Screening
-
Undergoing bone marrow investigation due to suspected symptomatic multiple myeloma or plasma cell leukaemia (PCL) or
Participants with biopsy-confirmed symptomatic multiple myeloma, willing to undergo a further study bone marrow biopsy for molecular profiling. Participants previously screened but found not to have symptomatic multiple myeloma but now have suspected symptomatic multiple myeloma may be re-screened
Aged 18 years or over Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion) Eastern Cooperative Oncology Group (ECOG) score ≤2
|
Confirmed solitary bone/solitary extramedullary plasmacytoma. Primary diagnosis of Waldenstrom’s disease. Monoclonal gammopathy of undetermined significance or smouldering multiple myeloma unless progression to symptomatic multiple myeloma is highly suspected or confirmed Received therapy for multiple myeloma Prior or concurrent invasive malignancies Any uncontrolled or severe cardiovascular or pulmonary disease Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0) Known/underlying medical conditions that, in the investigator’s opinion, would make the administration of the study drug hazardous Any clinically significant cardiac disease Known chronic obstructive pulmonary disease (COPD) Known to be seropositive for history of HIV or known to have active hepatitis B or hepatitis C. Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients or known sensitivity to mammalian-derived products. Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, bortezomib, daratumumab or dexamethasone. Previous treatment with daratumumab or any other anti-CD38 therapies. Participants with contraindication to thromboprophylaxis. Participants with POEMS syndrome Any concurrent medical or psychiatric condition or disease Known or suspected of not being able to comply with the study protocol 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. 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. 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. Imaging substudy
Only those taking part in the imaging sub study have these exclusions:
|
Treatment
Confirmation of high-risk (HR) status from ICR. Participants with confirmed PCL with >20% circulating plasma cells do not need confirmation of HR status from ICR to proceed to treatment. Confirmation of receipt of baseline bone marrow at HMDS and, blood and urine samples at the University of Birmingham Previously untreated participants, although participants may have received up to 2 cycles of CTD, CVD, CRD or VTD pretrial induction chemotherapy while awaiting the results of the laboratory analysis. -
Measurable disease before starting standard treatment
Non-measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance. Fit for intensive chemotherapy and autologous stem cell transplant (at clinician’s discretion). ECOG performance status ≤2. The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this: Females of childbearing potential (FCBP) must agree to use 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 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. Laboratory results Calculated creatinine clearance ≥30 mL/min (using Cockcroft-Gault formula). ALT or AST ≤2.5 times upper limit of normal (ULN). Bilirubin ≤2.0 × ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 times ULN Platelet count ≥75 × 109/L. (≥50 × 109/L if multiple myeloma involvement in the bone marrow is >50%). Platelet support is permitted. Absolute neutrophil count ≥1.0 × 109/L. Growth factor support is permitted. Haemoglobin ≥80 g/L. Participants may be receiving red blood cell transfusions in accordance with institutional guidelines. Corrected serum calcium ≤3.5 mmol/L
|
Solitary bone/solitary extramedullary plasmacytoma. Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma or Waldenstrom’s disease. Prior or concurrent invasive malignancies Known/underlying medical conditions that, in the investigator’s opinion, would make the administration of the study drug hazardous Any clinically significant cardiac disease Known COPD Known to be seropositive for history of HIV or known to have active hepatitis B or hepatitis C. Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients or known sensitivity to mammalian-derived products. Clinically significant allergies or known intolerance to cyclophosphamide, lenalidomide, bortezomib, daratumumab or dexamethasone. Previous treatment with daratumumab or any other anti-CD38 therapies. Participants with contraindication to thromboprophylaxis. Participants with POEMS syndrome Any concurrent medical or psychiatric condition or disease Known or suspected of not being able to comply with the study protocol 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. 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. 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. Imaging substudy
Only those taking part in the imaging sub study have these exclusions:
|
Autologous stem cell transplant
Minimum stem cell harvest of 2×106 CD34+ cells/kg body weight. Received a minimum of 4, unless CR has been achieved with a lesser number, or a maximum of 6 induction (CVRDd) cycles (including standard treatment). Achieved a response of stable disease or better. Dose modifications of any or all individual drugs within induction is permitted including complete stop of no more than one agent due to toxicity as long as the required number of cycles have been received
|
|
Consolidation part 1
Undergone autologous transplant with HDM-V conditioning (participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation). Neutrophils≥1.0 × 109/L. Growth factor support is permitted. Platelet count ≥75 × 109/L. Platelet support is permitted. Dose modifications because of toxicity including complete stop of weekly bortezomib is permitted
|
|
Consolidation part 2
Received 6 cycles of consolidation part 1 (VRDd) Neutrophils≥1.0 × 109/L. Growth factor support is permitted. Platelet count ≥75 × 109/L. Platelet support is permitted. Dose modification of any or all of the individual drugs in consolidation part 1 is permitted including complete stop of no more than one agent because of toxicity as long as the required number of cycles have been received.
|
|
Maintenance
Received 12 cycles of consolidation part 2 (VRD). Neutrophils≥1.0 × 109/L. Growth factor support is permitted. Platelet count ≥75 × 109/L. Platelet support is permitted. Dose modification of any or all of the individual drugs in consolidation part 2 is permitted including complete stop of no more than one agent because of toxicity as long as the required number of cycles have been received.
|
|
