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Trial registered on ANZCTR


Registration number
ACTRN12622001366741
Ethics application status
Approved
Date submitted
19/09/2022
Date registered
25/10/2022
Date last updated
21/01/2024
Date data sharing statement initially provided
25/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Risk Directed front-line therapy for Multiple Myeloma incorporating Selinexor: The RIDDLE-M-X trial
Scientific title
Investigating the efficacy of Risk Directed front-line therapy for Multiple Myeloma incorporating Selinexor: The RIDDLE-M-X trial
Secondary ID [1] 307995 0
AMaRC 21-04
Universal Trial Number (UTN)
Trial acronym
RIDDLE-M-X
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 327664 0
Condition category
Condition code
Cancer 324748 324748 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A. [RISK STRATIFICATION WITH SKY92 MM PROFILER]
Patients will be risk-stratified to either standard risk or high risk using the MM profiler with SKY92 algorithm - Partipicants will have a sample of their bone marrow taken for this test about 1 week before Day 1 of the first treatment cycle.

1. [HIGH RISK (HR) group]
1.1 - INDUCTION (4 cycles)
- 35-day cycle
- Bortezomib 1.3mg/m^2, as intravenous or subcutaneous injection, on days 1, 8, 15 and 22.
- Lenalidomide 25mg orally once daily on days 1 – 21.
- Dexamethasone 40mg orally on days 1, 8, 15 and 22.
- Selinexor 40mg orally on days 1, 8, 15 and 22 of each cycle.

1.2 AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT)
- Melphalan 200mg/m^2 intravenous infusion day -1; minimum of 2 x 10^6 CD34 peripheral blood stem cells for re-infusion day 0. Stem cell harvesting as per standard of care, after 2 cycles of induction.

1.3 HIGH RISK (HR) – CONSOLIDATION (2 cycles) - 90-100 days after ASCT
- 35-day cycle
- Bortezomib 1.3mg/m^2, as intravenous or subcutaneous injection, on days 1, 8, 15 and 22.
- Lenalidomide 25mg orally once daily on days 1 – 21.
- Dexamethasone 40mg orally on days 1, 8, 15 and 22.
- Selinexor 40mg orally on days 1, 8, 15 and 22 of each cycle.

2. [STANDARD RISK (SR) group]
2.1 - INDUCTION (4 cycles)
- 28-days cycle
- Bortezomib 1.3mg/m^2, as intravenous or subcutaneous injection, days 1, 8, 15 and 22.
- Lenalidomide 25mg orally once daily on days 1 – 21.
- Dexamethasone 40mg orally on days 1, 8, 15 and 22.

2.2 AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT)
- Melphalan 200mg/m^2 intravenous infusion day -1; minimum of 2 x 10^6 CD34 peripheral blood stem cells for re-infusion day 0. Stem cell harvesting as per standard of care, after 2 cycles of induction.

2.3 STANDARD RISK (SR) – CONSOLIDATION (2 cycles) - 90-100 days after ASCT
- 28-days duration
- Bortezomib 1.3mg/m^2, as intravenous or subcutaneous injection, days 1, 8, 15 and 22.
- Lenalidomide 25mg orally once daily on days 1 – 21.
- Dexamethasone 40mg orally on days 1, 8, 15 and 22.

B. [RESPONSE ADAPTATION WITH EUROFLOW]
Patients will then undergo EuroFlow testing to determine is there is any minimal resiudal disease (this means if there is a very small but detectable amount of myeloma cells). Partipicants will have a sample of their bone marrow taken for this test about 6 to 8 weeks after consolidation treatment finishes. Maintenance treatment will commence as soon as possible after the EuroFlow test becomes available:

1. [STANDARD RISK (SR) with minimal resiudal disease negative group]
- 28-day cycle.
- Lenalidomide 10mg orally every day continuously. Increasing to 15mg orally after 3 cycles if tolerated.
- Treatment will continue until disease progression or unacceptable toxicity

2. [HIGH RISK (HR) or STANDARD RISK (SR) with minimal resiudal disease positive group]):
- 28-day cycle.
- Lenalidomide 10mg orally every day continuously. Increasing to 15mg orally after 3 cycles if tolerated.
- Selinexor 40mg orally 1 day per week continuously
- Treatment will continue until disease progression or unacceptable toxicity

Any unused medication (e.g: capsules taken home) will need to be returned to the clinic at every clinic visit
Intervention code [1] 324449 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Active

Outcomes
Primary outcome [1] 332568 0
To assess the efficacy of the incorporation of selinexor into standard of care therapy in high-risk newly diagnosed MM.

Tests: Blood tests, bone marrow samples
Timepoint [1] 332568 0
Baseline, post induction, post consolidation, 6 and 12 months after commencement of maintenance therapy
Secondary outcome [1] 413942 0
To investigate the durability of response in standard-risk patients who commence maintenance therapy.

Tests: Blood tests, medical records.
Timepoint [1] 413942 0
Calculated from when the patient commences maintenance therapy to date of disease progression or death, from any cause, whichever comes first.
Secondary outcome [2] 414410 0
To assess overall survival (OS) of high-risk patients identified using SKY92 MMProfiler
Timepoint [2] 414410 0
Overall survival is defined as the duration from the start of treatment (Cycle 1 Day 1) to death from any cause. Overall survival be censored by the earlier of the closeout date and the date of last follow-up for patients who have withdrawn or have been deemed lost to follow-up. The close-out date for overall survival will be the earliest calendar date of the last date of contact for patients who have not withdrawn from the study, are not known to have died and have not been deemed to be lost to follow-up.
Secondary outcome [3] 414413 0
To assess overall survival (OS) of standard-risk patients identified using SKY92 MMProfiler and are minimal residual disease positive
Timepoint [3] 414413 0
Overall survival is defined as the duration from the start of treatment (Cycle 1 Day 1) to death from any cause. Overall survival be censored by the earlier of the closeout date and the date of last follow-up for patients who have withdrawn or have been deemed lost to follow-up. The close-out date for overall survival will be the earliest calendar date of the last date of contact for patients who have not withdrawn from the study, are not known to have died and have not been deemed to be lost to follow-up.
Secondary outcome [4] 414414 0
To assess overall survival (OS) of standard-risk patients identified using SKY92 MMProfiler and are minimal residual disease negative
Timepoint [4] 414414 0
Overall survival is defined as the duration from the start of treatment (Cycle 1 Day 1) to death from any cause. Overall survival be censored by the earlier of the closeout date and the date of last follow-up for patients who have withdrawn or have been deemed lost to follow-up. The close-out date for overall survival will be the earliest calendar date of the last date of contact for patients who have not withdrawn from the study, are not known to have died and have not been deemed to be lost to follow-up.
Secondary outcome [5] 414415 0
To document the safety of selinexor-bortezomib-lenalidomide-dexamethasone (XBLd) in high-risk MM.
Timepoint [5] 414415 0
For each cycle, worst grade (NCI-CTCAE V5.0) of each treatment-emergent adverse event (AE) experienced by a patient will be recorded
Secondary outcome [6] 414416 0
To document the deliverability of selinexor-BLd in high-risk MM.
Timepoint [6] 414416 0
Percentage of planned dose of each component of selinexor-BLd delivered in a cycle
Secondary outcome [7] 414417 0
To assess changes in patient-reported quality of life.
Timepoint [7] 414417 0
Responses to the EORTC QLQ-C30 and QLQ-MY20 during induction, post-consolidation and after 4, 8 and 12 months of maintenance therapy

Eligibility
Key inclusion criteria
1. Male and Female patients, 18 years of age or older
2. Able to provide written consent.
3. Newly diagnosed MM as per IMWG criteria eligible for ASCT.
4. Diagnostic bone marrow sample available for SKY92 risk analysis.
5. Measurable disease as defined by any of the following
o Serum M-component >5 g/L, and/or
o Urine M-component > 200 mg/24 h, and/or
o Involved serum FLC level >100mg/L.
6. No contraindication to the use of any of the study drugs and able to comply with trial requirements.
7. Adequate liver function (total bilirubin < 2.0x ULN, ALT < 5.0x ULN) unless considered secondary to MM.
8. Absolute neutrophil count >= 1.0 x 109/L.
9. Platelet count >= 50 x 109/L (>= 30 x 109/L if MM involvement in the marrow is greater than 50%), patients should not have received platelet transfusions within 7 days of the screening platelet count.
10. Hb >= 80g/L, red cell transfusions as per institutional protocol are allowed.
11. Woman of childbearing potential must agree to ongoing pregnancy testing, to be performed within 72 hours before during treatment and on day 28 after last dose of study treatment.
12. Women of childbearing potential must agree to use one highly effective method and preferably one additional effective (barrier) method during the study and for 28 days following the last dose of study treatment.
13. Male participants who are sexually active with WOCBP must use a condom during sexual contact during study and for at least 7 days after last dose of study treatment.
14. Male participants must not donate sperm during study and for at least 7 days after last dose of study treatment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who have had myocardial infarction within 6 months prior to enrolment, or New York Hospital Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
2. Any other serious or uncontrolled medical or psychiatric illness that could, in the investigators’ opinion, potentially interfere with the completion of treatment according to this protocol.
3. Known ongoing or active systemic infection, active hepatitis B or C infection, or known human immunodeficiency positivity.
4. Women who are pregnant or lactating. Women of child-bearing potential must have a negative urine pregnancy test at Screening.
5. Any patient who is unable or unwilling to meet the requirements of the lenalidomide pregnancy prevention programme.
6. Active malignancy with the exception of any of the following:
o Adequately treated basal cell carcinoma, squamous cell carcinoma or in situ cervical cancer.
o Adequately treated stage 1 cancer from which the subject is currently in remission from and has been in remission for > 2 years.
o Stage 1 prostate cancer that does not require treatment.
o Any other cancer from which the subject has been disease-free for > 2 years.
7. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
- Risk-adaptive approach: Risk stratification using SKY92 MM Profiler prior to study
- Response-adaptive approach: Response stratification using EuroFlow after consolidation and before maintenance therapy
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2023
Actual
15/05/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
13
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23170 0
The Alfred - Melbourne
Recruitment hospital [2] 24592 0
Nepean Hospital - Kingswood
Recruitment hospital [3] 26053 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [4] 26054 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [5] 26055 0
Border Medical Oncology - Albury
Recruitment hospital [6] 26056 0
The Northern Hospital - Epping
Recruitment hospital [7] 26057 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 41911 0
2050 - Camperdown
Recruitment postcode(s) [2] 41909 0
2640 - Albury
Recruitment postcode(s) [3] 40187 0
2747 - Kingswood
Recruitment postcode(s) [4] 38533 0
3004 - Melbourne
Recruitment postcode(s) [5] 41910 0
3076 - Epping
Recruitment postcode(s) [6] 41907 0
4029 - Herston
Recruitment postcode(s) [7] 41908 0
4575 - Birtinya

Funding & Sponsors
Funding source category [1] 312261 0
Other Collaborative groups
Name [1] 312261 0
Australasian Myeloma Research Consortium
Country [1] 312261 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Myeloma Research Consortium
Address
Level 2, South Block, 55 Commercial Road, Melbourne, VIC 3004
Country
Australia
Secondary sponsor category [1] 313801 0
None
Name [1] 313801 0
Address [1] 313801 0
Country [1] 313801 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311634 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 311634 0
55 Commercial Road
Melbourne VIC 3004
Ethics committee country [1] 311634 0
Australia
Date submitted for ethics approval [1] 311634 0
04/10/2022
Approval date [1] 311634 0
08/11/2022
Ethics approval number [1] 311634 0

Summary
Brief summary
Australian data shows that 20-25% of newly diagnosed myeloma patients who are treated with standard of care relapse within the first 12 months of starting treatment and their survival rate is lower than that of patients who relapse after 12 months of starting treatment. This group of patients are deemed to be at ‘high-risk’. The purpose of this study is to optimise treatment of newly diagnosed multiple myeloma (MM) patients who undergo autologous stem cell treatment (ASCT) by using diagnostic techniques to guide whether selinexor should be added to standard care, whether it is and beneficial to do so.

Who is it for?
You may be eligible for this study if you are aged 18 or older, you have been recently diagnosed with multiple myeloma. If must meet additional heart, liver and kidney health criteria prior to commencing treatment.

[Study details]
All participants who choose to enrol in this study will have a bone marrow sample taken and assessed to determine whether they are at high risk or standard risk disease. These details will then be used to allocate participants for ‘induction’ therapy, to either standard of care treatment (consisting of bortezomib, lenalidomide and dexamethasone), or standard of care treatment with added selinexor. This is a risk-adaptive approach to treatment, meaning your treatment is guided by the results of your myeloma risk profile. Participants will continue with their allocated treatments for 4-5 months. After this time, all participants will then undergo preparation for an autologous stem cell transplant, where healthy stem cells will be harvested from each participant and expanded externally, before being re-implanted back to stimulate further stem cell growth. At 5-6 months after the transplant, all participants will be required to provide a second bone marrow sample to undergo a second test to check how they are responding to treatment and assess if there is a very small but detectable number of myeloma cells. For standard risk patients, if there isn’t any detectable myeloma cells, you will continue treatment with only lenalidomide. If there are detectable cells, you will be given lenalidomide and selinexor. High-risk patients will be given lenalidomide and selinexor regardless of the results. This is called 'maintenance' therapy. Participants will then continue taking their second allocation of medications for maintenance for until the treatments are no longer effective. This could range from months to years. Further bone marrow samples will be required at 6 and 12 months after commencing maintenance treatment to test for detectable myeloma cells. The trial is intended to run over 4-5 years. You will be asked to complete short questionnaires about your multiple myeloma treatment and your health-related quality of life every month prior to the transplant, about 4-5 months after transplant and within 12 months after commencing maintenance therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121794 0
Prof Andrew Spencer
Address 121794 0
Alfred Health, 55 Commerical Road, Melbourne VIC 3004
Country 121794 0
Australia
Phone 121794 0
+61 3 9076 3393
Fax 121794 0
Email 121794 0
andrew.spencer@monash.edu
Contact person for public queries
Name 121795 0
Mr Khoa Le
Address 121795 0
Alfred Health, 55 Commerical Road, Melbourne VIC 3004
Country 121795 0
Australia
Phone 121795 0
+61 3 9076 7851
Fax 121795 0
Email 121795 0
amarc@alfred.org.au
Contact person for scientific queries
Name 121796 0
Prof Andrew Spencer
Address 121796 0
Alfred Health, 55 Commerical Road, Melbourne VIC 3004
Country 121796 0
Australia
Phone 121796 0
+61 3 9076 7851
Fax 121796 0
Email 121796 0
amarc@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.