Isatuximab and Iberdomide as Immunotherapy for High Risk in Smouldering Myeloma

Overview

The study will test a new combination of 3 drugs: Isatuximab (Isa), Iberdomide (Iber) and Dexamethasone (Dex), in patients who have intermediate or high risk smouldering myeloma. Smouldering myeloma is an early form of myeloma which may progress to active multiple myeloma, but at a slow rate. Patients with smouldering myeloma do not usually receive any treatment but will have regular check-ups and observation. Some patients have a diagnosis of smouldering myeloma which has a higher risk of progressing to active myeloma. The study will test if the combination of drugs is effective at preventing or delaying the disease progressing into active multiple myeloma. The study will also test if the combination is tolerated and accepted by patients.

Interventions

• Drug Isatuximab
  Subcutaneous isatuximab will be delivered using an unlicensed medical device (On Body Delivery System)
• Drug Iberdomide
  Oral iberdomide
• Drug Dexamethasone
  Oral dexamethasone

Primary outcome measures

• Treatment deliverability, measured by treatment discontinuation before completion of 26 cycles [Time frame: From the date of registration until the date of treatment completion/discontinuation (approximately 2 years or earlier if patients discontinue treatment early)]
• Treatment efficacy measured by best overall response rate by the end of treatment [Time frame: From the date of registration until the date of 1 month follow up assessment]

Secondary outcome measures (12)

• Progression Free Survival [Time frame: From the date of registration until the date of first disease progression or death, whichever comes first, assessed up to 5.5 years]
• Time to biochemical progression [Time frame: from the date of registration until the date of biochemical disease progression, assessed up to 5.5 years]
• Progression Free Survival 2 [Time frame: from the date of registration assessed up to 5.5 years]
• Best overall response to subsequent line of therapy [Time frame: From the date of registration until the end of follow up, assessed up to 5.5 years]
• Overall Survival [Time frame: From the date of registration until the date of death, assessed up to 5.5 years]
• MRD negativity rates [Time frame: From the date of screening until the date of 3 Years Post-Registration Follow Up]
• Very Good Partial Response and Complete response + MRD negative rates [Time frame: From the date of screening until the date of 3 Years Post-Registration Follow Up]
• Adverse Event and Adverse Device Effect rates [Time frame: From informed consent until the end of post-treatment safety reporting window (6 months after the last dose)]
• Median and cumulative doses of Iberdomide and Isatuximab [Time frame: From registration until end of treatment (approximately 2 years or earlier if patients discontinue treatment early)]
• Treatment compliance [Time frame: From registration until end of treatment (approximately 2 years or earlier if patients discontinue treatment early)]
• Patient Reported Outcome Measures (EORTC QLQ-C30) [Time frame: From the date of screening until the date of progression or Month 12 Follow up visit, whichever is latest]
• Patient Reported Outcome Measures (EORTC QLQ-MY20) [Time frame: From the date of screening until the date of progression or Month 12 Follow up visit, whichever is latest]

Eligibility criteria

Inclusion criteria

• Able and willing to provide written informed consent and comply with protocol-mandated visits, treatment plan, laboratory tests and other study procedures.
• Age ≥ 18 years
• Diagnosed with smouldering myeloma (SMM) within 5 years of study registration AND diagnosed with intermediate or high risk SMM within 2 years of registration.:

• i.e. patients may have been diagnosed de novo with intermediate or high risk smouldering myeloma within 2 years of study registration OR
• patients may have been diagnosed with low or low-intermediate smouldering myeloma within 5 years of study registration and then their risk classification has changed to intermediate or high risk within 2 years of study registration.
• Diagnosed with intermediate or high-risk SMM defined by IMWG diagnostic criteria and IMWG SMM risk stratification. Intermediate or high risk is defined by the presence of 2 or more of the following factors:

• BM plasma cell infiltrate >20%
• Serum paraprotein >20g/l
• Serum Free Light Chain (SFLC) Ratio >20 (but <100)
• Presence of t(4;14), t(14;16), del 17p, del 13q or 1q gain by fluorescence in situ hybridization (FISH) studies. Copy number abnormalities will be considered significant if present in ≥ 20% of cells.
• Measurable disease with at least one of the following:

• Paraprotein ≥5g/L
• Serum free light chains ≥100mg/L with abnormal light chain ratio
• Bence Jones protein ≥200mg/24hr
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN (if ALT and AST are tested, both must meet this criteria)
• Adequate marrow function:

• Neutrophils ≥1.0 x109/L (unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC ≥0.75 x 109/L is allowed),
• Haemoglobin (Hb) ≥ 100g/L
• Platelets ≥ 75 ×109/L
• Creatinine clearance (CrCl) ≥ 30 mL/minute, according to the Cockcroft-Gault formula, following correction of reversible causes (e.g. dehydration, hypercalcaemia, sepsis)
• Willing to comply with the contraceptive requirements of the trial

Exclusion criteria

• Multiple Myeloma requiring treatment, as defined by IMWG SLiM-CRAB or CRAB criteria.
• Monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma, primary amyloid light-chain (AL) amyloidosis.
• Low or Low-intermediate risk smouldering myeloma by IMWG criteria
• Received previous treatment for myeloma, smouldering myeloma or solitary plasmacytoma.
• Treatment with any other standard anti-cancer radiotherapy/chemotherapy/targeted therapy including investigational therapy (defined as treatment for which there is currently no regulatory authority approved indication) within 4 weeks prior to registration.
• Rapidly rising paraprotein or serum free light chains, defined as any of the following occurring within the space of 2 months:

• doubling of serum M-protein (minimum rise 5g/l)
• increase of serum M-protein by ≥10 g/L
• increase of involved serum-free light chains (FLC) level by ≥200 mg/L (plus abnormal ratio)
• increase of Bence Jones protein by ≥500mg/24hr
• Corticosteroid treatment with a dose >10 mg prednisone or equivalent per day within 28 days of initiation of study drugs.
• Unstable angina or myocardial infarction within 4 months prior to registration, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless patient has a pacemaker.
• 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 requiring no intervention. (Hormone monotherapy is permitted if overall survival is anticipated to be >5 years).
• Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention.
• Any cancer from which the patient has been disease-free for at least 3 years.
• Any major surgery within 21 days prior to registration which in the investigator's opinion would compromise trial treatment and/or the patient's ability to comply with trial visits.
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing.
• Active systemic infection
• Positive serologic and/or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection. (Note: Patients whose HBV infection status cannot be determined by serologic test results \[see CDC website https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf\] must be negative for HBV by PCR to be eligible for study participation). Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody \[HBcAb\]) may be included if HBV DNA is undetectable if they are willing to undergo DNA testing on Day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment and receive appropriate antiviral therapy.
• Positive test results for hepatitis C virus (HCV). Note: Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.
• Positive test results for human immunodeficiency virus (HIV). Note: Patients with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a CD4 count ≥ 200/μL, and have an undetectable viral load. HIV positive patients should be monitored per local/institutional standards while receiving study treatment.
• Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's participation in this study.
• Receipt of live vaccination within 30 days prior to registration, for the duration of the study and for 3 months after the last dose of study drug.
• Contraindication to thromboprophylaxis.
• Participant has risk factors for seizures or seizures that are not well controlled on current medication.
• Women who are pregnant or breastfeeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 2 centers

• Barts Health Trust — London
• Nottingham City Hospital — Nottingham

Identifiers

NCT: NCT06762769 · UCL/153707

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗