NCT03188172 · CITED IN SOURCE DOCUMENTS

MUK Nine b: OPTIMUM Treatment Protocol

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE2
Status at capture: UNKNOWN
Registry last update: 2024-05-14

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

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.
healthy Volunteers: false
maximum Age: 100 Years
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Induction: Cyclophosphamide 500mg, days 1, 8 Bortezomib 1.3mg/m2, days 1, 4, 8, 11 Lenalidomide 25mg, days 1-14 Daratumumab 16mg/kg, days 1, 8, 15 (cycles 1\& 2), day 1 only from cycle 3 Dexamethasone 20-40mg, days 1, 4, 8, 11 ASCT stem cell harvest: with Bortezomib 1.3mg/m2, (12 hours post melphalan) Bortezomib 1.3mg/m2, day +5, +14, weekly Consolidation part 1: Bortezomib 1.3mg/m2 days 1, 8, 15, 22 Lenalidomide 25mg days 1-21 Daratumumab 16mg/kg day 1 Dexamethasone 20-40mg days 1, 8, 15, 22 Consolidation part 2: Bortezomib 1.3mg/m2 days 1, 8, 15 Lenalidomide 25mg days 1-21 Daratumumab 16mg/kg day 1 Maintenance: Lenalidomide 10mg days 1-21 Daratumumab 16mg/kg day 1
intervention Names
Drug: Cyclophosphamide
Drug: Bortezomib
Drug: Lenalidomide
Drug: Daratumumab
Drug: Dexamethasone
Drug: Melphalan
Drug: Filgrastim
label
Trial Treatment
type
EXPERIMENTAL

interventions

arm Group Labels
Trial Treatment
description
Chemotherapy
name
Cyclophosphamide
type
DRUG
arm Group Labels
Trial Treatment
description
Chemotherapy
name
Bortezomib
other Names
Velcade
type
DRUG
arm Group Labels
Trial Treatment
description
Chemotherapy
name
Lenalidomide
other Names
Revlamid
type
DRUG
arm Group Labels
Trial Treatment
description
Chemotherapy
name
Daratumumab
other Names
Daralex
type
DRUG
arm Group Labels
Trial Treatment
description
Chemotherapy
name
Dexamethasone
type
DRUG
arm Group Labels
Trial Treatment
description
Chemotherapy
name
Melphalan
type
DRUG
arm Group Labels
Trial Treatment
description
Haematopoietic agent for the stem cell harvest
name
Filgrastim
type
DRUG

Study design

allocation

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.

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 95
type: ESTIMATED

Registered outcome plans (not posted results)

other Outcomes

description
Matched comparison of progression free survival
measure
Progression free survival (comparison with Myeloma XI/XI+ data)
time Frame
From registration until second disease progression, 3 years
description
Analysis will include any participant with a MRD assessment
measure
Impact of minimal residual disease on progression free survival
time Frame
From registration until second disease progression, 3 years
description
To be investigated in an exploratory manner and will include analysis of new genetic abnormalities
measure
Genomic instability
time Frame
From registration until second disease progression, 3 years

primary Outcomes

description
Defined as the time from registration until first documented evidence of progressive disease or death. Participants not progressed at analysis will be censored at the last date known to be alive and progression free.
measure
Progression free survival
time Frame
At 18 months post registration

secondary Outcomes

description
Will be reported based on occurrence of SAE \& SUSARs with details of causality and expectedness.
measure
Occurrence of Serious Adverse Events(SAE) and Suspected, Unexpected Serious Adverse Reactions (SUSAR)
time Frame
At 120 days post autologous stem cell transplant (ASCT)
description
Determine whether the treatment schedule should be dropped for futility
measure
Progression free survival at 100 days post autologous stem cell transplant
time Frame
At 100 days post ASCT
description
Defined as absence of aberrant phenotype plasma cells
measure
Minimal residual disease (MRD) negative disease
time Frame
At 100 days post ASCT
description
Median overall survival estimates
measure
Overall survival
time Frame
At 12 months, 24 months & 36 months post registration
description
Proportion of participants achieving each response category. Time from registration until the participant achieves a maximum response.
measure
Maximum response
time Frame
From registration to end of induction therapy, 100 days post ASCT, post consolidation part 2
description
Proportion of participants receiving at least a partial response
measure
Overall response
time Frame
At end of induction therapy, 100 days post ASCT, post consolidation part 2
description
Time from registration to second disease progression or death.
measure
Second progression free survival
time Frame
From registration until second disease progression, 3 years
description
Clinician assessment of treatment benefit will be obtained
measure
Overall treatment benefit
time Frame
At the end of induction therapy and 100 days post autologous stem cell transplant
description
Quality of life will be summarised at each post-registration timepoint, adjusting for baseline mean scores and 95% confidence intervals. This will also be summarised descriptively using bar charts, box plots, plots of mean QoL over time and summary tables.
measure
Quality of life using the EQ-5D questionnaire
time Frame
From registration until second disease progression, 3 years
description
Quality of life will be summarised at each post-registration timepoint, adjusting for baseline mean scores and 95% confidence intervals. This will also be summarised descriptively using bar charts, box plots, plots of mean QoL over time and summary tables.
measure
Quality of life using the EORTC QLQ-C30 questionnaire
time Frame
From registration until second disease progression, 3 years
description
Quality of life will be summarised at each post-registration timepoint, adjusting for baseline mean scores and 95% confidence intervals. This will also be summarised descriptively using bar charts, box plots, plots of mean QoL over time and summary tables.
measure
Quality of life using the QLQ-MY20 questionnaire
time Frame
From registration until second disease progression, 3 years

Full study description

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.

Source references

references

citation
Kaiser MF, Phillip RH, Brown SR, Holroyd A, Ferris E, de Tute RM, Roberts S, Clayton L, Bowles K, Garg M, Lokare A, Messiou C, Houlston RS, Jackson G, Cook G, Owen RG, Drayson MT, Pratt G, Hall A, Jenner MW. Induction and extended consolidation with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone in patients with high-risk multiple myeloma (OPTIMUM/MUKnine): 5-year follow-up of a multicentre, externally controlled, phase 2 trial. Lancet Oncol. 2026 Sep 7:S1470-2045(26)00286-X. doi: 10.1016/S1470-2045(26)00286-X. Online ahead of print.
pmid
42705255
type
DERIVED
citation
Keaveney S, Dragan A, Rata M, Blackledge M, Scurr E, Winfield JM, Shur J, Koh DM, Porta N, Candito A, King A, Rennie W, Gaba S, Suresh P, Malcolm P, Davis A, Nilak A, Shah A, Gandhi S, Albrizio M, Drury A, Pratt G, Cook G, Roberts S, Jenner M, Brown S, Kaiser M, Messiou C. Image quality in whole-body MRI using the MY-RADS protocol in a prospective multi-centre multiple myeloma study. Insights Imaging. 2023 Oct 15;14(1):170. doi: 10.1186/s13244-023-01498-3.
pmid
37840055
type
DERIVED
citation
Kaiser MF, Hall A, Walker K, Sherborne A, De Tute RM, Newnham N, Roberts S, Ingleson E, Bowles K, Garg M, Lokare A, Messiou C, Houlston RS, Jackson G, Cook G, Pratt G, Owen RG, Drayson MT, Brown SR, Jenner MW. Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma. J Clin Oncol. 2023 Aug 10;41(23):3945-3955. doi: 10.1200/JCO.22.02567. Epub 2023 Jun 14.
pmid
37315268
type
DERIVED
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.
pmid
35900614
type
DERIVED
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.
pmid
34826409
type
DERIVED
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.
pmid
33357481
type
DERIVED

Source notices and limitations

Discovery and provenance

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nts with high-risk cytogenetic abnormalities.</p> <div class="pdq-content-list"><ol id="_1162"><li>In the multicenter phase II <a href="/clinicaltrials/NCT03188172">OPTIMUM</a> trial (NCT03188172), 412 newly diagnosed patients were screened to identify 103 patients with ultra–high-risk (UHR) myeloma or plasma cell l
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bnormalities.</p> <div class="pdq-content-list"><ol id="_1162"><li>In the multicenter phase II <a href="/clinicaltrials/NCT03188172">OPTIMUM</a> trial (NCT03188172), 412 newly diagnosed patients were screened to identify 103 patients with ultra–high-risk (UHR) myeloma or plasma cell leukemia.[<a href="#cit/section_9
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Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version
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Preserved source evidence · Not medical advice