| 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 | 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
There are several primary objectives for this study, specific to each randomisation pathway. The overarching aim is to explore the role of precision medicine in the treatment of multiple myeloma. The pathway for participants with 'standard-risk' genetics focuses on treatment escalation and de-escalation pathways, allocating participants to a more or less intensive pathway based on their response to initial chemotherapy treatment. In the pathway for participants with 'high-risk' genetics the focus is on assessing the effect of intensive treatment.
More specifically the primary objectives are:
•To assess if stopping isatuximab medication after 12 months in standard-risk participants who have responded well to initial chemotherapy treatment is as effective as long-term treatment with isatuximab.
•To compare the effectiveness of varying combinations of lenalidomide, bortezomib, dexamethasone and isatuximab, in standard-risk participants who have not responded well to initial chemothe |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess:
•Time from randomisation to the first documentation of disease progression or death for randomisation 2 and randomisation 3
•Time to the first documentation of disease progression
•Time to second documentation of disease progression
•Overall survival
•Survival after disease progression
•Objective response rate (how the patient's myeloma reacts to treatment)
•Attainment of greater than or equal to VGPR (very good partial response) from treatment
•Attainment of MRD negativity (Minimal residual disease, the number of cancer cells that remain when the participant is in remission) 100 days post induction treatment
•Duration of MRD negativity
•Time to improved response
•Time to next treatment
•Treatment compliance and total amount of therapy delivered
•Toxicity and safety, including the incidence of second malignancies
•Quality of life
•Cost effectiveness |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for registration
1.Previously untreated patients with multiple myeloma requiring therapy, defined as having myeloma defining events or with biomarkers of malignancy according to IMWG diagnostic criteria
2.Eligible for stem cell transplant
3.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG >2 is due to effects of myeloma eg spinal cord compression);
4.Total bilirubin <3 x upper limit of normal (ULN)
5.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN
6.adequate marrow function:
•neutrophils ≥1.0 × 10^9/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC ≥0.75 x 109/L is allowed),
•haemaglobin (Hb) ≥ 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted,
•platelets ≥ 75 × 10^9/L (in the case of heavy bone marrow infiltration (>50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of ≥50 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted.
7.Creatinine clearance (CrCl) ≥ 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis)
8.Able to swallow oral medication
9.Aged at least 18 years
10.Agree to follow the pregnancy prevention guidelines
11.Able to provide written informed consent
Inclusion criteria for starting isatuximab maintenance, R1, R2 and R3
1.4 cycles of RCyBorD received
2.Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except in cases where ECOG >2 is due to effects of myeloma eg spinal cord compression);
3.Total bilirubin <3 x upper limit of normal (ULN)
4.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN
5.Adequate marrow function:
•neutrophils ≥1.0 × 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),
•haemaglobin (Hb) ≥ 80g/L. Blood transfusions within 3 days prior to eligibility assessments are not permitted,
•platelets ≥ 75 × 10^9/L (in the case of heavy bone marrow infiltration (>50%) which is, in the opinion of the investigator, the cause of the thrombocytopaenia and provided appropriate supportive measures and patient monitoring are in place, a platelet count of ≥50 × 10^9/L is permitted. Platelet transfusions within 3 days prior to eligibility assessments are not permitted.
6.Creatinine clearance (CrCl) ≥ 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis)
7.Agree to follow the pregnancy prevention guidelines
Additional inclusion criteria for starting isatuximab maintenance
1.Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q), as confirmed by the CTRU.
2.4 cycles of RCyBorD received
3.MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT
4.Received ≥100mg/m^2 high-dose melphalan and ASCT
5.Signed the Informed Consent Document for the R1 treatment pathway
Additional inclusion criteria for R1
1.12 cycles of isatuximab maintenance received
2.MRD-negative (proportion of malignant cells in the bone marrow is < 1 in 100,000, confirmed by HMDS central lab) after 12 cycles of isatuximab
Additional inclusion criteria for R2
1.Standard-risk (participant is not confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q) as confirmed by CTRU.
2.4 cycles of RCyBorD received
3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT
4.MRD-positive (proportion of malignant cells in the bone marrow is ≥ 1 in 100,000, confirmed by HMDS central lab) at 100 days post-ASCT
5.Received ≥100mg/m^2 high-dose melphalan and ASCT
6.Signed the Informed Consent Document for the R2 treatment pathway
Additional inclusion criteria for R3
1.High-risk (participant is confirmed to have at least two of these genetically adverse lesions: t(4;14), t(14;16), t(14;20), del(17p), gain(1q)) as confirmed by CTRU
2.4 cycles of RCyBord received
3.At least minimal response (MR; according to IMWG criteria) at 100 days post-ASCT
4.Received ≥100mg/m^2 high-dose melphalan and ASCT
5.Signed the Informed Consent Document for the R3 treatment pathway
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| E.4 | Principal exclusion criteria |
Exclusion criteria for registration (and for starting isatuximab maintenance, R1, R2 and R3)
1.Smouldering MM, monoclonal gammopathy of undetermined significance (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 160mg dexamethasone. This criteria is not applicable at R1, R2 and R3 when participants will have received previous treatment for MM as part of this trial.
3.Unstable angina or myocardial infarction within 4 months prior to registration (or at any time since registration for participants starting isatuximab maintenance, R1, R2 and R3), NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
4.Cardiac disorder identified according to local practice (eg left ventricular ejection fraction, LVEF; results from formal measurements acceptable within 28 days prior to registration)
5.Significant neuropathy (Grade ≥3, or Grade 2 with pain)
6.Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to registration. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed
7.Pregnant, lactating or breastfeeding female participants (within 28 days prior to starting isatuximab maintenance, R1, R2 and R3
8.Known resistance, intolerance or hypersensitivity to any component of the planned therapies, except in the case of hypersensitivity which is amenable to premedication with steroids or H2 blocker. Intolerance includes hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
9.Major surgery within 14 days before registration (or starting isatuximab maintenance, R1, R2 and R3). This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty.
10.Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing.
11.Active systemic infection
12.Participant is hepatitis B surface antigen positive, hepatitis C antibody positive or HIV positive. Participants must have hepatitis and HIV screening conducted within 28 days prior to registration.
13.Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant’s participation in this study.
14.Receipt of live vaccination within 30 days prior to registration, for the duration of the study and for 3 months after the last dose of study drug.
Exclusion criteria for starting isatuximab
1.Disease progression
2.MRD-positive at 100 days post-ASCT
3.Registration exclusion criteria
Exclusion criteria for R1
1.Disease progression
2.MRD-positive at 100 days post-ASCT or after 12 cycles of isatuximab
3.Registration exclusion criteria
Exclusion criteria for R2 and R3
1.Disease progression
2.Registration exclusion criteria in Section
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measures are:
Randomisation 1: Progression-free survival (PFS-1)
PFS-R1 is defined as the time from R1 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. Disease progression is defined according to the IMWG Uniform Response Criteria for Multiple Myeloma .
Randomisation 2: Attainment of MRD Negativity
Attainment of Minimal Residual Disease (MRD) negativity is defined as a binary endpoint. MRD negativity will be determined at 6 months post-R2 (end of cycle 6 post-ASCT treatment for participants allocated to maintenance only strategies and end of cycle 7 post-ASCT treatment for participants allocated to maintenance and consolidation strategies) according to the IMWG MRD criteria.
Randomisation 3: Progression-Free Survival Rate
The progression-free survival rate is defined as the proportion of participants who are alive and progression-free 28 months post-R3. Disease progression is defined according to the IMWG Uniform Response Criteria for Multiple Myeloma.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final analysis
R1:
2 years after the final participant has been randomised into R1
R2:
6 months after the final participant has been randomised into R2
R3:
28 months after the final participant has been randomised into R3
In addition to this interim analysis will be conducted approximately 6 months after the 40th participant has been randomised to R2 and when half the PFS events (119 progressions or deaths from any cause) have been observed in R1.
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| E.5.2 | Secondary end point(s) |
Progression-Free Survival (PFS-R2)
The time from R2 to the time of first documented evidence of disease progression or death from any cause.
Progression-Free Survival (PFS-R3)
The time from R3 to the time of first documented evidence of disease progression or death from any cause.
Time to progression (TTP)
The time from randomisation to the date of first documented evidence of disease progression.
Progression-Free Survival two (PFS2)
The time from randomisation to the time of the second documented disease progression.
Overall Survival (OS)
OS is defined separately for each randomisation. In each case it is the time from randomisation to the time of death from any cause.
Survival after progression
The date of first documented evidence of disease progression to the date of death from any cause.
Objective response rate (ORR)
ORR is defined as a categorical outcome consisting of whether a participant had sCR, CR, VGPR, PR, MR, SD or PD at the end of RCyBorD induction, 100 days post-ASCT in both the standard and high-risk pathways, at the end of consolidation*, after 6 months of post-ASCT treatment**, after 12 months of post-ASCT treatment*** and after 24 cycles of post-ASCT treatment in R1 only (equivalent to 12 cycles of post-R1 treatment).
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 RCyBorD induction, 100 days post-ASCT in both the standard and high-risk pathways, at the end of consolidation*, after 6 months of post-ASCT treatment**, after 12 months of post-ASCT treatment*** and after 24 months of post-ASCT treatment in R1 only (12 months post-R1).
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 RCyBorD induction, 100 days post-ASCT in both the standard and high-risk pathways, at the end of consolidation*, after 6 months of post-ASCT treatment**, after 12 months of post-ASCT treatment***, after 18 months of post-ASCT treatment in R2 and R3 only**** and after 24 months of post-ASCT treatment in R1 only (equivalent to 12 cycles of post-R1 treatment).
Duration of MRD Negativity
Duration of MRD negativity is first defined as whether the participant changes their MRD status between MRD sample timepoints. For R1 these are 100 days post-ASCT to 6 months of post-ASCT treatment (end of cycle 6 post-ASCT treatment), 100 days post-ASCT to 12 months of post-ASCT treatment (end of cycle 12 post-ASCT treatment, R1) and R1 to 12 months post R1 (end of cycle 24 post-ASCT treatment). For R2 and R3 these are 100 days post-ASCT to end of consolidation (end of cycle 4 post-ASCT), 100 days post-ASCT to 6 months post-randomisation**, 100 days post-ASCT to 12 months post-randomisation*** and 6 months post-randomisation to 18 months post randomisation (end of cycle 6 or 7 to end of cycle 18 or 19 post-ASCT treatment). The endpoint may then be extended to consider the time from the participant being identified as MRD-negative to the time they are not or death where the primary cause is myeloma.
Time to improved response
The time from randomisation to the date the response category is first improved. Subjects without any improvement of the baseline status at randomisation will be censored at the last date of response assessment.
Time to next treatment
The time from registration to the start date of the next line of treatment or death from any cause.
Treatment compliance & total amount of therapy delivered
Treatment compliance is defined as a binary outcome, the total amount of therapy delivered will be defined as the number of induction & maintenance (&/or consolidation) cycles which the participant received overall, by pathway & by randomisation.
Toxicity & safety, including incidence of second malignancies
Toxicity & safety will be reported based on the AEs. The number of SAEs will be reported according to MedDRA System Organ Class. All second primary malignancies will be reported based on information collected on the eCRF.
Quality of Life
Quality of Life is defined using the patient-reported outcome measures: EORTC-QLQ-C30, EORTC-QLQ-MY20, EQ-5D-3L and EQ-5D-VAS.
Cost effectiveness
Defined as a cost per incremental QALY below £20,000 and/or a positive incremental net monetary benefit. The cost-effectiveness of treatment options at each randomisation will be evaluated with respect to this criteria.
*3 months post R2 and R3
**equivalent to 6 cycles for R2 receiving R or RIsa; equivalent to 7 cycles for R2 and R3 receiving RBorD+R or RBorDIsa+RIsa
*** equivalent to 12 cycles for R2 receiving R or RIsa; equivalent to 13 cycles for R2 and R3 receiving RBorD+R or RBorDIsa+RIsa
**** equivalent to 18 cycles for R2 receiving R or RIsa; equivalent to 19 cycles for R2 and R3 receiving RBorD+R or RBorDIsa+ |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary end points will be analysed alongside the primary endpoints where appropriate and updated as required. |
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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 | Yes |
| 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) | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.1.7.1 | Other trial design description |
| Risk adapted, response-guided, discontinuation |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| 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.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 | Yes |
| 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 (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 | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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 | 0 |
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