 1 (<1) 0 0 2 (<1) 2 (<1) 0

Spleen disorders 1 (<1) 0 0 0 0 0

Anaemias haemolytic NEC 0 0 0 1 (<1) 0 1 (<1)

Nonhaematologic AEs of any cause

Infections and infestations (MedDRA SOC)† 292 (74) 55 (14) 3 (<1) 166 (64) 21 (8) 0

Viral infections NEC 104 (26) 3 (<1) 0 72 (28) 0 0

Lower respiratory tract and lung infections 92 (23) 30 (8) 1 (<1) 47 (18) 12 (5) 0

Herpes viral infections 51 (13) 5 (1) 0 23 (9) 4 (2) 0

Eye and eyelid infections 32 (8) 1 (<1) 0 14 (5) 0 0

Infections NEC 23 (6) 0 0 11 (4) 1 (<1) 0

Abdominal and gastrointestinal infections 19 (5) 2 (<1) 1 (<1) 8 (3) 1 (<1) 0

Dental and oral soft tissue infections 14 (4) 1 (<1) 0 8 (3) 1 (<1) 0

Ear infections 14 (4) 1 (<1) 0 8 (3) 0 0

Urinary tract infections 14 (4) 0 0 12 (5) 0 0

Skin structures and soft tissue infections 9 (2) 0 0 8 (3) 0 0

Candida infections 6 (2) 0 0 1 (<1) 0 0

Fungal infections NEC 6 (2) 0 0 4 (2) 0 0

Bacterial infections NEC 5 (1) 1 (<1) 1 (<1) 2 (<1) 0 0

Parainfluenzae viral infections 3 (<1) 2 (<1) 0 1 (<1) 0 0

Streptococcal infections 3 (<1) 2 (<1) 0 3 (1) 0 0

Bone and joint infections 1 (<1) 0 0 0 0 0

Breast infections 1 (<1) 0 0 0 0 0

Ectoparasitic infestations 1 (<1) 0 0 0 0 0

Escherichia infections 1 (<1) 1 (<1) 0 0 0 0

Female reproductive tract infections 1 (<1) 0 0 0 0 0

Hepatitis viral infections 1 (<1) 0 0 0 0 0

Moraxella infections 1 (<1) 0 0 0 0 0

Respiratory syncytial virus infections 1 (<1) 0 0 1 (<1) 1 (<1) 0

Sepsis, bacteraemia, viraemia and fungaemia NEC 1 (<1) 1 (<1) 0 0 0 0

Staphylococcal infections 1 (<1) 0 0 0 0 0

Tinea infections 1 (<1) 0 0 1 (<1) 0 0

Borrelial infections 0 0 0 1 (<1) 0 0

Flaviviral infections 0 0 0 1 (<1) 1 (<1) 0

Gastrointestinal disorders (MedDRA SOC) 270 (69) 25 (6) 0 124 (48) 3 (1) 0

Gastrointestinal atonic and hypomotility disorders NEC 47 (12) 1 (<1) 0 24 (9) 0 0

Gastrointestinal and abdominal pains (excl oral and throat) 33 (8) 2 (<1) 0 20 (8) 0 0

Stomatitis and ulceration 17 (4) 0 0 9 (3) 0 0

Dyspeptic signs and symptoms 13 (3) 0 0 16 (6) 0 0

Flatulence, bloating and distension 13 (3) 0 0 8 (3) 0 0

Dental pain and sensation disorders 10 (3) 0 0 3 (1) 0 0

Oral dryness and saliva altered 8 (2) 0 0 7 (3) 0 0

Dental and periodontal infections and inflammations 7 (2) 2 (<1) 0 3 (1) 0 0

Dental disorders NEC 7 (2) 1 (<1) 0 2 (<1) 0 0

Gastritis (excl infective) 7 (2) 1 (<1) 0 5 (2) 0 0

Haemorrhoids and gastrointestinal varices (exl oesophageal) 7 (2) 0 0 7 (3) 0 0

Gastrointestinal signs and symptoms NEC 5 (1) 0 0 3 (1) 0 0

Oral soft tissue pain and paraesthesia 5 (1) 0 0 4 (2) 0 0

Non-site specific gastrointestinal haemorrhages 5 (1) 0 0 1 (<1) 0 0

Oral soft tissue signs and symptoms 4 (<1) 0 0 4 (2) 0 0

Gastric and oesophageal haemorrhages 3 (<1) 0 0 0 0 0

Inguinal hernias 3 (<1) 1 (<1) 0 2 (<1) 0 0

Tongue signs and symptoms 3 (<1) 0 0 0 0 0

Acute and chronic pancreatitis 2 (<1) 0 0 0 0 0

Anal and rectal disorders NEC 2 (<1) 0 0 1 (<1) 0 0

Benign neoplasms gastrointestinal (excl oral cavity) 2 (<1) 0 0 0 0 0

Colitis (excl infective) 2 (<1) 1 (<1) 0 0 0 0

Diaphragmatic hernias 2 (<1) 1 (<1) 0 0 0 0

Diverticula 2 (<1) 0 0 0 0 0

Faecal abnormalities NEC 2 (<1) 0 0 0 0 0

Gastrointestinal disorders NEC 2 (<1) 0 0 2 (<1) 0 0

Gastrointestinal spastic and hypermotility disorders 2 (<1) 0 0 1 (<1) 0 0


Intestinal haemorrhages 2 (<1) 0 0 1 (<1) 0 0

Oral soft tissue disorders NEC 2 (<1) 0 0 0 0 0

Tongue disorders 2 (<1) 0 0 1 (<1) 0 0

Umbilical hernias 2 (<1) 0 0 0 0 0

Abdominal wall conditions NEC 1 (<1) 0 0 0 0 0

Anal and rectal signs and symptoms 1 (<1) 0 0 0 0 0

Gastric ulcers and perforation 1 (<1) 0 0 0 0 0

Gingival discolouration 1 (<1) 0 0 0 0 0

Gingival disorders NEC 1 (<1) 0 0 1 (<1) 0 0

Gingival haemorrhages 1 (<1) 0 0 0 0 0

Gingival pains 1 (<1) 0 0 0 0 0

Large intestinal stenosis and obstruction 1 (<1) 0 0 0 0 0

Oesophagitis (excl infective) 1 (<1) 0 0 0 0 0

Oral soft tissue swelling and oedema 1 (<1) 0 0 1 (<1) 0 0

Salivary gland enlargements 1 (<1) 0 0 0 0 0

Tooth missing 1 (<1) 0 0 0 0 0

Abdominal hernias NEC 0 0 0 1 (<1) 0 0

Anal and rectal ulcers and perforation 0 0 0 1 (<1) 0 0

Gastrointestinal inflammatory disorders NEC 0 0 0 1 (<1) 1 (<1) 0

Musculoskeletal and connective tissue pain and discomfort

(MedDRA SOC) 243 (62) 22 (6) 0 143 (55) 7 (3) 0

Musculoskeletal and connective tissue pain and discomfort 139 (35) 8 (2) 0 87 (34) 2 (<1) 0

Joint related signs and symptoms 93 (24) 4 (1) 0 31 (12) 1 (<1) 0

Bone related signs and symptoms 50 (13) 1 (<1) 0 36 (14) 2 (<1) 0

Muscle related signs and symptoms NEC 37 (9) 0 0 22 (8) 0 0

Muscle pains 22 (6) 0 0 14 (5) 0 0

Arthropathies NEC 11 (3) 0 0 1 (<1) 0 0

Joint related disorders NEC 9 (2) 1 (<1) 0 6 (2) 0 0

Osteoarthropathies 9 (2) 1 (<1) 0 8 (3) 0 0

Tendon disorders 8 (2) 0 0 8 (3) 0 0

Bone disorders NEC 8 (2) 4 (1) 0 3 (1) 1 (<1) 0

Fractures NEC 8 (2) 5 (1) 0 2 (<1) 1 (<1) 0

Metabolic bone disorders 7 (2) 0 0 0 0 0

Muscle weakness conditions 7 (2) 1 (<1) 0 0 0 0

Bursal disorders 6 (2) 0 0 2 (<1) 0 0

Synovial disorders 6 (2) 0 0 1 (<1) 0 0

Musculoskeletal and connective tissue signs and symptoms

NEC 4 (1) 0 0 3 (1) 0 0

Soft tissue disorders NEC 3 (<1) 1 (<1) 0 1 (<1) 0 0

Intervertebral disc disorders NEC 2 (<1) 0 0 2 (<1) 0 0

Musculoskeletal and connective tissue infections and

inflammations NEC 2 (<1)

0 0 0 0 0

Benign musculoskeletal and connective tissue neoplasms 1 (<1) 0 0 0 0 0

Cartilage disorders 1 (<1) 0 0 0 0 0

Muscle infections and inflammations 1 (<1) 0 0 0 0 0

Muscle tone abnormalities 1 (<1) 0 0 0 0 0

Spine and neck deformities 1 (<1) 1 (<1) 0 0 0 0

Crystal arthropathic disorders 0 0 0 1 (<1) 0 0

Spondyloarthropathies 0 0 0 1 (<1) 1 (<1) 0

General disorders and administration site conditions

(MedDRA SOC) 210 (53) 10 (3) 0 116 (45) 3 (1) 1 (<1)

Asthenic conditions 109 (28) 5 (1) 0 60 (23) 2 (<1) 0

General signs and symptoms NEC 44 (11) 1 (<1) 0 22 (8) 0 1 (<1)

Oedema NEC 40 (10) 1 (<1) 0 12 (5) 0 0

Pain and discomfort NEC 20 (5) 2 (<1) 0 11 (4) 1 (<1) 0

Feelings and sensations NEC 12 (3) 0 0 3 (1) 0 0

Inflammations 3 (<1) 0 0 1 (<1) 0 0

Gait disturbances 1 (<1) 0 0 0 0 0

Mass conditions NEC 1 (<1) 0 0 1 (<1) 0 0

Mucosal findings abnormal 1 (<1) 0 0 0 0 0

Therapeutic and nontherapeutic responses 1 (<1) 0 0 0 0 0

Vaccination site reactions 1 (<1) 0 0 3 (1) 0 0

Withdrawal and rebound effects 1 (<1) 0 0 1 (<1) 0 0

Complications associated with device NEC 0 0 0 1 (<1) 0 0

Nervous system disorders (MedDRA SOC) 177 (45) 13 (3) 1 (<1) 101 (39) 1 (<1) 0

Paraesthesias and dysaesthesias 41 (10) 1 (<1) 0 13 (5) 0 0

Neurological signs and symptoms NEC 35 (9) 1 (<1) 0 19 (7) 0 0

Sensory abnormalities NEC 25 (6) 0 0 14 (5) 0 0

Disturbances in consciousness NEC 11 (3) 7 (2) 0 6 (2) 1 (<1) 0

Lumbar spinal cord and nerve root disorders 7 (2) 1 (<1) 0 2 (<1) 0 0

Migraine headaches 5 (1) 0 0 2 (<1) 0 0

Tremor (excl congenital) 4 (1) 0 0 0 0 0


Memory loss (excl dementia) 3 (<1) 0 0 2 (<1) 0 0

Mental impairment (excl dementia and memory loss) 3 (<1) 0 0 0 0 0

Spinal cord and nerve root disorders NEC 3 (<1) 1 (<1) 1 (<1) 1 (<1) 0 0

Cortical dysfunction NEC 2 (<1) 0 0 0 0 0

Mononeuropathies 2 (<1) 1 (<1) 0 4 (2) 0 0

Central nervous system haemorrhages and cerebrovascular

accidents 1 (<1)

0 0

0

0 0

Cervical spinal cord and nerve root disorders 1 (<1) 0 0 0 0 0

Facial cranial nerve disorders 1 (<1) 0 0 1 (<1) 0 0

Olfactory nerve disorders 1 (<1) 0 0 4 (2) 0 0

Paralysis and paresis (excl cranial nerve) 1 (<1) 0 0 0 0 0

Seizures and seizure disorders NEC 1 (<1) 0 0 0 0 0

Sleep disturbances NEC 1 (<1) 0 0 1 (<1) 0 0

Speech and language abnormalities 1 (<1) 0 0 0 0 0

Coordination and balance disturbances 0 0 0 1 (<1) 0 0

Muscle tone abnormal 0 0 0 1 (<1) 0 0

Narcolepsy and hypersomnia 0 0 0 1 (<1) 0 0

Parkinson's disease and parkinsonism 0 0 0 1 (<1) 0 0

Transient cerebrovascular events 0 0 0 1 (<1) 0 0

Vagus nerve disorders 0 0 0 1 (<1) 0 0

Skin and subcutaneous tissue disorders (MedDRA SOC) 168 (43) 9 (2) 0 81 (31) 1 (<1) 0

Rashes, eruptions and exanthems NEC 84 (21) 5 (1) 0 35 (14) 0 0

Pruritus NEC 41 (10) 0 0 22 (8) 0 0

Dermal and epidermal conditions NEC 15 (4) 0 0 11 (4) 0 0

Dermatitis and eczema 15 (4) 2 (<1) 0 8 (3) 0 0

Erythemas 13 (3) 0 0 7 (3) 0 0

Alopecias 11 (3) 0 0 6 (2) 0 0

Apocrine and eccrine gland disorders 8 (2) 0 0 6 (2) 0 0

Urticarias 8 (2) 2 (<1) 0 3 (1) 0 0

Bullous conditions 7 (2) 0 0 1 (<1) 0 0

Dermatitis ascribed to specific agent 7 (2) 0 0 4 (2) 0 0

Skin preneoplastic conditions NEC 4 (1) 0 0 1 (<1) 0 0

Acnes 3 (<1) 0 0 2 (<1) 0 0

Angioedemas 3 (<1) 0 0 1 (<1) 0 0

Hyperpigmentation disorders 3 (<1) 0 0 0 0 0

Skin and subcutaneous tissue ulcerations 3 (<1) 0 0 0 0 0

Nail and nail bed conditions (excl infections and infestations) 2 (<1) 0 0 1 (<1) 0 0

Photosensitivity and photodermatosis conditions 2 (<1) 0 0 0 0 0

Psoriatic conditions 2 (<1) 0 0 0 0 0

Skin cysts and polyps 2 (<1) 0 0 0 0 0

Exfoliative conditions 1 (<1) 0 0 0 0 0

Hyperkeratoses 1 (<1) 0 0 0 0 0

Panniculitides 1 (<1) 0 0 1 (<1) 1 (<1) 0

Purpura and related conditions 1 (<1) 0 0 1 (<1) 0 0

Rosaceas 1 (<1) 0 0 0 0 0

Skin and subcutaneous conditions NEC 1 (<1) 0 0 1 (<1) 0 0

Skin vascular conditions NEC 1 (<1) 0 0 0 0 0

Skin vasculitides 1 (<1) 0 0 0 0 0

Skin dystrophies 0 0 0 1 (<1) 0 0

Respiratory, thoracic and mediastinal disorders (MedDRA

SOC) 154 (39) 5 (1) 0 94 (36) 1 (<1) 0

Upper respiratory tract signs and symptoms 48 (12) 0 0 31 (12) 0 0

Breathing abnormalities 18 (5) 1 (<1) 0 15 (6) 0 0

Bronchospasm and obstruction 10 (3) 2 (<1) 0 4 (2) 0 0

Nasal congestion and inflammations 8 (2) 0 0 4 (2) 0 0

Nasal disorders NEC 4 (1) 0 0 4 (2) 0 0

Pharyngeal disorders (excl infections and neoplasms) 4 (1) 0 0 1 (<1) 0 0

Pneumothorax and pleural effusions NEC 4 (1) 1 (<1) 0 0 0 0

Laryngeal and adjacent sites disorders NEC (excl infections and

neoplasms) 2 (<1) 0 0 1 (<1) 0 0

Paranasal sinus disorders (excl infections and neoplasms) 2 (<1) 0 0 1 (<1) 0 0

Parenchymal lung disorders NEC 2 (<1) 1 (<1) 0 0 0 0

Laryngeal spasm, oedema and obstruction 1 (<1) 0 0 0 0 0

Lower respiratory tract inflammatory and immunologic

conditions 1 (<1)

0

0 0 0 0

Pleural infections and inflammations 1 (<1) 0 0 1 (<1) 0 0

Respiratory signs and symptoms NEC 1 (<1) 0 0 0 0 0

Respiratory tract disorders NEC 1 (<1) 0 0 0 0 0

Bronchial conditions NEC 0 0 0 1 (<1) 0 0

Lower respiratory tract signs and symptoms 0 0 0 1 (<1) 0 0

Investigations (MedDRA SOC) 81 (21) 20 (5) 0 36 (14) 9 (3) 1 (<1)

Liver function analyses 19 (5) 6 (2) 0 7 (3) 3 (1) 1 (<1)


Physical examination procedures and organ system status 16 (4) 1 (<1) 0 6 (2) 0 0

Platelet analyses 13 (3) 3 (<1) 0 1 (<1) 0 0

White blood cell analyses 11 (3) 6 (2) 0 8 (3) 4 (2) 0

Renal function analyses 9 (2) 0 0 4 (2) 0 0

Tissue enzyme analyses NEC 7 (2) 1 (<1) 0 4 (2) 2 (<1) 0

Mineral and electrolyte analyses 5 (1) 0 0 2 (<1) 0 0

Protein analyses NEC 4 (1) 1 (<1) 0 2 (<1) 0 0

Cholesterol analyses 3 (<1) 1 (<1) 0 2 (<1) 0 0

Vascular tests NEC (incl blood pressure) 3 (<1) 1 (<1) 0 0 0 0

Immunoglobulin analyses 2 (<1) 0 0 3 (1) 1 (<1) 0

Metabolism tests NEC 2 (<1) 0 0 0 0 0

Vitamin analyses 2 (<1) 0 0 1 (<1) 0 0

Blood gas and acid base analyses 1 (<1) 0 0 1 (<1) 0 0

Digestive enzymes 1 (<1) 1 (<1) 0 0 0 0

ECG investigations 1 (<1) 0 0 0 0 0

Heart rate and pulse investigations 1 (<1) 0 0 0 0 0

Skeletal and cardiac muscle analyses 1 (<1) 0 0 0 0 0

Urinary tract function analyses NEC 1 (<1) 0 0 0 0 0

Virus identification and serology 0 0 0 2 (<1) 0 0

Metabolism and nutrition disorders (MedDRA SOC) 59 (15) 6 (2) 0 42 (16) 2 (<1) 3 (1)

Appetite disorders 23 (6) 1 (<1) 0 17 (7) 1 (<1) 0

Disorders of purine metabolism 10 (3) 0 0 4 (2) 0 0

Potassium imbalance 8 (2) 1 (<1) 0 7 (3) 0 1 (<1)

Calcium metabolism disorders 6 (2) 1 (<1) 0 4 (2) 0 0

Elevated cholesterol 4 (1) 0 0 2 (<1) 0 0

Hyperglycaemic conditions NEC 4 (1) 1 (<1) 0 4 (2) 0 1 (<1)

Elevated triglycerides 2 (<1) 0 0 0 0 0

Hyperlipidaemias NEC 2 (<1) 0 0 0 0 0

Iron deficiencies 2 (<1) 0 0 2 (<1) 0 0

Lipid metabolism and deposit disorders NEC 2 (<1) 0 0 1 (<1) 0 0

Total fluid volume decreased 2 (<1) 2 (<1) 0 1 (<1) 1 (<1) 0

Diabetes mellitus (incl subtypes) 1 (<1) 1 (<1) 0 0 0 0

Fat soluble vitamin deficiencies and disorders 1 (<1) 0 0 2 (<1) 0 0

Metabolic disorders NEC 1 (<1) 0 0 0 0 0

Phosphorus metabolism disorders 1 (<1) 0 0 2 (<1) 0 0

Sodium imbalance 1 (<1) 1 (<1) 0 1 (<1) 0 0

Total fluid volume increased 1 (<1) 0 0 0 0 0

Electrolyte imbalance NEC 0 0 0 1 (<1) 0 1 (<1)

Magnesium metabolism disorders 0 0 0 1 (<1) 0 0

Water soluble vitamin deficiencies 0 0 0 4 (2) 0 0

Psychiatric disorders (MedDRA SOC) 64 (16) 2 (<1) 0 32 (12) 1 (<1) 0

Disturbances in initiating and maintaining sleep 31 (8) 0 0 12 (5) 0 0

Depressive disorders 19 (5) 1 (<1) 0 7 (3) 1 (<1) 0

Anxiety symptoms 18 (5) 0 0 9 (3) 0 0

Sleep disorders NEC 4 (1) 0 0 0 0 0

Increased physical activity levels 2 (<1) 0 0 0 0 0

Confusion and disorientation 1 (<1) 0 0 3 (1) 0 0

Eating disorders NEC 1 (<1) 0 0 0 0 0

Emotional and mood disturbances NEC 1 (<1) 1 (<1) 0 1 (<1) 0 0

Mood disorders NEC 1 (<1) 0 0 0 0 0

Sexual desire disorders 1 (<1) 0 0 2 (<1) 0 0

Substance related and addictive disorders 1 (<1) 0 0 0 0 0

Deliria 0 0 0 1 (<1) 0 0

Mood alterations with depressive symptoms 0 0 0 1 (<1) 0 0

Psychiatric elimination disorders 0 0 0 1 (<1) 0 0

Injury, poisoning and procedural complications (MedDRA

SOC) 55 (14) 6 (2) 1 (<1) 35 (14) 2 (<1) 0

Non-site specific injuries NEC 14 (4) 0 0 10 (4) 0 0

Skin injuries NEC 10 (3) 0 0 3 (1) 0 0

Limb fractures and dislocations 9 (2) 1 (<1) 0 4 (2) 1 (<1) 0

Muscle, tendon and ligament injuries 5 (1) 1 (<1) 0 5 (2) 0 0

Non-site specific procedural complications 5 (1) 0 0 3 (1) 0 0

Site specific injuries NEC 5 (1) 0 0 6 (2) 0 0

Bone and joint injuries NEC 4 (1) 1 (<1) 0 0 0 0

Cerebral injuries NEC 1 (<1) 0 1 (<1) 0 0 0

Conditions caused by cold 1 (<1) 0 0 0 0 0

Fractures and dislocations NEC 1 (<1) 1 (<1)

0 0

0 0

Overdoses NEC 1 (<1) 0 0 0 0 0

Peripheral nerve injuries 1 (<1) 1 (<1) 0 0 0 0

Spinal fractures and dislocations 1 (<1) 1 (<1) 0 1 (<1) 1 (<1) 0

Thoracic cage fractures and dislocations 1 (<1) 0 0 1 (<1) 0 0


Transfusion related complications 1 (<1) 0 0 0 0 0

Vaccination related complications 1 (<1) 0 0 0 0 0

Cardiovascular injuries 0 0 0 1 (<1) 0 0

Chest and lung injuries NEC 0 0 0 1 (<1) 0 0

Poisoning and toxicity 0 0 0 1 (<1) 0 0

Vascular disorders (MedDRA SOC) 47 (12) 5 (1) 0 24 (9) 5 (2) 0

Vascular hypertensive disorders NEC 21 (5) 3 (<1) 0 18 (7) 4 (2) 0

Peripheral vascular disorders NEC 9 (2) 0 0 3 (1) 0 0

Haemorrhages NEC 5 (1) 0 0 3 (1) 0 0

Peripheral embolism and thrombosis 3 (<1) 0 0 0 0 0

Peripheral vasoconstriction, necrosis and vascular insufficiency 3 (<1) 0 0 0 0 0

Circulatory collapse and shock 2 (<1) 1 (<1) 0 0 0 0

Varicose veins NEC 2 (<1) 0 0 0 0 0

Non-site specific necrosis and vascular insufficiency NEC 1 (<1) 0 0 0 0 0

Non-site specific vascular disorders NEC 1 (<1) 0 0 0 0 0

Non-site specific embolism and thrombosis 0 0 0 1 (<1) 1 (<1) 0

Eye disorders (MedDRA SOC) 32 (8) 2 (<1) 0 25 (10) 2 (<1) 0

Lacrimation disorders 8 (2) 0 0 6 (2) 0 0

Ocular infections, inflammations and associated manifestations 7 (2) 0 0 3 (1) 0 0

Visual disorders NEC 6 (2) 0 0 6 (2) 0 0

Cataract conditions 5 (1) 2 (<1) 0 4 (2) 1 (<1) 0

Choroid and vitreous haemorrhages and vascular disorders 2 (<1) 0 0 0 0 0

Conjunctival infections, irritations and inflammations 2 (<1) 0 0 2 (<1) 0 0

Conjunctival structural change, deposit and degeneration 2 (<1) 0 0 0 0 0

Glaucomas (excl congenital) 2 (<1) 0 0 0 0 0

Corneal structural change, deposit and degeneration 1 (<1) 0 0 0 0 0

Lid bleeding and vascular disorders 1 (<1) 0 0 0 0 0

Lid, lash and lacrimal infections, irritations and inflammations 1 (<1) 0 0 1 (<1) 0 0

Ocular disorders NEC 1 (<1) 0 0 2 (<1) 0 0

Retinal structural change, deposit and degeneration 1 (<1) 0 0 1 (<1) 1 (<1) 0

Structural change, deposit and degeneration of eye NEC 1 (<1) 0 0 0 0 0

Blindness (excl colour blindness) 0 0 0 1 (<1) 0 0

Conjunctival and corneal bleeding and vascular disorders 0 0 0 2 (<1) 0 0

Corneal infections, oedemas and inflammations 0 0 0 1 (<1) 0 0

Retinal bleeding and vascular disorders (excl retinopathy) 0 0 0 1 (<1) 0 0

Ear and labyrinth disorders (MedDRA SOC) 29 (7) 1 (<1) 0 17 (7) 0 0

Inner ear signs and symptoms 19 (5) 1 (<1) 0 9 (3) 0 0

Hearing losses 7 (2) 0 0 3 (1) 0 0

Ear disorders NEC 2 (<1) 0 0 5 (2) 0 0

External ear disorders NEC 1 (<1) 0 0 0 0 0

Inner ear disorders NEC 1 (<1) 0 0 0 0 0

Tympanic membrane disorders (excl infections) 0 0 0 1 (<1) 0 0

Neoplasms benign, malignant and unspecified (incl cysts and

polyps) (MedDRA SOC) 28 (7) 6 (2) 1 (<1) 16 (6) 6 (2) 1 (<1)

Skin neoplasms benign 5 (1) 0 0 3 (1) 0 0

Skin neoplasms malignant and unspecified (excl melanoma) 5 (1) 0 0 3 (1) 0 0

Plasma cell myelomas 4 (1) 1 (<1) 1 (<1) 4 (2) 3 (1) 1 (<1)

Soft tissue neoplasms benign NEC 2 (<1) 0 0 1 (<1) 0 0

Lower gastrointestinal neoplasms benign 2 (<1) 0 0 0 0 0

Bladder neoplasms malignant 1 (<1) 1 (<1) 0 0 0 0

Fibrosarcomas malignant 1 (<1) 0 0 0 0 0

Hepatobiliary neoplasms benign 1 (<1) 0 0 0 0 0

Non-small cell neoplasms malignant of the respiratory tract cell

type specified 1 (<1)

0 0

0

0 0

Oncologic complications and emergencies 1 (<1) 0 0 2 (<1) 2 (<1) 0

Prostatic neoplasms malignant 1 (<1) 1 (<1) 0 1 (<1) 1 (<1) 0

Renal neoplasms benign 1 (<1) 0 0 0 0 0

Respiratory tract and pleural neoplasms malignant cell type

unspecified NEC 1 (<1) 1 (<1)

0

0

0 0

Skin melanomas (excl ocular) 1 (<1) 1 (<1) 0 0 0 0

Thyroid neoplasms benign 1 (<1) 0 0 0 0 0

Uterine neoplasms malignant NEC 1 (<1) 1 (<1) 0 0 0 0

Breast and nipple neoplasms malignant 0 0 0 1 (<1) 0 0

Colorectal neoplasms malignant 0 0 0 1 (<1) 1 (<1) 0

Metastases to specified sites 0 0 0 1 (<1) 0 0

Renal and urinary disorders (MedDRA SOC) 27 (7) 1 (<1) 0 14 (5) 1 (<1) 0

Bladder and urethral symptoms 14 (4) 0 0 7 (3) 0 0

Renal failure and impairment 5 (1) 1 (<1) 0 4 (2) 1 (<1) 0

Urinary tract lithiasis (excl renal) 2 (<1) 0 0 0 0 0

Urinary tract signs and symptoms NEC 2 (<1) 0 0 2 (<1) 0 0


Genital and urinary tract disorders NEC 1 (<1) 0 0 0 0 0

Renal failure complications 1 (<1) 0 0 1 (<1) 0 0

Renal neoplasms 1 (<1) 0 0 0 0 0

Urinary abnormalities 1 (<1) 0 0 0 0 0

Bladder infections and inflammations 0 0 0 1 (<1) 0 0

Nephropathies and tubular disorders NEC 0 0 0 1 (<1) 0 0

Reproductive system and breast disorders (MedDRA SOC) 20 (5) 1 (<1) 0 18 (7) 2 (<1) 0

Reproductive tract signs and symptoms NEC 3 (<1) 0 0 3 (1) 0 0

Breast disorders NEC 3 (<1) 0 0 2 (<1) 0 0

Benign and malignant breast neoplasms 2 (<1) 0 0 1 (<1) 0 0

Menopausal effects on the genitourinary tract 2 (<1) 1 (<1) 0 0 0 0

Penile and scrotal infections and inflammations 2 (<1) 0 0 1 (<1) 0 0

Breast signs and symptoms 1 (<1) 0 0 2 (<1) 0 0

Erection and ejaculation conditions and disorders 1 (<1) 0 0 2 (<1) 0 0

Menopausal effects NEC 1 (<1) 0 0 1 (<1) 1 (<1) 0

Penile disorders NEC (excl erection and ejaculation) 1 (<1) 0 0 0 0 0

Prostate and seminal vesicles infections and inflammations 1 (<1) 0 0 1 (<1) 1 (<1) 0

Prostatic neoplasms and hypertrophy 1 (<1) 0 0 1 (<1) 0 0

Prostatic signs, symptoms and disorders NEC 1 (<1) 0 0 0 0 0

Sexual function and fertility disorders NEC 1 (<1) 0 0 0 0 0

Testicular and epididymal disorders NEC 1 (<1) 0 0 0 0 0

Vulvovaginal disorders NEC 1 (<1) 0 0 0 0 0

Spermatogenesis and semen disorders 0 0 0 1 (<1) 0 0

Vulvovaginal signs and symptoms 0 0 0 4 (2) 0 0

Cardiac disorders (MedDRA SOC) 17 (4) 1 (<1) 0 10 (4) 2 (<1) 0

Supraventricular arrhythmias 6 (2) 1 (<1) 0 2 (<1) 1 (<1) 0

Cardiac signs and symptoms NEC 5 (1) 0 0 3 (1) 0 0

Ischaemic coronary artery disorders 3 (<1) 0 0 4 (2) 1 (<1) 0

Coronary artery disorders NEC 1 (<1) 0 0 0 0 0

Heart failures NEC 1 (<1) 0 0 1 (<1) 0 0

Rate and rhythm disorders NEC 1 (<1) 0 0 1 (<1) 0 0

Mitral valvular disorders 0 0 0 1 (<1) 0 0

Hepatobiliary disorders (MedDRA SOC) 6 (2) 3 (<1) 0 6 (2) 0 0

Hepatic enzymes and function abnormalities 4 (1) 2 (<1) 0 1 (<1) 0 0

Cholecystitis and cholelithiasis 1 (<1) 0 0 2 (<1) 0 0

Hepatocellular damage and hepatitis NEC 1 (<1) 1 (<1) 0 1 (<1) 0 0

Bile duct infections and inflammations 0 0 0 1 (<1) 0 0

Cholestasis and jaundice 0 0 0 1 (<1) 0 0

Hepatic fibrosis and cirrhosis 0 0 0 1 (<1) 0 0

Immune system disorders (MedDRA SOC) 6 (2) 0 0 4 (2) 1 (<1) 0

Allergies to foods, food additives, drugs and other chemicals 3 (<1) 0 0 2 (<1) 0 0

Allergic conditions NEC 3 (<1) 0 0 0 0 0

Primary immunodeficiency syndromes 0 0 0 2 (<1) 1 (<1) 0

Atopic disorders 0 0 0 1 (<1) 0 0

Endocrine disorders (MedDRA SOC) 4 (1) 0 0 2 (<1) 0 0

Thyroid hypofunction disorders 2 (<1) 0 0 0 0 0

Male gonadal function disorders 1 (<1) 0 0 1 (<1) 0 0

Thyroid hyperfunction disorders 1 (<1) 0 0 0 0 0

Adrenal cortical hyperfunctions 0 0 0 1 (<1) 0 0

Surgical and medical procedures (MedDRA SOC) 0 0 0 1 (<1) 0 0

Retinal therapeutic procedures 0 0 0 1 (<1) 0 0

AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; NEC=not elsewhere classified;

SOC=system organ class.

†1 patient in the ixazomib group had a grade 5 AE of pneumonia.


Supplementary References

1. Paiva B, Cedena MT, Puig N, et al. Minimal residual disease monitoring and immune profiling in

multiple myeloma in elderly patients. Blood 2016; 127(25): 3165-74.

2. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of

clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011; 117(18): 4691-5.

supplementary appendixde la fuente, yolanda gonzález montes, jesus martin sanchez, maria victoria...

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