Table 1 MUK five study inclusion and exclusion criteria

Inclusion criteria for initial randomisation

DISEASE RELATED

 - Diagnosed with symptomatic MM (according to IMWG 2003 criteria) and requiring therapy for first relapse or primary refractory disease. (Participants previously immunofixation negative who are now immunofixation positive need to demonstrate a greater than 5 g/l absolute increase in paraprotein to be eligible for inclusion).

 - Participants with measurable disease as defined by one or more of the following criteria (assessed within 21 days prior to randomisation):

  o Serum paraprotein ≥5 g/L (For IgA participants whose disease can only be reliably measured by serum quantitative immunoglobulin (IgA): ≥ 7.5 g/L)

  o Urine Bence Jones Protein: ≥200 mg/24 h

  o Serum LC assay: Involved FLC level ≥100 mg/L, provided serum FLC ratio is abnormal

DEMOGRAPHIC

 - Age ≥18 years

 - Life expectancy ≥6 months

 - Eastern Cooperative Oncology Group (ECOG) performance status 0–2

LABORATORY

 - Adequate hepatic function, with alanine transaminase (ALT) or aspartate transaminase (AST) <3 times the upper limit of normal and serum direct bilirubin ≤17 μmol/L (1 mg/100 ml) within 14 days prior to randomisation

 - Absolute neutrophil count (ANC) ≥1.0 × 10⁹/L within 14 days prior to randomisation. Growth factor support is not permitted. ANC ≥ 0.8 x 10⁹/L is allowed for participants with racial neutropenia.

 - Haemoglobin ≥8 g/dL (80 g/L) within 14 days prior to randomisation (participants may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)

 - Platelet count ≥75 × 10⁹/L (≥50 × 10⁹/L if myeloma involvement in the bone marrow is > 50 %) within 14 days prior to randomisation. Platelet support is not permitted

 - Creatinine clearance (CrCl) ≥ 20 mL/min or plasma creatinine ≤120 μmol/L within 14 days prior to randomisation, either measured or calculated using a standard formula (e.g. Cockcroft and Gault)

ETHICAL/OTHER

- Written informed consent

 - Female participants of child-bearing potential must have a negative pregnancy test prior to treatment and agree to use dual methods of contraception for the duration of the study and for 30 days following completion of study. Male participants must also agree to use a barrier method of contraception for the duration of the study and for 30 days following completion of study if sexually active with a female of child-bearing potential.

Exclusion criteria for initial randomisation

DISEASE RELATED

 - Non-secretory multiple myeloma

 - Extramedullary plasmacytoma (without evidence of myeloma)

 - Received therapy for their first relapsed or primary refractory disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone up to a maximum of 200 mg. (Radiotherapy sufficient to alleviate or control pain or local invasion is permitted).

 - Previous bortezomib therapy is permitted, providing participant was not refractory (achieved at least a PR, and no disease progression within 6 months of last dose of bortezomib)

 - Previous carfilzomib therapy

CONCURRENT CONDITIONS

 - Pregnant or lactating females

 - Major surgery within 21 days prior to randomisation

 - Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomisation

 - Known human immunodeficiency virus infection (testing is not required for the trial)

 - Active hepatitis B or C infection

 - Unstable angina or myocardial infarction within 6 months prior to randomisation, 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 participant has a pacemaker, history of torsade de pointe, QTc prolongation (>450 msec), LVEF <40

 - Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomisation

 - Previous or concurrent malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localised transitional cell carcinoma of the bladder or benign tumours of the adrenal or pancreas

 - Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to randomisation

 - Participants with haemorrhagic cystitis

 - Any history or known hypersensitivity to any of the study medications or excipients

 - Participants undergoing active treatment for infiltrative lung disease

 - Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and anti-platelet options, antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment

 - Contraindication to a programme of oral or IV hydration

 - Participants with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomisation

 - Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a participant’s ability to give informed consent