Clinical trial NCT05558319: NDMM Patients Candidates for ASCT Comparing Extended VRD Plus vs. Isa-VRD vs. Isa-V-Iberdomide
Official title: GEM21menos65. A Phase III Trial for NDMM Patients Who Are Candidates for ASCT Comparing Extended VRD Plus Early Rescue Intervention vs Isatuximab-VRD vs Isatuximab-V-Iberdomide-D
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Newly Diagnosed Multiple Myeloma
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Sanofi
name: Adknoma
name: Start from scratch
First posted: 2022-09-28
Enrollment: 480
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase III open-label, 3-arm, parallel, randomized, controlled trial. The allocation ratio 1:1:1 and outcome assessment are blind to group allocation. Patients will be randomized from 3 arms. Patients will receive VRD extended + ASCT plus ERI or Isatuximab-VRD + ASCT or Isatuximab-VID + ASCT.

Detailed description: Patients will receive induction treatment, which will consist: arm A (Isatuximab-VRD + ASCT) or arm B (VRD extended + ASCT plus ERI) or arm C (Isatuximab-VID + ASCT). After ASTC, patients will start consolidation which will be 2 cycles of similar treatment to induction.

Continuous treatment will follow after consolidation and patients will receive:

* arm A: Lenalidomide and monthly Isatuximab until progression, unacceptable toxicity, patient withdrawal, loss to follow up or death. During continuous treatment, dexamethasone 40 mg is used as a standardized premedication for Isatuximab.
* arm B: after 6 cycles of induction VRD, ASCT and two consolidation VRDs, treatment continues with 10 additional cycles of VRD. During the extension cycles, VRD changes the bortezomib and dexamethasone regimen. In these10 cycles, both bortezomib and dexamethasone will be administered, at the same doses as the previous ones, but on a weekly schedule, on days 1, 8, 15 and 22 of each cycle. The lenalidomide regimen remains unchanged.
* arm C: Iberdomide and monthly Isatuximab until progression, unacceptable toxicity, patient withdrawal, loss to follow up or death. During continuous treatment, dexamethasone 40 mg is used as a standardized premedication for Isatuximab.

The primary objective is to compare the efficacy of extended VRD + ASCT plus ERI (Arm B) vs. Isatuximab-VRD + ASCT (Arm A) in terms of proportion of patients who are MRD-negative by next generation flow cytometry (NGF) after 18 cycles + ASCT.

The primary endpoint, the MRD rate, takes as a reference the evaluation after the last extended VRD cycle, this is: 6 cycles for induction, 6 months for transplantation, 2 cycles for consolidation and 10 cycles until completing the 18 cycles of VRD, (in total about 24 months). For this reason,the primary endpoint in Arms A and C are established after a similar treatment time, which includes 4 cycles of induction, ASCT, 2 cycles of consolidation and 12 cycles of continuous treatment with Iberdomide plus Isatuximab (Dexamethasone to be determined).In patients of Arm B included in ERI, due to the great variability of the possible moments of incorporation in this therapeutic program, only rules are established for the moment and the realization or not of the transplant. The evaluation of the results will be carried out separately in the patients included, butalso in conjunction with the rest of the patients in Arm B to know the effect of the global strategy.

After the evaluation of the primary endpoint, continuous/maintenance treatment continues in Arms A, B and C, including patients in ARM B assigned to the ERI program. Obtaining conventional CR in either arm will require a BM analysis for MRD. In the case of stable response or improvement without RC, MRD controls have been pre-established. Due to the lack of data on tolerance and adherence to long-term treatment with Isatuximab and Iberdomide, changes in the therapeutic programs, for this reason, a complete revision of the therapeutic program has been predetermined at the moment in which the last patient included in the clinical trial reaches 36 months of treatment. At this point, taking into account the updated knowledge about continuous or maintenance treatments, the strategies for a second clinical trial or an extension of this clinical trial will be defined.

Eligibility criteria: Inclusion Criteria:

1. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.
2. Patient must be able to understand the study procedures.
3. Patient has given voluntary written informed consent before performance of any studyrelated procedure non 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.
4. Newly diagnosed multiple myeloma patient who requires start active treatment according to the 2014 IMWG criteria, namely clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcaemia, Anaemia, Renal Insufficiency, or Bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET-CT), and any one or more of the following biomarkers: clonal BMPC% ≥60%, i/u free light ratio ≥100 or \> 1 focal lesions on MRI or PET/CT) \[Lancet Oncol. 2014;15(12): e538-e548\].
5. 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 whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal serum FLC ratio.
6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
7. Patient must be ≤ 65 years of age.
8. Patient must have adequate organ function, defined as follows:

   * Absolute neutrophil count (ANC) ≥1.0 X 109/L without G-CSF use in the prior 7 days
   * Hemoglobin ≥8.0 g/dL (prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted)
   * Platelets ≥ 75 x 109/L in participants in whom \<50% of bone marrow nucleated cells are plasma cells and ≥ 50×109/L in participants in whom ≥50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test).
   * Calcium Corrected serum calcium ≤13.5 mg/dL (≤3.4 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L).
   * Total bilirubin ≤2 X ULN
   * ALT ≤2.5 X ULN
   * AST ≤2.5 X ULN
   * Renal: eGFRa: ≥40 mL/min/ 1.73 m2
   * Cardiac: LVEF (echo) ≥ 50%
9. Female patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female patient is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

   * Is not a woman of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy OR
   * Is a WOCBP and

     * She understands the potential teratogenic risk to the unborn child
     * She understands the need for effective contraception as stated in the protocol, without interruption, 28 days before starting study treatment, throughout the entire duration of study treatment, during dose interruptions and for at least 28 days after the last dose of study treatment.
     * She understands and agrees to inform the Investigator if a change or stop of method of contraception is needed.
     * She must be capable of complying with effective contraceptive measures.
     * She is informed and understands the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy.
     * She understands the need to commence study treatment as soon as it is dispensed following a negative pregnancy test.
     * She understands and accepts the need to undergo pregnancy testing based on the frequency outlined in this plan and in the Informed Consent.
     * She acknowledges she understands the hazards iberdomide or lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of study drugs.

   The Investigator must ensure that a WOCBP: i) Complies with the conditions of the pregnancy prevention plan, including confirmation that she has an adequate level of understanding. ii) Acknowledges the aforementioned requirements.

   A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study drug.

   Nonchildbearing potential is defined as follows (by other than medical reasons):
   * Has not achieved menarche at some point.
   * Has undergone a hysterectomy or bilateral oophorectomy.
   * Has been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
10. Male patient: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

    Male patient is eligible to participate if he agrees to the following from the time of first dose of study until 6 months after the last dose of iberdomide or lenalidomide to allow for clearance of any altered sperm:
    * Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a WOCBP.
    * Understand the need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a pregnant female or a FCBP
    * Understand the potential teratogenic risk, so the subject should not donate semen or sperm.. Understand that the effects on fertility are currently unknown, therefore all family planning options and/or alternatives should be thoroughly discussed with the study doctor prior to receiving iberdomide.
11. All prior 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 except for alopecia.

Exclusion Criteria:

1. Patient has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome at the time of screening.
2. Patient has had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma.
3. Prior history of malignancies, other than multiple myeloma (except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or the breast), unless the patient has been free of the disease for ≥ 5 years.
4. Any serious medical condition that places the subject at an unacceptable risk if he or she participates in this study; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and/or lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatment.
5. Pregnant or breastfeeding females.
6. Men and women of reproductive potential who are not using effective contraceptive methods (double barrier method, intrauterine device, oral contraception).
7. Patient is simultaneously enrolled in other interventional clinical trial.
8. Patient has used an investigational drug within 28 days or five half-lives, whichever is longer, preceding the first dose of study drug.
9. Patient must not have received prior radiotherapy (except localized palliative radiotherapy for pain, palliation or fracture) within 2 weeks of start of study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
10. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
11. Patient has peripheral neuropathy or neuropathic pain grade 1 with pain or ≥2, as defined by the National Cancer Institute Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
12. Patient evidence of cardiovascular risk including any of the following:

    * Myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV).
    * Uncontrolled cardiac arrhythmia.
    * Screening 12-lead ECG showing a baseline interval QTcF\> 470 msec (exception: subjects with pacemaker).
    * Patients with uncontrolled hypertension.
13. Patients who have current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.
14. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect patient's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.
15. Evidence of active mucosal or internal bleeding.
16. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
17. 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).
18. Patient with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
19. Patient with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEV1) less than 50%.
20. History of interstitial lung disease or ongoing interstitial lung disease.
21. Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
22. Patient has an active infection requiring systemic antibiotic, antiviral, or antifungal treatment at the time of starting treatment.
23. Patient has known HIV infection.
24. Patient has positive hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb) at screening or within 3 months prior to first dose of study treatment.
25. Patient has positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Note: Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required.
26. Patient require concurrent administration of a strong inhibitor or inducer of cytochrome P450 (CYP3A4/5) (including within 14 days of initiating study treatment).
27. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to iberdomide or drugs chemically related to iberdomide.
28. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to isatuximab or drugs chemically related to isatuximab, hypersensitivity reactions, or idiosyncratic reactions to other molecular antibodies.
29. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to lenalidomide or dexamethasone or drugs chemically related to lenalidomide or dexamethasone.

Primary outcomes:
measure: Efficacy in terms of patients who are MRD-negative by NGF
timeFrame: 24 months
Secondary outcomes:
measure: Frequency of adverse events (AEs)
timeFrame: Throughout the study. Approximately 78 months.
measure: Progression-Free Survival (PFS)
timeFrame: Throughout the study. Approximately 78 months
Other outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Throughout the study. Approximately 78 months
measure: Complete Response Rate (CRR)
timeFrame: Throughout the study. Approximately 78 months
measure: Time to Response (TTR)
timeFrame: Throughout the study. Approximately 78 months
measure: Duration of Response (DoR)
timeFrame: Throughout the study. Approximately 78 months
measure: Overall Survival (OS)
timeFrame: Throughout the study. Approximately 78 months
Locations:
city: Alcalá de Henares
country: Spain
facility: Hospital Principe de Asturias
state: Madrid
city: Pozuelo De Alarcón
country: Spain
facility: Hospital Universitario Quirón Salud Madrid
state: Madrid
city: Pamplona
country: Spain
facility: Clinica Universidad Navarra (CUN)
state: Navarra
city: Albacete
country: Spain
facility: Hospital General Universitario de Albacete
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol (ICO BADALONA)
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d´Hebron
city: Barcelona
country: Spain
facility: ICO L´Hospitalet
city: Bilbao
country: Spain
facility: Hospital Universitario de Cruces
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Cáceres
country: Spain
facility: Complejo Hospitalario de Cáceres
city: Gijón
country: Spain
facility: Hospital Universitario de Cabueñes
city: Girona
country: Spain
facility: Hospital Universitari Dr. Josep Trueta (ICO Girona)
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Guadalajara
country: Spain
facility: Hospital Universitario de Guadalajara
city: Jerez De La Frontera
country: Spain
facility: H.Universitario de Jerez de la Frontera
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
city: León
country: Spain
facility: Complejo Asistencial Universitario de León
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova (Lleida)
city: Logroño
country: Spain
facility: Hospital San Pedro
city: Lugo
country: Spain
facility: Complejo Hospitalario Lucus Augusti
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz-Ute
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital HLA Universitario Moncloa
city: Madrid
country: Spain
facility: Hospital Universitario 12 de octubre
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario de Fuenlabrada
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Alcorcón
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario La Zarzuela
city: Madrid
country: Spain
facility: Hospital Universitario Puerta del Hierro
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Murcia
country: Spain
facility: H. Morales Meseguer
city: Murcia
country: Spain
facility: H. Un. Virgen de la Arrixaca
city: Murcia
country: Spain
facility: Hospital General Universitario Santa Lucía
city: Málaga
country: Spain
facility: Hospital Costa del Sol
city: Málaga
country: Spain
facility: Hospital Regional de Málaga
city: Málaga
country: Spain
facility: Hospital U Niversitario Virgen de La Victoria
city: Móstoles
country: Spain
facility: Hospital Universitario Rey Juan Carlos
city: Ourense
country: Spain
facility: Complejo Hospitalario Universitario de Ourense
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llatzer
city: Palma De Mallorca
country: Spain
facility: Hospital Universitari Son Espases
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Pontevedra
country: Spain
facility: Complejo Hospitalario de Pontevedra
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario Salamanca
city: San Sebastián De Los Reyes
country: Spain
facility: Hospital Universitario Infanta Sofía
city: San Sebastián
country: Spain
facility: Hospital Universitario de Donostia
city: Santa Cruz De Tenerife
country: Spain
facility: Complejo Hospitalario Universitario Nuestra Señora de la Candelaria
city: Santander
country: Spain
facility: H. Universitario Marqués de Valdecilla
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Santiago (CHUS)
city: Segovia
country: Spain
facility: Hospital General de Segovia
city: Sevilla
country: Spain
facility: Complejo Hospitalario Regional Virgen Del Rocío
city: Sevilla
country: Spain
facility: H. Universitario de Valme
city: Sevilla
country: Spain
facility: Hospital Universitario Reina Sofía
city: Tarragona
country: Spain
facility: Hospital Universitari de Tarragona Joan XXIII
city: Terrassa
country: Spain
facility: Hospital Universitari Mutua Terrassa
city: Toledo
country: Spain
facility: Complejo Hospitalario de Toledo (Virgen de la Salud)
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic la Fe
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset Aleixandre
city: Vitoria
country: Spain
facility: H. U. Txagorritxu
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Universitario 12 de Octubre
name: Juan José Lahuerta Palacios, Dr
role: STUDY_CHAIR
affiliation: Hospital Clinic of Barcelona
name: Joan Bladé, Dr
role: STUDY_CHAIR
affiliation: Hospital Clínico Universitario de Salamanca
name: Mª Victoria Mateos, Dr
role: STUDY_CHAIR
affiliation: Hospital Universitario Marqués de Valdecilla
name: Enrique M Ocio, Dr
role: STUDY_CHAIR
affiliation: Clínica Universitaria de Navarra
name: Jesús San Miguel, Dr
role: STUDY_CHAIR
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citation: Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Mace S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. doi: 10.1016/S0140-6736(19)32556-5. Epub 2019 Nov 14.
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