Clinical trial NCT03742297: Treatment for Elderly Fit Newly Diagnosed Multiple Myeloma Patients Aged Between 65 and 80 Years
Official title: Induction Therapy With Bortezomib-melphalan and Prednisone (VMP) Followed by Lenalidomide and Dexamethasone (Rd) Versus Carfilzomib, Lenalidomide and Dexamethasone (KRd) Plus/Minus Daratumumab, 18 Cycles, Followed by Consolidation and Maintenance Therapy With Lenalidomide and Daratumumab: Phase III, Multicenter, Randomized Trial for Elderly Fit Newly Diagnosed Multiple Myeloma Patients Aged Between 65 and 80 Years
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Newly Diagnosed Multiple Myeloma
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
First posted: 2018-11-15
Enrollment: 462
Sex: ALL
Minimum age (years): 65
Maximum age (years): 80
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is designed as a randomized, controlled, open-label, assessor blind, multicenter superiority trial with three parallel groups, and primary endpoint of immunophenotypic complete responses at 18 months after randomization. Block randomization will be performed with a 1:1:1 allocation ratio.

Patients will be randomized up front to 3 arms. Patients will receive "standard" PETHEMA arm for fit elderly VMP x 9 + Rd x 9 (arm 1, control arm), a KRd regimen (arm 2a) (18 cycles) or a Carfilzomib-lenalidomida-dexametasona regimen combined with DARATUMUMAB (arm 2b) (18 cycles).

Detailed description: After 18 cycles, patients not having received daratumumab before (arm 1 and 2a), will receive consolidation with 4 cycles of Lenalidomida-dexamethasone at low dose-DARATUMUMAB.

At this point (after 22 months on treatment for the VMP-Rd and KRd arm and after 18 months of the Carfilzomib-lenalidomida-dexametasona-DARATUMUMAB arm) patients will be stratified according MRD status by flow and in both MRD- and MRD+ groups, patients will be randomized with a 1:1 allocation ratio to:

1. no further treatment or
2. continuous treatment with DARATUMUMAB-R (daratumumab plus lenalidomide up to 2 years and then lenalidomide continuous until progression).

Patients on no maintenance that show biological relapse will be rechallenged with DARATUMUMAB-R.

The translational part will be very robust with dysplasia monitoring (especially relevant for the Bortezomib-melfalán-prednisona + Lenalidomida-dexamethasone at low dose arm), clonal evolution/resistance follow up and immune reconstitution longitudinal follow up alongside with MRD status (at diagnosis, 9 months, 18 months, 22 months and treatment discontinuation).

The trial is designed as a two-stage study (induction, followed by consolidation and maintenance). The first stage is confirmatory and addresses the primary efficacy objective. The second stage is exploratory and addresses the secondary efficacy and safety objectives.

In the first stage, investigators will compare an optimized standard induction Bortezomib, talidomida and prednisone followed by Rd (18 cycles) versus KRd, that will be tested in this trial with or without daratumumab x 18 cycles. The main objective in this stage will be to compare the immunophenotypic complete response rate assessed by next generation flow at the end of induction.

The second stage is exploratory and includes the consolidation and maintenance phases. In this second stage, the main objectives are:

1. To compare the above mentioned induction strategies in terms of PFS at the end of the different treatment phases (induction, consolidation and maintenance).
2. To investigate the capacity of consolidation with daratumumab-lenalidomide to reduce MRD levels in patients treated in the control arm as well as those that received KRd without daratumumab. In addition we will explore if this short consolidation can abrogate the potential benefit of a prolonged induction with KRd+daratumumab
3. To explore the value of maintenance therapy according to MRD status (positive or negative) to prolong PFS (after a second randomization to receive or not maintenance therapy with lenalidomide and daratumumab) In order to prevent a potential treatment deficiency for patients randomized to "no-maintenance" in both MRD+ and MRD- subgroups, they will be offered to be re-challenged with lenalidomide-daratumumab as soon as they have a biological progression and have been censored for PFS. Moreover, if 30% of the patients randomized to "no-maintenance" relapse or progress during the first year, the protocol will be amended so that all patients receive maintenance therapy.

Investigators consider that the here proposed multidrug sequential "intensive" approach designed to obtain the best possible and most durable response, assessed through the kinetics of MRD clearance, may have an impact in establishing future clinical practice in fit elderly patients. Moreover, in addition to the MRD analysis (based on next generation flow (NGF), NGS and CT-PET) comprehensive biological investigations, including immunoprofile, clonal selection, analysis of dysplastic features and circulating tumor cells, are planned in order to better understand the relationship between patients outcome and myeloma biology.

The overall treatment plan has been designed for NDMM patients not candidates to SCT strategies but fit enough to tolerate a relatively intensive therapeutic strategy. According to the International Myeloma Working Group guidelines as well as the results obtained in our GEM2010 trial for elderly patients, we have decided to restrict this trial to fit elderly patients aged between 65 and 80 years because in our experience patients older than 80 years usually intensive treatments are poorly tolerated \[1\].

Investigators will evaluate the frailty using a comprehensive health status assessment scale (Geriatric Assessment in Hematology, GAH scale, annex 11), already validated in patients with hematological diseases and preliminary results in multiple myeloma patients

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed multiple myeloma patients who require start active treatment according to the IMWG published in 2014
* Age between 65 and 80 years, both included
* Fit patient assessed using the comprehensive health status assessment scale (Geriatric Assessment in Hematology, GAH scale, annex 11) (0-94 points GAH scale). Patients with a punctuation ≤42 will be included.
* Signed informed consent
* Patients must have measurable disease, defined as follows:

For secretory Multiple Myeloma, measurable disease is defined as the presence of quantifiable monoclonal component, ≥ 0.5 g/dL or, the urine light chains excretion is 200 mg/24h or higher.

For poor secretory or non secretory Multiple Myeloma, the level of the affected serum free light chain must be ≥ 10 mg/dL (≥ 100 mg/L, with an abnormal free light-chain ratio)

* Eastern Cooperative Oncology Group (ECOG) Performance status ≤2
* Life expectancy more than 3 months
* Adequate organ functions:

Platelet count ≥ 50000/mm3, hemoglobin ≥ 8 g/dl and absolute neutrophil count ≥ 1000/mm3. Lower values are allowed only if they are due to BM infiltration.

Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 2.5 x Upper Limit of Normal.

Total bilirubin: ≤2 x Upper Limit of Normal. Serum creatinine ≤ 2 mg/dl. Calcium ≤14mg/dl or corrected serum calcium ≤14mg/dl in patients whose albumin level is out of range Left ventricle ejection fraction ≥ 40%

* At the discretion of the investigator patient must be able to adhere to all study requirements.
* Male patients that receives lenalidomide should commit to use of a condom while taking the study drug every time he has sexual contact with a pregnant female of female of childbearing potential even if he has undergone a successful vasectomy; or practice complete abstinence (when this is the preferred and usual lifestyle of the subject); including during periods of dose interruptions and for at least 30 days after treatment completion. Also males under lenalidomide should commit not to donate semen or sperm during study drug treatment, including during periods of dose interruptions, and for at least 90 days after treatment completion.

NOTE: Given the age of patients to be included on this Clinical Trial (between 65 and 80 years, both included), there is no possibility of Females of Childbearing Potential (FCBP), therefore the Pregnancy Prevention Program (annex 12) has been modified accordingly.

Exclusion Criteria:

* Patients older than 81 years or younger than 65
* Patients that do not qualify for fit according to the GAH scale (annex 11) (\>43 points GAH scale)
* Patients who have previously received treatment for multiple myeloma, except for steroid pulses in case of emergency, the administration of bisphosphonates or antialgesic radiotherapy or due to the presence of plasmacytomas requiring some emergency.
* Men who does not agree to use a condom every time he has sexual contact with a pregnant female or female of childbearing potential, even if he has undergone a successful vasectomy, or men who does not agree to practice complete abstinence (if this is the preferred and usual lifestyle of the subject).
* Left ventricular ejection fraction \<40% 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.
* Other relevant diseases or adverse clinical conditions:

Myocardial infarction within the 6 months prior to inclusion in the clinical trial A NYHA functional class III-IV, heart failure, uncontrolled angina, uncontrolled ventricular arrhythmia or acute ischemia detected electrocardiographically or conduction system anomalies.

History of significant neurological or psychiatric disorders. Active infection. Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis).

Poorly controlled arterial hypertension. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.

* Human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive or active hepatitis C infection
* Limitation of the patient's ability to comply with the treatment or follow-up protocol.
* 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).
* Patients having a peripheral neuropathy ≥ Grade 2 within the 14 days prior to inclusion.
* Known hypersensibility to any of the study drugs or their excipients.
* Patients treated with any investigational drug during the previous 30 days.
* Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
* Patients who are unable or unwilling to undergo antithrombotic therapy.
* Patients with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEVI) less than 50%.

Primary outcomes:
measure: Efficacy in terms of numbers of compleat responses
timeFrame: 18 months
Secondary outcomes:
Other outcomes:
Locations:
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: Albacete
country: Spain
facility: Complejo Hospitalario Universitario de Albacete
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Badalona
country: Spain
facility: Hospital Universitari 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: Cáceres
country: Spain
facility: Complejo Hospitalario de Cáceres
city: Córdoba
country: Spain
facility: Complejo Hospitalario Regional Reina Sofía
city: Gijón
country: Spain
facility: Hospital de Cabueñes
city: Girona
country: Spain
facility: Hospital Universitari Dr. Josep Trueta (ICO Girona)
city: Jerez De La Frontera
country: Spain
facility: Hospital de Especialidades de Jerez de la Frontera
city: Las Palmas De Gran Canaria
country: Spain
facility: Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín
city: León
country: Spain
facility: Complejo Asistencial Universitario de León
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Logroño
country: Spain
facility: Hospital San Pedro
city: Lugo
country: Spain
facility: Complejo Hospitalario Lucus Augusti
city: MAdrid
country: Spain
facility: Hospital 12 de octubre
city: Madrid
country: Spain
facility: Hospital clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
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 Madrid Sanchinarro
city: Madrid
country: Spain
facility: HU Gregorio Marañón
city: Manresa
country: Spain
facility: Hospital San Joan de Deu (Althaia)
city: Murcia
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
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 Virgen de la Victoria
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 Universitario Son Espases
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Pontevedra
country: Spain
facility: Complejo Hospitalario de Pontevedra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
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: Hospital Universitario Marqués de Valdecilla
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Segovia
country: Spain
facility: Hospital General de Segovia
city: Sevilla
country: Spain
facility: H. Universitario Virgen de Rocío
city: Sevilla
country: Spain
facility: Hospital Nuestra Señona de Valme
city: Tarragona
country: Spain
facility: Hospital Universitari Joan XXIII de Tarragona
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
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: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
city: Zaragoza
country: Spain
facility: Hospital Clínico Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Clínica Universidad de Navarra
name: Jesús F San Miguel
role: STUDY_CHAIR
affiliation: Hospital Clinic of Barcelona
name: Joan Blade, Dr
role: STUDY_CHAIR
affiliation: Hospital 12 de Octubre
name: Juan Jose Lahuerta, Dr
role: STUDY_CHAIR
References: