F railty-adjusted therapy i n T ransplant N on- E ligible patient s with newly diagno s ed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial

Abstract

Introduction: Multiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life.

Methods and analysis: Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance.

Ethics and dissemination: Ethical approval has been obtained from the North East-Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications.

Trial registration number: ISRCTN17973108, NCT03720041.

Keywords: CHEMOTHERAPY; Clinical trials; Myeloma.

Figure 1

Overall survival in MRC-IX and NCRI-XI TE pathway (A). Overall survival in MRC-IX and NCRI-XI TNE pathway (B). MRC-IX, Medical Research Council Myeloma IX trial (ISRCTN49407852); NCRI-XI, National Cancer Research Institute Myeloma XI Trial (ISRCTN68454111); TE, transplant eligible; TNE, transplant non-eligible.

Figure 2

Reasons for ceasing induction treatment in NCRI-XI (n=928). NCRI-XI, National Cancer Research Institute Myeloma XI Trial (ISRCTN68454111).

Figure 3

Flow diagram of Myeloma XIV (Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma) Trial. ADL, activity of daily living; HE, health economics; IADL, instrumental activity of daily living; IMWG, International Myeloma Working Group; IRD, ixazomib, lenalidomide and dexamethasone; QoL, quality of life; R+I, lenalidomide+ixazomib.

Figure 4

Summary of investigations (local and central). ADL, activity of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CR, complete response; CRP, C-reactive protein; CTRU, Clinical Trial Research Unit; eCRFs, electronic case report forms; EDTA, edetic acid; EORTC QLQ C30, European Organisation for Research and Treatment of cancer quality of life questionaire; EQ-5D, Euroqol 5 dimensions; FBC, full blood count; FISH, fluorescence in situ hybridization; HMDS, Haematology Malignancy Diagnostic Service; IADL, instrumental activity of daily living; ICR, Institute of Cancer Research; IMWG, International Myeloma Working Group; IRD, ixazomib, lenalidomide and dexamethasone; LDH, lactate dehydrogenase; LFTs, liver function test; LIMR, Leeds Institute of Medical Research; MRD, minimal residual disease; QLQ-MY20, myeloma quality of life questionaire; SAEs, serious adverse events; sCR, stringent complete response; SPMs, secondary primary malignancies; SUSARs, suspected unexpected serious adverse reactions; U&E's, urea and electrolytes. a. The FBC should be repeated mid-cycle 1 (Day 14 +/−3 days) or more frequently and during subsequent cycles if there is a concern about cytopenias, b. Pregnancy test must also be performed at 4 weeks after the end of study treatment, c. Or at 6 and 12 months post-R2 if treatment is stopped prior to this for reasons other than disease progression, d. Or at 2, 6 and 12 months post-R1 if treatment is stopped prior to this for reasons other than disease progression, e. The imaging at baseline/pre-registration is mandatory. Subsequent imaging will be as per local protocols/standard of care - imaging will only need to be repeated if extramedullary disease was detected at baseline, or in the event of new symptoms suggestive of new extramedullary disease, cord compression, new fracture, etc, or to investigate new hypercalcaemia. In the rare event of participants with extramedullary disease at baseline, imaging should be performed at the end of IRD induction to confirm the end of induction response, and at any other time the disease parameters suggest that the participant has achieved a complete response (if not already achieved at the end of induction) to confirm that the extramedullary disease has resolved, f. Performance status should be recorded at the same timepoints as the frailty index (ie, prior to R1, after cycles 2, 4, 6 and 12 of induction, and after cycles 6 and 12 of maintenance). Performance status should also be recorded at the time of disease progression. Or at 2, 6 and 12 months post-R1 if treatment is stopped prior to this for reasons other than disease progression, g. If the participant did not consent to the pre-trial bone marrow registration part of Myeloma XIV, the bone marrow biopsy will need to be taken after full informed consent. ^¥If not sent at bone marrow and blood sample consent, *At pre-randomisation 1 a CD138 negative portion of the bone marrow aspirate will be sent to LIMR after CD138 positive selection at ICR, **At the end of induction bone marrow aspirate will be sent to ICR after CD138 positive selection at LIMR.