MUK Nine b: OPTIMUM Treatment Protocol

Inclusion Criteria: 1. Confirmation of High Risk status from Institute of Cancer Research (ICR) following bone marrow and blood sample processed through the MUKnine a screening protocol. 2. Previously untreated participants, although participants may have received up to 2 cycles of cyclophosphamide, thalidomide, dexamethasone (CTD), cyclophosphamide, velcade, dexamethasone (CVD), cyclophosphamide, lenalidomide, dexamethasone (CRD) or velcade, thalidomide, dexamethasone (VTD) pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUKnine a Screening Protocol. (In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160mg or radiotherapy sufficient to alleviate or control pain or local invasion is permitted). 3. Measurable disease with at least one of the following or willing to undergo further bone marrows for assessment: \- Paraprotein ≥ 5g/L or ≥ 0.5 g/L for IgD subtypes. \- Serum free kappa or lambda light chains ≥ 100 mg/L with abnormal ratio (for light chain only myeloma). \- Urinary Bence Jones protein ≥ 200 mg/L. 4. Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance. 5. Aged 18 years or over. 6. Fit for intensive chemotherapy and autologous stem cell transplant (at clinician's discretion). 7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. 8. The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this: * Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe. * Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy o Males must also agree to refrain from donating semen or sperm while on trial treatment including during any dose interruptions and for at least 6 months after discontinuation from this trial * All participants must agree to refrain from donating blood while on trial drug including during dose interruptions and for 28 days after discontinuation from this trial. 9. Calculated creatinine clearance ≥ 30mL/min (using Cockcroft-Gault formula). 10. Alanine transaminase (ALT) and/or Aspartate transaminase (AST) ≤ 2.5 times upper limit of normal (ULN). 11. Bilirubin ≤ 2.0 x ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 times ULN 12. Platelet count ≥ 75 x 109/L. (≥ 50 x 109/L if myeloma involvement in the bone marrow is \>50%). Platelet support is permitted. 13. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. Growth factor support is permitted. 14. Haemoglobin ≥ 80 g/L. (Participants may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines. 15. Corrected serum calcium ≤ 3.5 mmol/L. Exclusion Criteria: 1. Solitary bone/solitary extramedullary plasmacytoma. 2. Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom's Disease. 3. 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. * Any cancer from which the subject has been disease free for at least 3 years. 4. Known/underlying medical conditions that, in the investigator's opinion, would make the administration of the study drug hazardous (e.g. uncontrolled diabetes or uncontrolled coronary artery disease). 5. Any clinically significant cardiac disease, including: \- myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV. \- Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4 Grade ≥2) or clinically significant ECG abnormalities. \- screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec. · Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume \[FEV\] in 1 second \<60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Participants with known or suspected COPD or asthma must have a FEV1 test during screening. 6. Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C. 7. Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts), or known sensitivity to mammalian-derived products. 8. Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone. · Previous treatment with daratumumab or any other anti-CD38 therapies. 9. Participants with contraindication to thromboprophylaxis. 10. Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0). 11. Participants with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). 12. Any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study. 13. Known or suspected of not being able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder). Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. 14. Participant is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this trial or within at least 6 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial or within at least 6 months after the last dose of trial treatment. 15. Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery. 16. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study. Inclusion Criteria for ASCT 1. Minimum stem cell harvest of 2 x 106 CD34+ cells/kg body weight. 2. Received a minimum of 4, unless a complete response (CR) has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd) cycles. 3. Achieved a response of stable disease (SD) or better. Exclusion Criteria for ASCT 1. Participants that have progressive disease. Inclusion Criteria for Consolidation Part 1 (VRDd) 1. Undergone autologous transplant with high dose melphalan-velcade (HDM-V) conditioning (Participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation). 2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted. 3. Platelet count ≥ 75 x 109/L. Platelet support is permitted. Exclusion Criteria for Consolidation Part 1 (VRDd) 1\. Participants that have progressive disease. Inclusion Criteria for Consolidation Part 2 (VRD) 1. Received 6 cycles of Consolidation Part 1 (VRDd) or 1 cycle of VRd pre-harvest plus 5 cycles of Consolidation Part 1 (VRDd). 2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted. 3. Platelet count ≥ 75 x 109/L. Platelet support is permitted. Exclusion Criteria for Consolidation Part 2 (VRD) 1\. Participants that have progressive disease. Inclusion Criteria for Maintenance (RD) 1. Received 12 cycles of Consolidation Part 2 (VRD). 2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted. 3. Platelet count ≥ 75 x 109/L. Platelet support is permitted. Exclusion Criteria for Maintenance (RD) 1\. Participants that have progressive disease.