Multiple Myeloma Refractory, Multiple Myeloma in Relapse
Conditions
Keywords
Elranatamab, Mezigdomide, Dexamethasone, minimal residual disease, Refractory Multiple Myeloma, Relapse Multiple Myeloma
Brief summary
The goal of this clinical trial is to learn if the drug combination Elranatamab plus Mezigdomide plus Dexametahsone works to cure patients with relapsed/refractory multiple myeloma. The main questions it aims to answer are: Do participants receiving Elranatamab plus Mezigdomide plus Dexametahsone achieve optimal treatment response by showing negative minimal residual disease at the end of treatment? By evaluating the incidence of adverse events and severe adverse events, is this drug combination tolerable for participants? All participants will receive 1 cycle of Elranatamab plus Dexamethasone followed by 5 cycles of Elranatamab plus Mezigdomide plus Dexamethasone, and 6 cycles of Elranatamab plus Mezigdomide. At this timepoint (end of cycle 12), the level of minimal residual disease will be assessed to decide if patients receive Mezigdomide alone as maintenance (for patients with negative minimal residual disease), or continue reciving Elranatamab plus Mezigdomide.
Detailed description
This is a open-label, phase II clinical trial in which participants with relapsed or refractory multiple myeloma will receive a drug combination of Elranatamab plus Mezigdomide plus Dexametahsone to evaluate the proportion of patients who achieve negative minimal residual disease (defined by the presence of less than 1 tumoral cell out of 100.000 healthy hematopoietic cells). In additon, the tolerability of this drug combination will be assessed by recording the incidence of adverse and severe adverse events. All participants will receive 1 cycle of Elranatamab plus Dexamethasone followed by 5 cycles of Elranatamab plus Mezigdomide plus Dexamethasone, and 6 cycles of Elranatamab plus Mezigdomide. At this timepoint (end of cycle 12), the level of minimal residual disease will be assessed to decide if patients receive Mezigdomide alone as maintenance (for patients with negative minimal residual disease) until unacceptable toxicity, disease progression, patient withdrawal, loss of follow-up, end of study, or death, whichever occurs first; or continue reciving Elranatamab plus Mezigdomide (for patients with positive minimal residual disease) until unacceptable toxicity, disease progression, patient withdrawal, loss of follow-up, end of study, or death, whichever occurs first. In those participants receiving Mezigdomide as maintenance therapy from cycle 13 onwards (good responders) who show biological disease progression (according to the International Myeloma Working Group, IMWG) or positivization of minimal resdual disease, Elranatamab will be introduced to the Mezigdomide maintenance therapy.
Interventions
DRUGDexamethasone
Oral at a dose of 20 mg/day (≤ 75 years old) or 10 mg/day (\>75 years old) weekly from cycle 1 to cycle 6.
DRUGMezigdomide
Oral at a dose of 0.6 mg daily on days 1 to 21 of the 28-day cycle from C2 onwards (not in C1).
DRUGElranatamab
Subcutaneous Elranatamab willl be given as follows: * Cycle 1: day1 (step-up dose 12 mg), day4 (step-up dose 32 mg), day8 (target dose 76 mg), day15 (76 mg), and D22 (76 mg) of a 28-day cycle. * Cycles 2 and 3: day1 and day15 (76 mg) of each 28-day cycle. * From C4 onwards: day1 (76 mg) of each 28-day cycle. * From C13 onwards: those patients who have achieved MRD negativity sustained for at least 3 cycles, will discontinue elranatamab and will continue with mezigdomide alone as maintenance. In those patients who discontinue elranatamab due to sustained MRD negativity, it will be reintroduced as from the cycle 2 in case of biological progression (IMWG criteria) or positivization of MRD.
Sponsors
PETHEMA Foundation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patient is, in the investigator's opinion, willing and able to adhere/comply with visit schedule and other protocol requirements. b. Patient must be able to understand the study procedures. c. Patients aged ≥18 years at the time of signing the informed consent form. d. Patients have documented diagnosis of MM according to the IMWG criteria (Lancet Oncol 2014). e. Patients have a relapsed MM who have previously received treatment with at least one line of antimyeloma therapy. f. Patients must have documented disease progression during or after their last antimyeloma regimen. g. Patients must have received prior treatment with a lenalidomide-containing regimen and must be intolerant or refractory to it, defined as occurrence of disease progression on lenalidomide or within 60 days after the last dose of treatment to lenalidomide. h. Patient must have a measurable disease, defined as follows: * Serum monoclonal protein (M-protein) ≥0,5 g/dl by serum protein electrophoresis (sPEP) or * Urine light-chain excretion ≥200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) or * Serum free light-chain (sFLC) levels \>100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambdda FLC ratio (for patients whose disease is only measurable by serum FLC) i. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2. j. All prior relevant treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 must be ≤grade 1 at the time of enrolment. k. Reproductive Status * Individuals of childbearing potential (IOCBP) must agree and adhere to all testing and contraception requirements for elranatamab based on SmPC and/or IB, and in the mezigdomide Clinical Trial Pregnancy Risk Awareness Checklist. IOCBPs must either commit to true abstinence\* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with 2 effective forms of contraception without interruption: 28 days prior to starting study intervention, during treatment (including dose interruptions), and for at least 28 days after the last dose of mezigdomide\*\* or for at least 4 months (or 150 days) following last elranatamab dose whichever is longer. * Male participants must practice true abstinence\* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant individual or an IOCBP while participating in the study, during dose interruptions and for at least 28 days after the last dose of mezigdomide, or for at least 4 months (or 150 days) following last elranatamab dose whichever is longer, even if he has undergone a successful vasectomy. \*True Abstinence is acceptable when this is in line with the preferred and usual lifestyle of the individual. Periodic abstinence (eg, calendar, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. * Male participants must agree to refrain from donating semen or sperm while taking mezigdomide or during dose interruptions and that they will not donate semen or sperm for at least 28 days after the last dose of mezigdomide. * Females must agree to refrain from donating eggs and breastfeeding a baby while taking mezigdomide, during dose interruptions and for 28 days after the last dose of mezigdomide. Participants must agree to refrain from donating blood while on study treatment, during dose interruptions, and for at least 28 days following the last dose of Mezigdomide or for 4 months (or 150 days) following last dose of elranatamab, whatever happens later.
Exclusion criteria
1. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form. 2. Other plasma cell disorders/associated syndromes, e.g. plasma cell leukemia, POEMS, amyloidosis 3. Prior therapy with mezigdomide or any BCMA bispecific agent. Prior therapy with a BCMA-targeted CAR T-cell therapy or ADC are allowed if \>6 months have elapsed from the last dose. 4. Patients with non-adequate hematological and/or non-hematological parameters defined as the following laboratory abnormalities: * Absolute neutrophil count (ANC) \<1 x109/L without previous granulocyte colony-stimulating factor G-CSF support in the last 7 days prior to screening blood count. * Platelet count \<75 x109/L without previous platelet transfusions in the last 7 days prior to screening blood count. * Hemoglobin \<8.0 g/dl (Erythropoietin or RBC transfusions allowed). * Calculated or measured creatinine clearance / estimated glomerular filtration rate (eGFR) \<30 mL/min (calculated from the Cockcroft and Gault formula) (APPENDIX 5) or requiring dialysis. * Serum aspartate transaminase (AST): \> 2.5 x the upper limit of normal (ULN). * Serum alanine transaminase (ALT): \> 2.5 x ULN. * Serum total bilirubin: \> 2 x ULN * Corrected serum calcium \> 13.5 mg/dL (\> 3.4 mmol/L). 5. Left ventricular ejection fraction (LVEF) \<50%. 6. The following relevant diseases or adverse clinical conditions: * Uncontrolled cardiac arrhythmias (i.e., requiring a change in medication within the last 3 months or a hospital admission within the past 6 months) or clinically significant electrocardiogram abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block. * History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 12 months before screening. * Class III or IV heart failure as defined by the New York Heart Association functional classification system \[NYHA, 1994\]. * Uncontrolled arterial hypertension (defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment). * History of significant neurological or psychiatric disorders. * Ongoing Grade 2 or higher peripheral sensory or motor neuropathy, history of Guillain Barre Syndrome (GBS) or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy. * Active infection requiring antibiotic, antiviral, or antifungal treatment. * Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis) * Uncontrolled endocrine diseases (i.e., diabetes mellitus, hypothyroidism, or hyperthyroidism) (i.e., requiring relevant changes in medication within the last month, or hospital admission within the last 3 months). 7. Patient is known to be positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, active hepatitis A, or active hepatitis C. In case of doubt, viral load must be negative. 8. Administration of live or live-attenuated vaccines within 30 days prior to the day 1 of cycle 1. 9. Prior history of neoplastic disease/malignancies other than MM in the last 5 years (except for basal cell carcinoma, skin epithelioma or carcinoma in situ of any site \[i.e., breast, cervix\]). 10. Use of any antimyeloma therapy within 14 days prior to day 1 of cycle 1. 11. Stem cell transplant within 12 weeks prior to enrolment, active GVHD or active immunosuppressive therapy for GVHD. 12. Radiation therapy, other than local palliative therapy, for myeloma associated bone lesions within 14 days prior to day 1 of cycle 1. 13. Major surgery 14 days prior to initiating study therapy / prior to day 1 of cycle 1. 14. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to mezigdomide or drugs chemically related to mezigdomide, or any of the excipients contained in the formulation of the study treatment. 15. Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other bispecific antibodies. 16. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study; 17. Subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment. 18. Women who are pregnant or breastfeeding, or who intends to become pregnant during participation in the study, and men and women of reproductive potential who are not using effective contraceptive methods (double barrier method, intrauterine device, oral contraception). 19. Patient is simultaneously enrolled in other interventional clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients achieving minimal residual disease (MRD) negativity. | 5 years | To evaluate the percentage of participants achieving negative MRD. Negative MRD is defined as the presence of less than 1 tumour cell among 100,000 healthy hematopoietic cells by Next Generation Flow Cytometry in bone marrow, according to the IMWG criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants showing sustained MRD negativity at 24 months | 5 years | Percentage of participants showing sustained MRD negativity at 24. Negative MRD is defined as the presence of less than 1 tumour cell among 100,000 healthy hematopoietic cells by Next Generation Flow Cytometry in bone marrow, according to the IMWG criteria. |
| Proportion of participants showing MRD negativity after early rescue intervention with elranatamab in patients on mezigdomide alone after C12. | 5 years | Those participants showing good initial treatment response (allocated in the MRD negative at end cycle 12 intervention arm and receiving Mezigdomide maintenance therapy) who show MRD positivization during maintenance therapy with Mezigdomide alone, will be evaluated to detect the rate of MRD negativization after early rescue intervention with Elranatamab. Negative MRD is defined as the presence of less than 1 tumour cell among 100,000 healthy hematopoietic cells by Next Generation Flow Cytometry in bone marrow, according to the IMWG criteria. |
| To evaluate the Complete Response rate to elranatamab in combination with mezigdomide and dexamethasone, based on confirmed response according to the IMWG criteria. | 5 years | Defined as the percentage of patients who show the following 4 parameters: i) absence of monoclonal protein in serum, ii) absence of monoclonal protein in urine, iii) disappearance of any previous soft tissue plasmacytomas, iv) less than 5% plasma cells in bone marrow aspirates or biopsy |
| To evaluate the Very Good Partial Response rate to elranatamab in combination with mezigdomide and dexamethasone, based on confirmed response according to the IMWG criteria. | 5 years | Defined as having the following conditions: i) \>90% reduction of M protein in serum, ii) less than 100 mg of M protein un urine within 24 hours, iiI) no presence of plasmocitomas. |
| To evaluate the Partial Response rate to elranatamab in combination with mezigdomide and dexamethasone, based on confirmed response according to the IMWG criteria. | 5 years | Defined as havong the following: i) \>50% reduction of serum M protein, ii) \<200mg of M-protein in urine in 24-hour. |
| To evaluate the Minimal Response rate to elranatamab in combination with mezigdomide and dexamethasone, based on confirmed response according to the IMWG criteria. | 5 years | Defined as showing a 25% to 49% reduction in serum monoclonal M-protein alongside a 50% to 89% reduction in 24-hour urinary M-protein. |
| To evaluate the Stable Disease rate to elranatamab in combination with mezigdomide and dexamethasone, based on confirmed response according to the IMWG criteria. | 5 years | Defined as \>25% reduction in serum monoclonal M-protein alongside a \>50% reduction in 24-hour urine M-protein. |
| To evaluate the Duration of Response with Elranatamab in combination with mezigdomide and dexamethasone. | 5 years | Defined as the time from the achievement of at least a Partial Response until the earliest date of documented disease progression by IMWG criteria. |
| To evaluate the Progression-free Survival with Elranatamab in combination with mezigdomide and dexamethasone. | 5 years | Defined as the time from the date of Elranatamab treatment initiation until the earliest date of documented disease progression by IMWG criteria or death due to any cause. |
| To evaluate the Overall Survival with Elranatamab in combination with mezigdomide and dexamethasone. | 5 years | Defined as the time from the date of Elranatamab treatment initiation until the date of death due to any cause. |
| Incidence of Adverse Events (AE) related with the treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Number of adverse events registered within the clinical trial study period related with the treatment with elranatamab in combination with mezigdomide and dexamethasone. Adverse Events are defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure, and are evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |
| Discontinuation of therapy due to Adverse Event related with the treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Defined as the percentage of patients discontinuing therapy due to Adverse Events of treatment with elranatamab in combination with mezigdomide and dexamethasone |
| Dose modifications due to Adverse Events related with treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Defined as the percentage of patients requiring dose modifications due to Adverse Events of treatment with elranatamab in combination with mezigdomide and dexamethasone |
| Incidence of Severe Adverse Events of treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Number of severe adverse events, defined as: Any untoward medical occurrence that, at any dose; * Results in death; * Is life threatening; * Requires inpatient hospitalization\* or prolongation of existing hospitalization; * Results in persistent or significant disability/incapacity; * Is a congenital anomaly/birth defect; * Is an important medical event; * Is associated with liver injury and impaired liver function defined as: ALT ≥3 x ULN and total bilirubina ≥2 x ULN (\>35% direct), or ALT ≥3 x ULN and INRb \>1.5. * Any suspected transmission of any infectious agent via a product (medically significant) |
| Changes in laboratory analytes from the hematology and blood chemistry panel related to treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Defined as the number of the changes in laboratory analytes from the hematology and blood chemistry panel related to treatment with elranatamab in combination with mezigdomide and dexamethasone |
| Incidence of deaths related with the treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Defined as the number of deaths related with the treatment with elranatamab in combination with mezigdomide and dexamethasone |
| Primary cause of death of treatment with elranatamab in combination with mezigdomide and dexamethasone | 5 years | Defined as the description of the cause of death related with the treatment with elranatamab in combination with mezigdomide and dexamethasone |
Countries
Spain
Contacts
CONTACTAlfonso Santiago, PhD
PRINCIPAL_INVESTIGATOREnrique Ocio, PhD
Hospital Universitario Marqués de Valdecilla
PRINCIPAL_INVESTIGATORAlbert Oriol, PhD
Institut Català d'Oncologia - Hospital Germans Trias i Pujol
Outcome results
None listed