Multiple Myeloma in Relapse
Conditions
Keywords
Relapsed Refractory Multiple Myeloma, Elranatamab
Brief summary
The goal of this phase II, open-label, single-arm, multicenter study is to evaluate i) the efficacy and ii) safety of elranatamab monotherapy at the dose of 76 mg subcutaneously in participants with RRMM after at least one or two prior lines of therapy who have received prior treatment with immunomodulatory drugs, protease inhibitors, and anti-CD38 therapy and were refractory to the last line of therapy, defined as progression while receiving treatment or in the first 60 days after the last dose of treatment. Efficacy refers to the rate of Undetectable Measurable Residual Disease at 6 and 12 months as per International Myeloma Working Group (IMWG) criteria evaluated by the investigators. Safety refers to the measurement of: i) Adverse events (AEs) and serious adverse events (SAEs) according to standard clinical and laboratory tests (hematology and chemistry, physical examination, vital sign measurements, and diagnostic tests). ii) Incidence and severity of Cytokine Release Syndrome (CRS) and Immune effector cell associated neurotoxicity syndrome (ICANS) according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. iii) Incidence and severity of other neurotoxicities. iv) Incidence of cytopenias and infections The study consists of a screening/baseline period, a treatment period, and a posttreatment follow-up period. The study includes a periodic review of safety data, that will be independently analyzed by the Data Safety Independent Committee (DSMC) and will recommend how to proceed with the study.
Detailed description
Treatment with elranatamab will be initiated using a 2-step-up priming regimen: the initial doses of elranatamab will be 12 mg (Cycle 1 Day 1) and 32 mg (Cycle1 Day 4). Participants should be hospitalized and monitored for toxicity (especially CRS/ICANS) for at least 2 days (\ 48 hours) beginning on Cycle 1 Day 1, and for 1 day (\ 24 hours) for Cycle1 Day 4. The dose of elranatamab should be increased to 76 mg on Cycle 1 Day 8 as long as the participant meets the redosing criteria or deferred until the criteria are met. The scheme of administration includes weekly administrations for at least six 4-weeks cycles and, if patients have achieved at least PR (or better) persisting for at least 2 months, the dose interval should be changed from weekly to every other week. Treatment will be scheduled with a response-adapted duration and patients achieving undetectable measurable residual disease and maintained for 12 months will stop therapy. After stopping therapy, and if the patient is in sustained undetectable measurable residual disease for at least 12 months, it would be possible to re-start treatment with elranatamab in case the measurable residual disease will be detectable or relapse from CR will occur. Patients who will not achieve undetectable measurable residual disease sustained for 12 months will receive continuous treatment until progressive disease. In both situations, the occurrence of unacceptable toxicity might result into the treatment discontinuation.
Interventions
The scheme of administration includes weekly administrations for at least six 4-weeks cycles and, if patients have achieved at least PR (or better) persisting for at least 2 months, the dose interval should be changed from weekly to every other week. Treatment will be scheduled with a response-adapted duration and patients achieving undetectable measurable residual disease (MRD) and maintained for 12 months will stop therapy. After stopping therapy, and if the patient is in sustained undetectable MRD for at least 12 months, it would be possible to re-start treatment with elranatamab in case the MRD will be detectable or relapse from CR will occur. Patients who will not achieve undetectable MRD sustained for 12 months will receive continuous treatment until progressive disease.
Sponsors
PETHEMA Foundation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (Open Label)
Intervention model description
This is an open label, multicenter, phase II study of Elranatamab as single agent. The primary aiming is to evaluate the efficacy of elranatamab monotherapy in participants with relapsed refractory multiple myeloma (RRMM) who had received prior treatment with immunomodulatory drugs, protease inhibitors, and anti-CD38 therapy and were refractory to the last line of therapy as evaluated with the rate of complete Response and Undetectable Measurable Residual Disease. Efficacy refers to the rate of Undetectable Measurable Residual Disease at 6 and 12 months as per International Myeloma Working Group (IMWG) criteria evaluated by the investigators.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 years or older (at the time consent is obtained). * Patient who, in the investigator's opinion, is able to comply with the protocol requirements. * Prior diagnosis of MM as defined according to IMWG criteria. * Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. * Relapse multiple myeloma patients that have received at least 1 or 2 prior lines of therapy including at least to one proteasome inhibitor (bortezomib, carfilzomib or ixazomib), one immunomodulatory drug (lenalidomide is mandatory and patients can be also have been exposed to pomalidomide) and at least one anti-CD38 monoclonal antibody (daratumumab or isatuximab). * Patients must be refractory to the last line of therapy, defined as progression while receiving treatment or in the first 60 days after the last dose of treatment. * Patient must have a measurable secretory disease defined as either serum monoclonal protein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24 h. For patients in whom disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal serum FLC ratio.
Exclusion criteria
* Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), POEMS syndrome (defined by the presence of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma-cells proliferative disorder, and skin changes) or plasma cell leukemia. * Prior anti-BCMA treatment. * Subject has peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by the National Cancer Institute Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. * History of Guillain-Barré syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy. * Stem cell transplant within 12 weeks prior to enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the rate of Undetectable Measurable Residual Disease (uMRD) at 6 and 12 months as per International Myeloma Working Group (IMWG) criteria evaluated by the investigators of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 Years | To evaluate the rate of uMRD at 6 and 12 months (defined as the percentage of participants who are MRD negative by next generation flow cytometry (NGF) method and with a sensitivity level of at least 10-5) of elranatamab in patients with relapsed/refractory multiple myeloma. Next generation flow cytometry is a reproducible biomarker to detect the presence of phenotypically abnormal clonal plasma cells (Measurable Residual Disease). The presence of surface markers (CD138, CD27, CD38, CD56, CD45, CD19) and certain morphological characteristics (FSC and SSC) permit the specific identification of plasma cells (PC). This will permit unique, high specificity confirmation of the monoclonality of phenotypically abnormal plasma cells (by light chain restriction). Said cells will have been clearly identified by low antigen expression (CD19, CD27, CD38, CD45, CD81) or overexpression (CD56, CD117, CD138). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity Adverse Events (AEs) and Serious Adverse Event (SAEs) as assessed by changes in laboratory values in blood and biochemistry tests. | 5 Years | Blood test will measure complete blood count, hemoglobin, white blood cell count with differential count and platelet count. Biochemistry test will measure urea, creatinine, uric acid, bilirubin, alkaline phosphatase, LDH, AST, ALT, sodium, chloride, calcium, potassium and, glucose, magnesium, GGT, CRP and CPK. |
| Incidence and severity Adverse Events (AEs) and Serious Adverse Event (SAEs) as assessed by changes in physical examination and ECOG performance status scale (0-5). | 5 Years | Physical examination will include the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, absomen, back, lymph nodes, extremities, vascular and neurological. Heght in centimetres (cm), body weight (kg). ECOG performance status has scale from 0 (fully active) to 5 (dead). |
| Incidence and severity Adverse Events (AEs) and Serious Adverse Event (SAEs) as assessed by changes in vital sign measurements. | 5 Years | Vital signs will include the systolic and diastolic blood pressure, temperature, pulse rate, respiratory rate and oxygen saturation. Vital signs must be measured after resting for at least 5 minutes. Vital signs must be measured more frequently if warranted by the clinical condition of the participant. Vital signs are to be monitored at least every 4 hours (± 15 min) during first 48 hours after the first dose of study intervention (C1D1) and 24 hours after second dose of study intervention (C1D4). |
| Incidence and severity Adverse Events (AEs) and Serious Adverse Event (SAEs) as assessed by pregnancy test. | 5 Years | Pregnancy test will be assessed by Serum beta-human chorionic gonadotropin (β -HCG) pregnancy test for female participants of childbearing potential only. |
| Incidence and severity Adverse Events (AEs) and Serious Adverse Event (SAEs) as assessed by changes in 12-lead ECG. | 5 Years | Electrocardiograms (ECG) must be recorded after 10 minutes rest in the supine position to ensure a table baseline. ECG will be performed at screening and end of treatment, but this test can be repeated throughout the study at the discretion of investigators. A standard 12-lead ECG will include a general diagnostic impression as well as measurement of the heart rate, PR interval, QRS duration, QT interval, and the Fridericia-corrected QT interval (QTcF). The QTcF must be used for clinical decisions. The investigator must calculate QTcF if its is not auto calculated by the ECG machine. |
| Incidence and severity Adverse Events (AEs) and Serious Adverse Event (SAEs) as assessed by changes in Echocardiogram / MUGA. | 5 Years | This test will be will be performed at screening and end of treatment, but can be repeated when clinically indicated based on patient condition. A MUGA scan is also valid. Echocardiogram will include a Left ventricular ejection fraction (LVEF %). |
| To determine Circulating Tumor Cells (CTC) at baseline to evaluate its prognostic value. | 5 Years | Counting of CTC by next generation flow cytometry and correlation of the number of CTC with MRD and survival will be done. |
| To determine serum BCMA levels and its correlation with response. | 5 Years | Values of BCMA in blood samples (serum) will be correlated with MRD and survival. |
| To do gene expression techniques (RNA sequencing and single cell sequencing studies) coupled with intelligent clinical and molecular data analysis (i.e. machine learning) to identify factors that could predict response to elranatamab. | 5 Years | Statistical analysis will be done to find significant changes in gene expression which identify markers of response (MRD negativity or positivity) to elranatamab. |
| To determine MRD value with alternative methods | 5 Years | Mass spectrometry (alternative method) will be used to complement the evaluation of the response by the conventional techniques like electrophoresis, immunofixation and next generation flow cytometry. |
| To evaluate annually by NGF until loss of response, the rate of Undetectable Measurable Residual Disease (% of patients with MRD negative by NGF method and with a sensitivity level of 10-5) of elranatamab in patients with R/R multiple myeloma. | 5 Years | To evaluate annually by Next Generation Flow Cytometry until loss of response, the rate of Undetectable Measurable Residual Disease (defined as the percentage of participants who are MRD negative by next generation flow cytometry method and with a sensitivity level of at least 10-5) of elranatamab in patients with relapsed/refractory multiple myeloma. Next generation flow cytometry is a reproducible biomarker to detect the presence of phenotypically abnormal clonal plasma cells (Measurable Residual Disease). The presence of surface markers (CD138, CD27, CD38, CD56, CD45, CD19) and certain morphological characteristics (FSC and SSC) permit the specific identification of plasma cells (PC). This will permit unique, high specificity confirmation of the monoclonality of phenotypically abnormal plasma cells (by light chain restriction). Said cells will have been clearly identified by low antigen expression (CD19, CD27, CD38, CD45, CD81) or overexpression (CD56, CD117, CD138). |
| To define genomic determinants of response/resistance | 5 Years | This determination will be done by next generation flow cytometry by Fluorescence-Activated Cell Sorting (FACS) sorting of T and Pathological Plasma Cells at inclusion and at progressive disease, and of T cells after the first dose. |
| To evaluate Overall Response Rate of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | Measurement of Overall response rate and the different responses categories according to the IMWG criteria as evaluated by investigator |
| To evaluate Duration of Response of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | Duration of response refers to the time from Complete Remission achievement to loss of response/disease progression. |
| To evaluate Time to first and best response of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | Time to first and best response refers to the time from first Complete Remission achievement to disease progression. The degree of response is also assessed and correltaes with the level of MRD measured by Next Generation Flow Cytometry. |
| To evaluate Progression-free survival (PFS) of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | PFS is defined as the time from the date of first dose of study drug to the date of first documented disease progression, as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. For subjects who have not progressed and are alive, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy. PFS is measured in months |
| To evaluate Overall survival (OS) of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | OS is defined as the time from the date of first dose of study drug to the date of the subject's death. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known to be alive. OS is measured in months. |
| To evaluate PFS in those patients who stop treatment because of sustained MRD-positive for 12 months of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 yerars | The same definitions used above but restricted to patients with poor response to therapy (sustained MRD-positive for 12 months) |
| To evaluate OS in those patients who stop treatment because of sustained MRD-positive for 12 months of elranatamab in patients with relapsed/refractory multiple myeloma. | 5 yerars | The same definitions used above but restricted to patients with poor response to therapy (sustained MRD-positive for 12 months) |
| To evaluate the Incidence of neurologic effects related to elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | Incidence and severity of Cytokine Release Syndrome (CRS) and Immune effector cell associated neurotoxicity syndrome (ICANS) will be collected according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Incidence and degree of other neurotoxicities. |
| To evaluate the Incidence of cytopenias and infections related to elranatamab in patients with relapsed/refractory multiple myeloma. | 5 years | Incidence and degree of cytopenias and infections according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. |
| To characterize patients' immune system | 5 Years | Next generation flow cytometry (NGF) will be used to identify and characterize T, B, NK, monocytes and normal/clonal Plasma Cells (including BCMA antigen expression). NGF for the quantification of soluble factors: IL6, IL2, IFNγ and TNFα. |
Countries
Spain
Contacts
Primary ContactMaría-Victoria Mateos, MD
Backup ContactVerónica González de la Calle, MD
Outcome results
None listed