MUK Nine b: OPTIMUM

ISRCTN	ISRCTN16847817
DOI	https://doi.org/10.1186/ISRCTN16847817
EudraCT/CTIS number	2016-002670-12
IRAS number	215490
ClinicalTrials.gov number	NCT03188172
Secondary identifying numbers	33205

Submission date: 24/04/2017
Registration date: 08/05/2017
Last edited: 16/06/2025

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-new-combination-treatment-newly-diagnosed-high-risk-myeloma-plasma-cell-leukaemia-muk-9-b-optimum

Contact information

Mrs Sadie Roberts
Scientific

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom

Phone	+44 (0)113 343 9645
Email	s.n.roberts@leeds.ac.uk

Study information

Study design	Non-randomised; Interventional; Design type: Treatment, Drug
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific 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 acronym	OPTIMUM
Study objectives	The aim of this study is to look at whether a combination of bortezomib (Velcade), lenalidomide (Revlimid), daratumumab (Darzalex) and dexamethasone with cyclophosphamide is active in high-risk patients, to take forward into a phase III trial compared to standard treatment.
Ethics approval(s)	Approved 25/01/2017, London- South East Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 8177; londonsoutheast.rec@hra.nhs.uk), ref: 17/LO/0023
Health condition(s) or problem(s) studied	Multiple myeloma and malignant plasma cell neoplasms
Intervention	All participants undergo the following treatment: Induction (6 cycles): Cyclophosphamide 500 mg on days 1 and 8, bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, lenalidomide 25 mg on days 1-14 daratumumab 16 mg/kg on days 1, 8 and 15 (cycles 1& 2) and day 1 only from cycle 3, and dexamethasone 20-40 mg on days 1, 4, 8 and 11 ASCT stem cell harvest: with bortezomib 1.3 mg/m2, (12 hours post Melphalan) bortezomib 1.3 mg/m2, day +5, +14, weekly Consolidation part 1 (6 cycles): Bortezomib 1.3 mg/m2 on days 1, 8, 15 and 22, lenalidomide 25 mg on days 1-21, daratumumab 16 mg/kg on day 1, dexamethasone 20-40 mg on days 1, 8, 15 and 22 Consolidation part 2 (12 cycles): Bortezomib 1.3 mg/m2 on days 1, 8 and 15, lenalidomide 25 mg on days 1-21, daratumumab 16 mg/kg on day 1 Maintenance (until disease progression): Lenalidomide 10 mg on days 1-21, daratumumab 16 mg/kg on day 1 Participants will be required to attend a follow-up visit at 3 months post the end of treatment to allow any adverse reactions up to 90 days post the last dose of trial treatment to be documented.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Bortezomib (Velcade), lenalidomide (Revlimid), daratumumab (Darzalex), dexamethasone, cyclophosphamide
Primary outcome measure	Whether a combination of four agents bortezomib, lenalidomide, daratumumab & dexamethasone in combination with low-dose cyclophosphamide is sufficiently active in a high-risk population of myeloma patients, to take forward into a phase, as determined during analysis at the end of the recruitment.
Secondary outcome measures	1. The safety and toxicity profile will be determined by capturing AEs, ARs, SAEs and SUSARs from registrations to 90 days post treatment discontinuation 2. Clinical activity will be measured by collecting bone marrow samples and measuring response from registration until the end of the trial. 3. Treatment compliance is assessed by reviewing the patient’s data at the end of each cycle during the treatment period 4. Overall treatment benefit and a clinician’s assessment of treatment benefit is measured on how both the patient and clinicians feel that the patient is doing on treatment. This is captured at the end of induction therapy and 100 days post-ASCT 5. Quality of life will be captured on QOL questionnaires at the end of induction, 100 days post-transplant, at day 1 of consolidation 1 and 2 and at day 1 of maintenance
Overall study start date	01/10/2014
Completion date	31/05/2029

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 95; UK Sample Size: 95
Total final enrolment	108
Key inclusion criteria	1. Confirmation of High Risk status from 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 CTD, CVD, CRD or VTD pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUK nine a Screening Protocol. (In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160 mg 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: 3.1. Paraprotein ≥5g/L or ≥0.5 g/L for IgD subtypes 3.2. Serum-free kappa or lambda light chains ≥100 mg/L with abnormal ratio (for light chain only myeloma). 3.3. 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: 8.1. 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 8.2. 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 o 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. ALT and/or 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 10(9)/L. (≥50 x 10(9)/L if myeloma involvement in the bone marrow is >50%). Platelet support is permitted. 13. Absolute neutrophil count (ANC) ≥1.0 x 10(9)/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 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 CR has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd) cycles 3. Achieved a response of SD or better Inclusion Criteria for Consolidation Part 1 (VRDd) 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) 2. Neutrophils ≥1.0 x 10(9)/L. Growth factor support is permitted 3. Platelet count ≥75 x 10(9)/L. Platelet support is permitted 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 10(9)/L. Growth factor support is permitted 3. Platelet count ≥75 x 10(9)/L. Platelet support is permitted Inclusion Criteria for Maintenance (RD) 1. Received 12 cycles of Consolidation Part 2 (VRD) 2. Neutrophils ≥1.0 x 10(9)/L. Growth factor support is permitted 3. Platelet count ≥75 x 10(9)/L. Platelet support is permitted
Key exclusion criteria	1. Participants that have progressive disease 2. Solitary bone/solitary extramedullary plasmacytoma 3.Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom’s Disease Medical history and Concurrent disease: 1. Prior or concurrent invasive malignancies except the following: 1.1. Adequately treated basal cell or squamous cell skin cancer 1.2. Incidental finding of low grade (Gleason 3+3 or less) prostate cancer 1.3. Any cancer from which the subject has been disease free for at least 3 years 2. 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) 3. Any clinically significant cardiac disease, including: 3.1. Myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV 3.2. Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade > = 2) or clinically significant ECG (Electrocardiogram) abnormalities 3.3. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec 4. 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 5. Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C 6. Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products 7. Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone 8. 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 (eg, 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, 4 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, within 4 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
Date of first enrolment	30/05/2017
Date of final enrolment	24/09/2019

Locations

Countries of recruitment

England
Scotland
United Kingdom

Study participating centres

The Royal Marsden NHS Foundation Trust

Fulham road
London
SW3 6JJ
United Kingdom

University Hospitals of Leicester NHS Trust

Gwendolen House
Gwendolen Road
Leicester
LE5 4QF
United Kingdom

Southampton University Hospitals NHS Trust

Mailpoint 18 s
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

King's College Hospital NHS Foundation Trust

Denmark Hill
London
SE5 9RS
United Kingdom

University Hospitals Bristol NHS Foundation Trust

Marlborough Street
Bristol
BS1 3NU
United Kingdom

University Hospital Birmingham NHS Foundation Trust

Trust HQ
PO box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom

Heart of England NHS Foundation Trust Birmingham

Heartlands Hospital
Bordesley Green East
Birmingham
B9 5ST
United Kingdom

Nottingham University Hospitals NHS Trust

Trust Headquarters
QMC Campus
Derby Road
Nottingham
NG7 2UH
United Kingdom

Central Manchester University Hospitals NHS Foundation Trust

Trust Headquarters
Cobbett House
Manchester Royal Infirmary
Oxford Road
Manchester
M13 9WL
United Kingdom

NHS Tayside

Department of Haematology
Ninewells Hospital
Dundee
DD2 1UB
United Kingdom

Beatson West of Scotland Cancer Centre

Department of Haematology
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Oxford Radcliffe Hospitals NHS Trust

John Radcliffe Hospital
Headley way
Headington
Oxford
OX3 9DU
United Kingdom

Royal Stoke University Hospital

Newcastle Road
Stoke-on-trent
ST4 6QG
United Kingdom

James Cook University Hospital Laboratory

James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

Freeman Hospital

Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Norfolk & Norwich University Hospital

Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom

Victoria Hospital (blackpool)

Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

Royal Bournemouth General Hospital

Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

East Yorkshire Hospitals NHS Trust (head Office)

Castle Hill Hospital
Castle Road
Cottingham
HU16 5JQ
United Kingdom

Sponsor information

University of Leeds
University/education

Leeds Sponsor Quality Assurance Office
34 Hyde Terrace
Leeds
LS9 6LN
England
United Kingdom

Phone	+44 113 392 6473
Email	daniel.skinner@nhs.net
"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Charity

Myeloma UK
Private sector organisation / Other non-profit organizations

Location: United Kingdom

Results and Publications

Intention to publish date	10/08/2025
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal
IPD sharing plan	Current IPD sharing statement as of 18/07/2022: De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance). Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data. CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security) and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project. The CTRU encourages a collaborative approach to data sharing and believes it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree on suitable requirements for release. Previous IPD sharing statement: The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Abstract results	Early results	28/05/2021	25/04/2023	No	No
Abstract results	Molecular stratification of participants		25/04/2023	No	No
Protocol article		24/03/2021	25/04/2023	Yes	No
HRA research summary			28/06/2023	No	No
Results article		10/08/2023	14/05/2024	Yes	No

Editorial Notes

16/06/2025: The following changes were made:
1. IRAS number added.
2. The overall study end date was changed from 31/05/2026 to 31/05/2029.
3. Barts and the London NHS Trust, Leeds Teaching Hospitals NHS Trust, Guy's and St Thomas' NHS Foundation Trust, Belfast City Hospital and Cambridge University Hospitals NHS Foundation Trust were removed from the study participating centres.
4. Royal Stoke University Hospital, James Cook University Hospital Laboratory, The Christie NHS Foundation Trust, Freeman Hospital, Norfolk & Norwich University Hospital, Victoria Hospital (blackpool), Royal Hallamshire Hospital, Royal Bournemouth General Hospital, and East Yorkshire Hospitals NHS Trust (head Office) were added to the study participating centres.
5. The intention to publish date was changed from 10/08/2023 to 10/08/2025.
6. Northern Ireland was removed from the countries of recruitment.
14/05/2024: Publication reference added.
13/05/2024: The following changes were made:
1. The overall study end date was changed from 01/10/2028 to 31/05/2026.
2. The intention to publish date was changed from 01/05/2023 to 10/08/2023.
25/04/2023: Publication references added.
06/02/2023: The following changes have been made:
1. The overall trial end date has been changed from 31/12/2021 to 01/10/2028.
2. The intention to publish date has been changed from 01/12/2022 to 01/05/2023.
3. Contact details updated.
18/07/2022: IPD sharing statement added.
20/09/2021: Internal review.
06/03/2020: The trial contact has been updated.
02/03/2020: The following changes have been made:
1. The recruitment end date has been changed from 30/11/2019 to 24/09/2019.
2. The intention to publish date has been changed from 01/12/2014 to 01/12/2022.
3. The total final enrolment number has been added.
04/07/2019: ClinicalTrials.gov number added.
26/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissu" to "Multiple myeloma and malignant plasma cell neoplasms" following a request from the NIHR.
13/06/2018: Cancer Research UK lay summary link added to plain English summary field
14/05/2018; Internal review.
16/01/2018: Internal review.
16/10/2017: Internal review.