Inclusion Criteria:
* Previously untreated patients with symptomatic MM (see appendix 3) eligible for stem cell transplantation, with the exception of the following treatments:
* local radiotherapy to relieve bone pain and/or spinal cord compression
* bisphosphonates
* corticosteroids within the last 3 months. Within 14 days prior to study entry, the maximum permitted dose is 160mg (i.e. 4 days of Dexamethasone at 40mg, or equivalent), unless otherwise agreed by the TMG.
* Suitable for high dose therapy and ASCT
* Age ≥ 18 years
* Life expectancy ≥ 3 months
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2)
* Measurable disease as defined by one of the following:
* Secretory myeloma: Monoclonal protein in the serum (≥10 g/L) or monoclonal light chain in the urine (Bence Jones protein ≥200mg/24hours), or serum free light chain (SFLC, involved light chain ≥100mg/L provided the FLC ratio is abnormal)
* Non-secretory myeloma:
* Either ≥30% clonal plasma cells in bone marrow (aspirate or trephine)
* Or 10-30% clonal plasma cells in the marrow and \>1 soft tissue or extra-osseous plasmacytoma ≥ 2 cm that is measurable for response assessment by CT or MRI
* Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to registration
* Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to registration and subject has not received any growth factor support within 7 days of testing. ANC≥0.8x109/L allowed for patients with racial neutropenia.
* Haemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to registration (subjects 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 registration and subject has not received any platelet transfusions within 7 days prior to testing.
* Creatinine clearance (CrCl) ≥ 30 mL/minute within 14 days prior to registration, either measured or calculated using a standard formula (e.g. Cockcroft and Gault).
* Written informed consent
* Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception.
* Male subjects must agree to practice contraception.
Exclusion criteria
* Pregnant or breast-feeding females (lactating women may participate if breastfeeding ceases for the duration of trial treatment and until 12 months after last treatment)
* Previous systemic chemotherapy for myeloma, with the exception of steroids, as detailed above (see section 6.3.1)
* Any major surgery within 21 days prior to registration which in the investigator's opinion would compromise trial treatment and/or the patient's ability to comply with trial visits. Surgery to relieve spinal cord compression or for treatment of bone fractures is permitted.
* Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) 7 days prior to planned start of treatment, unless otherwise agreed by the TMG.
* Known human immunodeficiency virus (HIV) infection
* Active hepatitis B or C infection (refer to appendix 4)
* Unstable angina or myocardial infarction within 4 months prior to registration, 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
* Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration
* Non-haematologic 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 tumors of the adrenal or pancreas
* Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to registration
* Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilise carfilzomib)
* Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary, cardiac or renal impairment
* Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration
* Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
