| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed multiple myeloma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028566 |
| E.1.2 | Term | Myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The principal research question for randomisation one focuses on whether a scoring system, the IMWG frailty index, can determine frailty in trial participants. Half of the participants are assigned different doses of treatment.
The scoring system takes into account the participant's age, other illnesses and whether they can live independently to determine how frail they are, giving them both a frailty score and a category (fit, unfit, frail). The scoring system will be measured by comparing the number of participants who stop trial treatment for any reason within 60 days of randomisation one between the two arms; standard dosing (standard of care) and frailty-score adjusted dosing.
If a patient is still alive and disease progression-free after 12 cycles of treatment they will be randomised again to receive either lenalidomide and placebo or lenalidomide and ixazomib. The principal research question for the randomisation two is to determine whether the addition of ixazomib to lenalido |
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| E.2.2 | Secondary objectives of the trial |
The secondary research questions are:-
For randomisation one:
• the time from randomisation one to progression or death
• the number of participant’s dying within 12 months of randomisation one
• patient’s response to treatment
• the length of the response to treatment
• the time until the participant requires a new non-trial anti-myeloma treatment.
For randomisation two:
• the time it takes for a patient’s response to treatment improve.
The secondary objectives for randomisation one are to assess the frailty score adjusted dosing strategy in terms of:
• Progression-free survival (PFS)
• Time to progression
• Time to 2nd PFS event (PFS2)
• Overall Survival (OS)
• Survival after progression
• Deaths within 12 months of R1
• Overall response rate (ORR)
• Attainment of ≥VGPR
• Attainment of Minimal Residual Disease (MRD) negativity
• Duration of response (DoR)
• Time to next treatment
• Treatment compliance and total amount of therapy delivered
• Toxicity & safety, including the incide |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
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| E.4 | Principal exclusion criteria |
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
R1: Early treatment cessation
Early treatment cessation is defined as a binary endpoint. Participants will be defined to have experienced an event if they die, progress, or are withdrawn from treatment (by a treating clinician) or withdraw consent for trial treatment, within 60 days of R1.
R2: Progression-free survival (PFS-R2)
PFS-R2 is defined as the time from R2 to the time of first documented evidence of disease progression or death from any cause. Individuals who are lost to follow-up or progression-free at the time of analysis will be censored at their last known date to be alive and progression-free.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Both primary outcome measures will be evaluated at their interim analysis and when all participants have reached the required time point. For R1 the interim will be when 370 participants have reached 60 days post-R1 and the final analysis will be when all 740 participants have reached 60 days post-R1. For R2 the interim analysis will take place when 151 patients have progressed or died following R2 and the final analysis will take place when 252 patients have progressed or died following R2 and it is at least two-years following the randomisation of the last participant into R2. |
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| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS-R1)
PFS-R1 is defined the same as the primary endpoint PFS-R2 but measured from randomisation 1 instead of randomisation 2.
Time to progression
Time to disease progression is defined for both R1 and R2 as the time from randomisation to the date of first documented evidence of disease progression. Participants who die prior to documentation of disease progression will be censored in the analysis at their date of death. Participants not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Participants dying from causes not primarily due to progression will also be censored.
Progression-free survival two (PFS2)
For both R1 and R2, progression-free survival two is defined as the time from randomisation to the time of the second documented disease progression or death from any cause. Individuals who are lost to follow-up or alive and second progression-free at the time of analysis will be censored at their last known date to be alive and second progression-free.
Overall survival (OS)
Overall survival is defined separately for each randomisation. In each case it is the time from randomisation to the time of death from any cause. Individuals who are lost to follow-up or still alive at the time of analysis will be censored at their last known date to be alive.
Survival after progression
Survival after progression is defined from the date of first documented evidence of disease progression to the date of death from any cause. Individuals who are lost to follow-up or alive at the time of analysis will be censored at their last known date to be alive following their first documented evidence of disease progression.
Deaths within 12 months of R1
Deaths within 12 months of R1 is defined as a binary endpoint. Participants will be defined to have experienced an event if they die within 12 months of R1.
Overall response rate (ORR)
Overall response rate is defined as a categorical outcome consisting of whether a participant had sCR, CR, VGPR, PR, MR, SD or PD at the end of induction.
Attainment of ≥VGPR
Attainment of ≥VGPR is defined as a binary outcome of whether a participant had ≥VGPR (VGPR, CR, sCR) or <VGPR (PR, MR, SD, PD) at the end of induction.
Attainment of Minimal Residual Disease (MRD) negativity
Attainment of Minimal Residual Disease (MRD) negativity is defined as a binary endpoint. MRD negativity will be determined at the end of induction therapy and 12 months post R2.
Duration of response (DoR)
Duration of response is defined as the time from the first observation of response ≥ PR, following R1, to the time of first documented evidence of disease progression or death confirmed related to progression. Individuals who are lost to follow-up, or still alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Individuals whose cause of death is unrelated to disease progression will be censored at their date of death.
Time to improved response
Time to improved response is defined as the time from the date of R2 to the date the response category is first improved. Subjects without any improvement of the baseline status at R2 will be censored at the last date of response assessment.
Time to next treatment
Time to next treatment is defined as the time from R1 to the start date of the next line of treatment or death from any cause.
Treatment compliance and total amount of therapy delivered
In the first instance treatment compliance is defined as a binary outcome i.e. did the participant receive 12 cycles of induction treatment. The total amount of therapy delivered will be first defined as the number of induction and maintenance cycles which the participant received. This may be extended to consider the percentage of protocol dose delivered. For each treatment (ixazomib, lenalidomide, dexamethasone) this will be defined as the total dose received in a cycle compared to the total dose the participant should have received in the cycle without modifications, averaged across all cycles of treatment.
Toxicity & safety, including incidence of second malignancies
Toxicity and safety will be reported based on the adverse events, as graded by CTCAE V5 and determined by routine clinical assessments. The number of SAEs will be reported according to MedDRA System Organ Class. All second primary malignancies will be reported based on information recorded.
Quality of Life (QoL)
Quality of Life is defined using the patient-reported outcome measures; EORTC-QLQ-C30, EORTC-QLQ-MY20 and EQ-5D (3 Level).
Cost effectiveness of delivery of IRD and R+I
Cost-effectiveness is defined as a cost per incremental QALY below £20,000 and/or a positive incremental net monetary benefit. This will compare the cost-effectiveness of the intervention to the control for each of the randomisations separately.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints for R1 will be analysed alongside the analysis of the primary endpoint detailed above. They will then be updated when the primary endpoint for R2 is analysed alongside the corresponding secondary endpoints of R2. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 70 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the trial is defined as the date of the collection of the last participant’s last data item. Participants will be followed up until death or until the final analysis as described (whichever is sooner). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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