Teclistamab-Daratumumab and Talquestamab-Daratumumab in Newly Diagnosed High-risk Multiple Myeloma

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.