teclistamab-daratumumab and talquestamab-daratumumab in newly diagnosed high-risk multiple myeloma

Conditions: High-Risk de Novo Multiple Myeloma

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.

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.

Eligibility criteria:
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.

Keywords: high-risk de novo multiple myeloma teclistamab talquetamab daratumumab