Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Monoclonal Gammopathy of Undetermined Significance

Smoldering Multiple Myeloma

Paraproteinemias

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Hypergammaglobulinemia

Precancerous Conditions

Participants will be recruited at the point of either diagnosis or relapse. Any standard investigations that the clinician deems necessary will be carried out. Following recruitment, participants will undergo the first study appointment, the experimental combined MR imaging protocol, the DXA imaging scan and the bone biomarker blood and urine tests.

This will be repeated at 6 months.

Participants will have the experimental combined MR imaging.

Using the expertise of the Oxford Centre For Clinical Magnetic Resonance Research (OCMR) for imaging protocol development, and the new Fine Structural Analysis (FSA, Osteotronix Ltd, formerly Acuitas Medical) bone density quantification MRI method (Rafferty et al 2016), we will test a single protocol which combines three emerging experimental imaging sequences into a simple, non-invasive whole body imaging protocol to quantify disease burden and bone disease. To our knowledge, this has never been done before; if shown to be feasible, such a method would have two important applications: to precisely guide commissioned therapies in the clinic, so improving patient management; and as an exciting, novel research tool for the longitudinal combined assessment of tumour burden and cancer-induced bone disease in response to therapy.

Diffusion Weighted Magnetic Resonance Imaging (DWMRI)

DXA scan

Samples will be taken to assess bone biomarkers

Bloods and urine

Karthik Ramasamy

In the proposed study, the investigators will aim to develop and pilot a Magnetic Resonance (MR) imaging protocol and assess its ability to achieve the following: quantification of tumour burden and bone loss, detecting longitudinal changes in tumour load with therapy and detecting longitudinal changes in microarchitecture with therapy. The investigators also aim to investigate whether bone loss is better, worse or the same with different imaging techniques. This will be investigated by correlating the DXA imaging data with Diffusion-Weighted Magnetic Resonance Imaging (DWMRI) to see if it is possible to achieve quantifiable data of bone density.

In the proposed study, the investigators will aim to develop and pilot a Magnetic Resonance (MR) imaging protocol and assess its ability to achieve the following: quantification of tumour burden and bone loss, detecting longitudinal changes in tumour load with therapy and detecting longitudinal changes in microarchitecture with therapy. The investigators also aim to investigate whether bone loss is better, worse or the same with different imaging techniques. This will be investigated by correlating the DXA imaging data with Diffusion-Weighted Magnetic Resonance Imaging (DWMRI) to see if it is possible to achieve quantifiable data of bone density.

Using the expertise of the Oxford Centre For Clinical Magnetic Resonance Research (OCMR) for imaging protocol development, and the new Fine Structural Analysis (FSA, Osteotronix Ltd, formerly Acuitas Medical) bone density quantification MRI method (Rafferty et al 2016), the investigators will test a single protocol which combines three emerging experimental imaging sequences into a simple, non-invasive whole body imaging protocol to quantify disease burden and bone disease. This has never been done before; if shown to be feasible, such a method would have two important applications: to precisely guide commissioned therapies in the clinic, so improving patient management; and as an exciting, novel research tool for the longitudinal combined assessment of tumour burden and cancer-induced bone disease in response to therapy.

The investigators hypothesize that this imaging tool will be superior to the combined current standard-of-care investigations in the quantification of tumour burden and bone loss. There are currently no tools available for quantifying structural changes to bone and overall bone loss in myeloma.

The Development and Pilot Testing of a New MR Imaging Protocol to Quantify Myeloma Disease Burden and Bone Loss

The Development and Pilot Testing of a New Magnetic Resonance (MR) Imaging Protocol to Quantify Both Myeloma Disease Burden and Associated Bone Loss

This will be calculated using the DW-MRI scans at both baseline and follow up

This will be calculated using the DW-MRI scans at both baseline and follow up 3. Total spine 'collapse' volume 4. FSA: trabecular wall thickness (Rafferty et al, 2016)

All imaging will be repeated at 6 months. The scans will be analysed to see the difference in number of tumour sites before and after therapy (at baseline and at six months). Scans at both time points will be compared to see the difference in ADC, total spinal 'hole' volume, total spine 'collapse' volume and the trabecular wall thickness.

Assess participants Quality of Life (EQ-5D) throughout the study life using data from the EQ-5D-5L questionnaire.

The EQ-5D assess the mobility, self-care, usual activities, pain/discomfort, anxiety and depression via 3 options ranging from 'no problems' to 'unable to do/extreme pain/anxious'. The second part of the EQ-5D assess health on a scale where 100 is the best and 0 is the worst.

Analyse participants experience of the novel MR imaging using data from MRI/DXA scanning questionnaire.

This questionnaire assesses the experience of the novel imaging scan, whether any pain/discomfort was experienced. These answers are recorded on a 5 point likert scale where the lower number represents a better outcome.

Amgen

Oxford University Hospitals NHS Trust

Primary Investigator

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Lenalidomide

Dexamethasone acetate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Rd combination (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles).

KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles).

Carfilzomib

4 cycles 20 mg days 1,2,8,9,15,16,22,23 followed by 5 cycles 10mg days 1,2,8,9,15,16,22,23

9 cycles 25mg days 1-21 followed by 24 extended dosing cycles 10mg days 1-21

A. Broijl

Randomized (2:1) multi-center open-label phase II trial. Patients with high-risk SMM will be enrolled on the study and treated with KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9) or Rd combination (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles).

Background of the study:

A recent study has shown that intervention with the use of novel agents in smoldering myeloma (SMM) resulted in prolonged PFS and OS without significant toxicity. A more recent pilot study in high-risk smoldering myeloma using carfilzomib, lenalidomide in combination with dexamethasone resulted in 100% CR rate and 10 out of 12 patients reached MRD negativity. These studies formed the rationale to compare the efficacy and safety of carfilzomib, lenalidomide and dexamethasone vs. lenalidomide, dexamethasone, both followed by 24 months of lenalidomide maintenance in high-risk SMM.

This study is designed to compare 2 treatment modalities to find the optimal treatment in efficacy and safety for highrisk SMM, to define new risk stratifiers for outcome to treatment in SMM and to better understand the biology of SMM.

Objective of the study:

The primary objective of the study is :

To assess the progression-free survival rate of KRd versus Rd in patients with high-risk SMM

Secondary objectives:

* To assess MRD status after 4 and 9 cycles induction treatment
* To assess the correlation between PFS and MRD
* To determine progression-free survival-2 (PFS2 )
* To determine duration of response (DOR)
* To determine overall survival (OS)
* To assess correlation of MRD status with PFS2, DOR and OS To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone).
* To evaluate disease heterogeneity in relation to clinical outcomes (molecular profiling on bone marrow samples)

Study design:

Randomized multi-center open-label phase 2 trial.

Study population:

Patients with high-risk SMM, age 18 years or older

Intervention (if applicable):

Patients will be treated with KRd combination 9 cycles a 28 days (carfilzomib , lenalidomide , dexamethasone) or Rd combination (lenalidomide , dexamethasone ); followed by extended lenalidomide dosing (for 24 cycles a 28 days).

Primary study parameters/outcome of the study:

- Progression-free survival rate, defined as time from study entry to progression or death, whichever comes first;

Secundary study parameters/outcome of the study (if applicable):

* MRD status after induction cycle 4 and 9,
* Progression-free survival-2 (PFS2), defined at time from randomization to progression after second-line treatment or death, whichever comes first;
* Duration of response (DOR), defined as time from response to progression or death, whichever comes first;
* Overall survival (OS), defined as time from study entry to death from any cause. Patients still alive at the date last contact will be censored;
* Correlation of MRD status with PFS, PFS2, DOR and OS;
* Toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone). Nature and extent of the burden and risks associated with participation, benefit and group relatedness (if applicable): Given the high rates of progression specific to the high risk SMM populations and low toxicity profile of combination therapy, risk of exposure does not seem to outweigh the clinical benefit that patients may derive from therapy. More importantly, much of patient morbidity in MM is associated with pain from irreversible skeletal related events. This study aims to treat or cure the disease before irreversible bone damage occurs or before aggressive clinical MM occurs.

Discomfort from venipuncture, bone marrow biopsy, and CT scan is minimal and of limited risk

Carfilzomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in High- Risk SMM

Carfilzomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in High- Risk Smoldering Multiple Myeloma: A Randomized Phase II Study.

Time from study entry to progression or death, whichever comes first

MRD assessment by immunophenotyping in bone marrow after induction cycles 4 and 9

Time from randomization to progression after second-line treatment or death, whichever comes first

Time from response to progression or death, whichever comes first

Time from study entry to death from any cause. Patients still alive at the date last contact will be censored.

Correlation of MRD status with PFS, PFS2, DOR and OS

Measured by tabulation of the incidence of adverse events with CTCAE grade 1 or more, separately for induction treatment and for extended treatment, by randomization arm.

Stichting Hemato-Oncologie voor Volwassenen Nederland

No intervention

Kwee Yong, Prof

Louise Ainley, MD

Kwee Yong, prof

Observational clinical trial recruiting Smouldering Myeloma patients (SMM) or potential SMM patients. Study involves collecting blood and bone marrow samples to determine the features of the tumour genome and BM microenvironment, including immune dysfunction that are key drivers of progression from precursor conditions (MGUS and SMM) to MM.

MM is a cancer of plasma cells characterised by bone marrow infiltration by malignant plasma cells, kidney impairment, bone pain and elevated calcium levels1. There are approximately 5,500 new cases diagnosed annually in the UK, with a median survival of 5 years2. Significantly, despite improvements in conventional treatment options, MM remains incurable; patients inevitably relapse and will eventually die from their disease.3 MM is always preceded by defined precursor conditions, termed MGUS, and SMM. However, only 7% of MGUS patients and 50% of SMM patients progress to MM over a 5-year period4. In the UK, current practice favours commencing treatment only when there is evidence of end organ damage as the overall benefit of initiating early therapy is uncertain.

There is an increasing understanding that progression is determined by evolving changes in the tumour genome5 and changes in the immune microenvironment which support tumour growth, leading to progressively dysfunctional anti-tumour immunity. This project correlates changes in the tumour genome and immune microenvironment in individual patients with tumour progression and also aims to compare characteristics in patients with good and poor clinical outcomes with the objective of defining the drivers for disease progression. Furthermore, we aim to explore the use of blood samples to monitor tumour dynamics and immune function. Finally, we will also study the spatial distribution of immune cells and tumour cells in the bone marrow.

Clinical impact: A deeper understanding of the pathogenesis of MM will allow us to risk stratify patients with MGUS and SMM, and manage them accordingly as well as identifying subgroups of patients with MM who require different types of therapies, eg. more intensive multi-drug approaches for patients with adverse risk genetics.

BM aspirates and blood samples will be processed to extract tumour and non-tumour cells, as well as plasma and sera. Mononuclear cells (MNCs) will be prepared from these samples by centrifugal sedimentation, or red cell lysis, and plasma cells will be selected using immuno-magnetic beads coupled to monoclonal antibody specific to the plasma cell marker, CD138. In some cases, purified MM cells will be isolated by negative selection using RosetteSep method, which depletes immature progenitors, T-lymphocytes and NK cells. Immune cells, including CD4 and CD8 T cells will be separated by similar means for further assessment.

MM cells, immune cells and bulk MNCs will be frozen and stored for future DNA and RNA extraction. Cell lysates will be made for immuno-blotting and live cells will be frozen for use in functional assays.

Biology and Genetics of Smouldering Myeloma

Characterising Risk and Biology Of Smouldering Myeloma for Early Detection Of Symptomatic Myeloma

To characterise genomic markers of progression by sequencing and studying the biology of bone marrow (BM) derived tumour cells.

To define clonal heterogeneity and biomarkers of progression using liquid biopsies(blood), comparing with BM, and exploring the utility of serial samples.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Development and Pilot Testing of a New MR Imaging Protocol to Quantify Myeloma Disease Burden and Bone Loss	NCT03951220	Myeloma Monoclonal Gamm... Smouldering Mye...	Diffusion Weigh... DXA scan Bloods and urin...	18 Years - 99 Years	Oxford University Hospitals NHS Trust
Carfilzomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in High- Risk SMM	NCT03673826	Smouldering Mye...	Carfilzomib Dexamethasone Lenalidomide	18 Years -	Stichting Hemato-Oncologie voor Volwassenen Nederland
Biology and Genetics of Smouldering Myeloma	NCT05047107	Smouldering Mye... MGUS Multiple Myelom...	No intervention	18 Years -	University College, London

Spots Global Cancer Trial Database for smouldering myeloma