Clinical trial NCT03188172: MUK Nine b: OPTIMUM Treatment Protocol
Official title: MUK Nine b: OPTIMUM. A Phase II Study Evaluating Optimised Combination of Biological Therapy in Newly Diagnosed High Risk Multiple Myeloma and Plasma Cell Leukaemia.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Myeloma UK
name: Celgene
name: Janssen, LP
First posted: 2017-06-15
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The trial is designed as a single arm phase II trial with interim assessments for futility, using a Bayesian strategy for monitoring multiple outcomes.
Primary purpose: TREATMENT

Brief summary: To determine whether a combination of four novel agents bortezomib(Velcade), lenalidomide (Revlimid), Daratumumab (Darzalex) \& dexamethasone in combination with low-dose cyclophosphamide is sufficiently active in a high risk population of myeloma patients, to take forward into a phase III trial compared to standard treatment.

Detailed description: Multiple myeloma (MM) is a plasma cell tumour with an annual incidence in the UK of approximately 40 -50 per million i.e. 4500 new cases per annum. Approximately 20% of the patients diagnosed with multiple myeloma have a significantly worse prognosis at 3 years than other multiple myeloma patients and these are characterised as having high risk (HR) disease defined by genetic lesions and gene expression profiles (GEP). There have been no significant improvements in outcome over the last decade for patients with HR disease. Therefore, it is important to identify more effective treatment options for this group of patients especially given that the number of novel agents are potentially available and which can be given as part of intensive therapy regimen.

Intensive treatment in HR patients has been used outside the UK with promising results but access to drugs in the UK has been challenging with constraints in the NHS treatment pathway. This is the first time in the UK that newly diagnosed multiple myeloma patients may be entered into a clinical trial prospectively according to their genetic risk profile. It provides a unique opportunity to improve outcomes and provide evidence for high cost novel treatment strategies in this restricted population of poor prognosis patients.

The MUKnine trial is designed to evaluate the novel treatment strategies for multiple myeloma patients with HR disease and incorporate a genetic screening component. Patients identified as having HR disease are then invited to take part in the phase II single arm, multi centre trial that investigates the intensive treatment schedule comprising four novel agents bortezomib (Velcade), lenalidomide (Revlimid), daratumumab (Daralex), dexamethasone with cyclophosphamide. The trial will determine if this treatment strategy is sufficiently active to take forward in to further testing in this population. Patients identified as not having HR disease will receive standard local treatment and will be followed up in a cohort study to assess response, progression free survival and overall survival.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression free survival
timeFrame: At 18 months post registration
Secondary outcomes:
measure: Occurrence of Serious Adverse Events(SAE) and Suspected, Unexpected Serious Adverse Reactions (SUSAR)
timeFrame: At 120 days post autologous stem cell transplant (ASCT)
measure: Progression free survival at 100 days post autologous stem cell transplant
timeFrame: At 100 days post ASCT
measure: Minimal residual disease (MRD) negative disease
timeFrame: At 100 days post ASCT
measure: Overall survival
timeFrame: At 12 months, 24 months & 36 months post registration
measure: Maximum response
timeFrame: From registration to end of induction therapy, 100 days post ASCT, post consolidation part 2
measure: Overall response
timeFrame: At end of induction therapy, 100 days post ASCT, post consolidation part 2
measure: Second progression free survival
timeFrame: From registration until second disease progression, 3 years
measure: Overall treatment benefit
timeFrame: At the end of induction therapy and 100 days post autologous stem cell transplant
measure: Quality of life using the EQ-5D questionnaire
timeFrame: From registration until second disease progression, 3 years
measure: Quality of life using the EORTC QLQ-C30 questionnaire
timeFrame: From registration until second disease progression, 3 years
measure: Quality of life using the QLQ-MY20 questionnaire
timeFrame: From registration until second disease progression, 3 years
Other outcomes:
measure: Progression free survival (comparison with Myeloma XI/XI+ data)
timeFrame: From registration until second disease progression, 3 years
measure: Impact of minimal residual disease on progression free survival
timeFrame: From registration until second disease progression, 3 years
measure: Genomic instability
timeFrame: From registration until second disease progression, 3 years
Locations:
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Hampshire County Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: Bristol Haematology & Oncology Centre
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Glasgow
country: United Kingdom
facility: Beatson Oncology Centre
city: Kettering
country: United Kingdom
facility: Kettering General Hosptial
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: London
country: United Kingdom
facility: Kings College Hosptial
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hosptial
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
city: Worcester
country: United Kingdom
facility: Worcester Royal Hospital
Study officials:
affiliation: University of Leeds
name: Martin Kaiser
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rata M, Blackledge M, Scurr E, Winfield J, Koh DM, Dragan A, Candito A, King A, Rennie W, Gaba S, Suresh P, Malcolm P, Davis A, Nilak A, Shah A, Gandhi S, Albrizio M, Drury A, Roberts S, Jenner M, Brown S, Kaiser M, Messiou C. Implementation of Whole-Body MRI (MY-RADS) within the OPTIMUM/MUKnine multi-centre clinical trial for patients with myeloma. Insights Imaging. 2022 Jul 28;13(1):123. doi: 10.1186/s13244-022-01253-0.
citation: Oliva S, Kaiser MF. Is it time to tailor treatment on the basis of minimal residual disease in multiple myeloma? Lancet Haematol. 2021 Dec;8(12):e876-e877. doi: 10.1016/S2352-3026(21)00341-0. No abstract available.
citation: Pawlyn C. High-risk myeloma: a challenge to define and to determine the optimal treatment. Lancet Haematol. 2021 Jan;8(1):e4-e6. doi: 10.1016/S2352-3026(20)30361-6. Epub 2020 Dec 22. No abstract available.