High-Risk de Novo Multiple Myeloma
Conditions
Keywords
High-Risk de novo Multiple Myeloma, Teclistamab, Talquetamab, Daratumumab
Brief summary
The goal of this Phase 2, open-label, multicenter, non-randomized pilot study is to evaluate the efficacy (in terms of MRD negative CR rate after Intensification therapy) and safety of Tec-Dara (Teclistamab+Daratumumab) and Tal-Dara (Talquetamab+Daratumumab) in de novo high-risk multiple myeloma (DNHRMM) patients.
Detailed description
A total of 30 transplant eligible or elderly fit patients with high risk multiple myeloma will be enrolled 1\. Patients will receive a 4-cycle Dara+VRD (daratumumab, bortezomib, lenalidomide, dexamethasone) INDUCTION therapy. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for VRD. After the 4-cycle Induction, all patients will receive the 1st INTENSIFICATION treatment which consists of 6 cycles of Tec-Dara. Cycles will be of 28 days (4-week cycles) in duration for daratumumab and for teclistamab. 1st Intsensification, patients will receive a 6-cycle Dara+Teclistamab. 2\. At the end of 1st Intensification timepoint treatments depends on MRD status: 2.1) MRD negative patients in CR at the end of Intensification will receive MAINTENANCE therapy with Tec-Dara continuously for 2 years. Cycles will be of 28-days in duration for Tec-Dara. Teclistamab (SC) and daratumumab (SC). 2.2) MRD positive patients or patients who didn't achieve CR despite MRD negativity, will have EARLY RESCUE INTERVENTION (ERI) with Tal-Dara for 6 cycles. MRD and response will be evaluated again after 6 cycles treatment with Tal-Dara. MRD negative patients in CR will receive continuous treatment with Tal-Dara for 2 years. 2.2.1 Early Rescue Intervention with Tal-Dara: Patients who are MRD+ after intensification or who convert from MRD negative into positive or experience a relapse from CR (without fulfilling criteria for disease progression) at any time during Tec-Dara treatment will have ERI with Tal-Dara. Cycles will be of 28 days in duration. 2.2.2. MRD negative patients in CR will receive continuous treatment with Tal-Dara for 2 years. Cycles will be of 28-days of duration for Tal-Dara. 4\. SALVAGE therapy: If the patient remains MRD+ or doesn't achieve CR despite MRD negativity after 6 cycles of ERI with Tal-Dara or has disease progression at any time, further treatment will be offered as per the investigation decision outside of the study.
Interventions
DRUGDaratumumab
Daratumumab will be administered by SC injection.
DRUGBortezomib
Bortezomib dose will be calculated using the patient's actual body surface area (BSA) at baseline and will be administered by subcutaneous (SC) injection.
DRUGLenalidomide
Lenalidomide will be administered by oral route.
DRUGTeclistamab
Teclistamab will be administered by SC injection.
DRUGTalquetamab
Talquetamab will be administered by subcutaneous (SC) injection.
Sponsors
PETHEMA Foundation
Janssen Pharmaceutica N.V., Belgium
Study design
Allocation
NA
Intervention model
SEQUENTIAL
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 comply with the protocol requirements. * Patient has given voluntary written informed consent before performance of any study-related procedure nor 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. * Patient is ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent. * Patient has documented diagnosis of multiple myeloma according to IMWG diagnostic criteria, with at least one of the following high-risk features: 1. High-risk FISH: del(17p), t(4;14), t(14;16) and 1q amplifications. 2. R-ISS 3 3. Presence of extramedullary disease, defined as presence of paramedullary lesions or extramedullary plasmacytoma. Note: In order to have a representative population with high-risk features, 50% of patients included will have ultra-high risk disease defined as: i) R-ISS 3; ii) Double hit (at least two high-risk cytogenetic abnormalities); iii) One high-risk cytogenetic abnormality + extramedullary disease. * Patients eligible for transplant with age ≤ 70 years old (young and transplant-eligible) or patients not eligible for transplant with ECOG-PS modified frailty score of 0-1 (elderly-fit). * Patient has an ECOG performance status of 0, 1or 2.
Exclusion criteria
* Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of 1 cycle of antimyeloma treatment or the emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment while waiting for results of genetic analysis. A cycle of therapy may include treatment with proteasome inhibitors, immunomodulatory drugs, alkylators and corticosteroids, and/or anti-CD38 monoclonal antibodies (i.e, bortezomib-thalidomide-dexamethasone, D-VTD, bortezomib-lenalidomide-dexamethasone, or bortezomib-cyclophosphamide-dexamethasone, are valid options). * Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5. * Patient has a diagnosis of primary light chain amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) at the time of screening. * Myelodysplastic syndrome or active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than relapsed/refractory multiple myeloma. The only allowed exceptions are malignancies treated within the last 24 months that are considered completely cured: 1. Non-muscle invasive bladder cancer (solitary Ta-papillary urothelial neoplasm of low malignancy or low grade, \< 3 cm, no carcinoma in situ). 2. Skin cancer (non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone). 3. Noninvasive cervical cancer. 4. Localized prostate cancer (M0, N0) with a Gleason score of ≤ 7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment). 5. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents. 6. Other malignancy that is considered cured with minimal risk of recurrence. * Patient has CNS or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate efficacy in terms of Measurable Residual Disease (MRD) negative Complete Remission rate by Next Generation Flow Cytometry after Teclistamab plus Daratumumab intensification. | 22 months approximately | MRD measured by Next Generation Flow Cytometry (NGF, with a sensitivity level of 10-6) after 6 cycles of Tec-Dara therapy. |
| Evaluate efficacy in terms of Measurable Residual Disease (MRD) negative Complete Remission rate by Fluorodeoxyglucose Positron Emission Tomography-Computerized Tomography (FDG PET-CT) scan using the Deauville score, after Tec-Dara intensification. | 22 months approximately | MRD measured by Fluorodeoxyglucose Positron Emission Tomography-Computerized Tomography (FDG PET-CT) scan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate MRD negative CR rate after Daratumumab plus bortezomib, lenalidomide and dexamethasone (D-VRD) induction. | 16 months approximately | MRD measured by Next Generation Flow Cytometry. |
| To evaluate MRD negativity after Teclistamab plus Daratumumab (Tec-Dara) intensification using alternative methods | 22 months approximately | MRD negative rates measured by Next Generation Sequencing (NGS), and Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) after 6 cycles of Tec-Dara therapy. |
| To evaluate MRD conversion after early rescue intervention with Talqutamab plus Daratumumab (Tal-Dara) | 4 years approximately | Percentage of patients converting from positive MRD to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan. |
| To evaluate MRD conversion after Tec-Dara intensification | 22 months approximately | Percentage of patients converting from positive MRD after D-VRD induction to negative MRD evaluated by NGF, NGS, QIP-MS-FLC and FDGPET-CT scan after Tec-Dara intensification. |
| To evaluate sustained MRD negativity during maintenance treatment in both Tec-Dara and Tal-Dara treatment arms | 76 months approximately | Proportion of patients with persistent MRD negative disease at month 6, 12, 18 and 24 of maintenance treatment in both Tec-Dara and TalDara treatment, by NGF, NGS, QIP-MS-FLC and FDG-PET-CT scan and annually thereafter. |
| To assess reappearance of MRD positivity or relapse from CR in patients during the Tec-Dara treatment. | 46 months | Proportion of patients relapsing from MRD negative CR to MRD positive or who relapse from CR (not fulfilling criteria for disease progression) during any phase of Tec-Dara treatment (intensification or maintenance). |
| To assess Time to PFS | 76 months approximately | 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 assess Time to EFS | 76 months approximately | EFS is defined as the time from the date of first dose of study drug to the date of first documentation of an event. Definition of event for EFS calculation is: relapse from CR, conversion from Measurable Residual Disease (MRD) negativity (absence of phenotypically aberrant clonal plasma cells by next generation flow with a sensitivity level of 10-6 using the EuroFlow standard operation procedure and complete metabolic response by PET-CT (Deauville score ≤ 3)) to MRD positivity (presence of phenotypically aberrant clonal plasma cells by next generation flow with a sensitivity level of 10-6 using the EuroFlow standard operation procedure and complete metabolic response by PET-CT (Deauville score ≤ 3)), disease progression or death due to any cause, whichever occurs first. For subjects who have not experience any of these events, data will be censored at the last visit. EFS is measured in months. |
| To assess Time to TNT | 76 months approximately | TNT is defined as the time between date of first dose of study drug and the first dose of the next treatment received. TNT is measured in months. |
| To assess Time to DoR | 76 months approximately | DoR is the date of initial documentation of a response (Partial Response or better) to the date of first documented evidence of progressive disease, as defined in the International Myeloma Working Group (IMWG) criteria. Relapse from complete response is not considered as disease progression. For subjects who have not progressed, data will be censored at the last disease evaluation before the start of any subsequent anti-myeloma therapy. DoR is measured in months |
| To assess Time to OS | 76 months approximately | 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 assess the safety of the treatment described in the protocol | 76 months approximately | Incidence of treatment-emergent adverse events |
| Immune profiling and genetic characterization | 76 months approximately | Analysis of immune subpopulation and genetic markers |
Countries
Spain
Contacts
STUDY_CHAIRJuan José Lahuerta Palacios, Dr
Hospital Universitario 12 de Octubre
STUDY_CHAIRJoan Bladé, Dr
Hospital Clinic of Barcelona
STUDY_CHAIRMª Victoria Mateos, Dr
Hospital Clínico Universitario de Salamanca
STUDY_CHAIRPaula Rodríguez Otero, Dr
Clínica Universidad de Navarra
STUDY_CHAIRJesús San Miguel, Dr
Clínica Universidad de Navarra
Outcome results
None listed