Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma

Trial Title:

FiTNEss (UK-MRA Myeloma XIV) - Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma

Overview:

A phase III, multi-centre, randomised controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant.

All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomised on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose-modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomisation on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians will be blinded to maintenance allocation.

Participant population:

* Newly diagnosed as having Multiple Myeloma (MM) according to the updated IMWG diagnostic criteria 2014 (see Appendix 1 for criteria)
* Not eligible for stem cell transplant
* Aged at least 18 years
* Able to provide written informed consent

Number of participants:

740 participants will be entered into the trial at Randomisation 1 (R1), with 478 participants at Randomisation 2 (R2).

Objectives:

The primary objectives of this study are to determine:

* Early treatment cessation (within 60 days of randomisation) for standard versus frailty-adjusted up-front dosing
* Progression-free survival (PFS, from maintenance randomisation) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (R+I)

The secondary objectives of this study are to assess progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, 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 MRD negativity, duration of response, time to improved response, time to next treatment, treatment compliance and total amount of therapy delivered, toxicity \& safety including the incidence of SPMs, Quality of Life (QoL), cost effectiveness of standard versus frailty-adjusted up-front dosing of IRD and cost-effectiveness of R + I versus R.

Exploratory objectives are prospective validation of a novel frailty risk score (UK-MRA Myeloma Risk Profile - MRP), usefulness of Karnofsky Performance Status (PS), and association of molecular subgroups with response, PFS and OS.


Eligibility Criteria:
Eligibility criteria for Randomisation 1 (R1) Participants must meet all of the following inclusion criteria and none of the exclusion criteria.

Inclusion criteria for R1

1. Newly diagnosed as having MM according to the updated IMWG diagnostic criteria 2014 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:
   1. 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.
   2. 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.
   3. Haemoglobin ≥ 80 g/L. The use of red blood cell transfusions is permitted.

      Biochemical:
   4. Total bilirubin ≤ 3 x upper limit of normal (ULN).
   5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN.
5. Meet the pregnancy prevention requirements:

   Female participants who:
   1. Are not of childbearing potential, OR
   2. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR
   3. 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:
   1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
   2. 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, 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.

Exclusion criteria for 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 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 participation in this study.

Eligibility criteria for Randomisation 2 (R2) Participants must meet all of the following inclusion criteria and none of the exclusion criteria.

Inclusion criteria for 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, with no evidence of progression prior to R2.
3. Meet all of the following blood criteria within 14 days before R2:

Haematological:

1. 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.
2. 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.
3. Haemoglobin ≥ 80 g/L. The use of red blood cell transfusions is permitted.

   Biochemical:
4. Total bilirubin ≤ 3 x upper limit of normal (ULN).
5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN.

Exclusion criteria for 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.
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 or known hepatitis B surface antigen positive or hepatitis C antibody positive.
11. Active systemic infection.
12. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's continued participation in this study.