Treatment for Elderly Fit Newly Diagnosed Multiple Myeloma Patients Aged Between 65 and 80 Years

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Newly Diagnosed Multiple Myeloma
• Intervention / Treatment: Drug: Prednisone; Drug: Dexamethasone; Drug: Bortezomib; Drug: Lenalidomide.; Drug: Melphalan; Drug: Carfilzomib; Drug: Daratumumab

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

• Study Type: Interventional
• Enrollment (Actual): 462
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • A Coruña, Spain
    • Complejo Hospitalario Universitario A Coruña
  • Albacete, Spain
    • Complejo Hospitalario Universitario de Albacete
  • Alicante, Spain
    • Hospital General Universitario de Alicante
  • Badalona, Spain
    • Hospital Universitari Germans Trias i Pujol (ICO Badalona)
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain
    • Hospital Universitari Vall d´Hebrón
  • Barcelona, Spain
    • ICO L´Hospitalet
  • Bilbao, Spain
    • Hospital Universitario de Cruces
  • Cáceres, Spain
    • Complejo Hospitalario de Cáceres
  • Córdoba, Spain
    • Complejo Hospitalario Regional Reina Sofía
  • Gijón, Spain
    • Hospital de Cabuenes
  • Girona, Spain
    • Hospital Universitari Dr. Josep Trueta (ICO Girona)
  • Jerez De La Frontera, Spain
    • Hospital de Especialidades de Jerez de La Frontera
  • Las Palmas De Gran Canaria, Spain
    • Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín
  • León, Spain
    • Complejo Asistencial Universitario de León
  • Lleida, Spain
    • Hospital Universitari Arnau de Vilanova de Lleida
  • Logroño, Spain
    • Hospital San Pedro
  • Lugo, Spain
    • Complejo Hospitalario Lucus Augusti
  • MAdrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • Hospital Clinico San Carlos
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Madrid, Spain
    • Hospital Universitario de la Princesa
  • Madrid, Spain
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain
    • Hospital Universitario Infanta Leonor
  • Madrid, Spain
    • Hospital Universitario Madrid Sanchinarro
  • Madrid, Spain
    • HU Gregorio Marañón
  • Manresa, Spain
    • Hospital San Joan de Deu (Althaia)
  • Murcia, Spain
    • Hospital Clinico Universitario Virgen de la Arrixaca
  • Murcia, Spain
    • Hospital General Universitario Morales Meseguer
  • Murcia, Spain
    • Hospital General Universitario Santa Lucía
  • Málaga, Spain
    • Hospital Virgen de la Victoria
  • Málaga, Spain
    • Hospital Costa del Sol
  • Oviedo, Spain
    • Hospital Universitario Central de Asturias
  • Palma De Mallorca, Spain
    • Hospital Son Llàtzer
  • Palma De Mallorca, Spain
    • Hospital Universitario Son Espases
  • Pamplona, Spain
    • Clinica Universitaria de Navarra
  • Pamplona, Spain
    • Complejo Hospitalario de Navarra
  • Pontevedra, Spain
    • Complejo Hospitalario de Pontevedra
  • Salamanca, Spain
    • Hospital Universitario de Salamanca
  • San Sebastián, Spain
    • Hospital Universitario DE Donostia
  • Santa Cruz De Tenerife, Spain
    • Complejo Hospitalario Universitario Nuestra Señora de la Candelaria
  • Santander, Spain
    • Hospital Universitario Marqués de Valdecilla
  • Santiago De Compostela, Spain
    • Complejo Hospitalario Universitario de Santiago
  • Segovia, Spain
    • Hospital General de Segovia
  • Sevilla, Spain
    • H. Universitario Virgen de Rocío
  • Sevilla, Spain
    • Hospital Nuestra Señona de Valme
  • Tarragona, Spain
    • Hospital Universitari Joan Xxiii de Tarragona
  • Tenerife, Spain
    • Hospital Universitario de Canarias
  • Toledo, Spain
    • Complejo Hospitalario de Toledo (Virgen de la Salud)
  • Valencia, Spain
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain
    • Hospital Universitari i Politecnic La Fe
  • Valencia, Spain
    • Hospital Universitario Dr. Peset Aleixandre
  • Vigo, Spain
    • Complejo Hospitalario Universitario de Vigo
  • Vitoria, Spain
    • Hospital Txagorritxu
  • Zaragoza, Spain
    • Hospital Universitario Miguel Servet
  • Zaragoza, Spain
    • Hospital Clinico Lozano Blesa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 61 years to 76 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: VMP x 9 + Lenalidomida-dexamethasone x 9; Bortezomib-melfalán-prednisone. Melfalán: 9mg/m2D1-4. Prednisone: 60mg/m2D1-4. Bortezomib: 1.3mg/m2 One 6 week cycleD1, 4, 8, 11, 22, 25, 29 and 32; followed by eight4-week cycleD1, 8, 15 and 22 Lenalidomida-dexametasona at low dose	Drug: Prednisone; Prednisone; Drug: Dexamethasone; Dexamethasone; Drug: Bortezomib; Bortezomib; Drug: Lenalidomide.; Lenalidomide; Drug: Melphalan; Melphalan
Experimental: Carfilzomib-lenalidomida-dexamethasone regimen; carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15.Lenalidomida: 25 mg, d1-21 Dexamethasone : 40 mg, d1, 8, 15, 2218 28-day cycle	Drug: Dexamethasone; Dexamethasone; Drug: Lenalidomide.; Lenalidomide; Drug: Carfilzomib; Carfilzomib
Experimental: Carfilzomib-lenalidomida-dexamethason with daratumumab; Carfilzomib: 1 st cycle: 20mg/m2 day 1 and 36 mg/m2 days 2, 8, 9 & 15, 16. 2nd cycle: 36 mg/m2 days 1, 2, 8, 9 & 15, 16. Cycles 3-18: 56 mg/m2 days 1, 8 & 15. Lenalidomida: 25 mg, d1-21 Dexamethasone: 40 mg, d1, 8, 15, 22. Daratumumab 1800mg SC Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18	Drug: Dexamethasone; Dexamethasone; Drug: Lenalidomide.; Lenalidomide; Drug: Carfilzomib; Carfilzomib; Drug: Daratumumab; Daratumumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy in terms of numbers of compleat responses	Rate of immunophenotypic complete responses at 18 months, of the standard treatment in Spain for newly diagnosed multiple myeloma patients not candidates to stem cell transplantation,	18 months

Collaborators and Investigators

• Sponsor: PETHEMA Foundation
• Investigators: Study Chair: Joan Bladé, Dr, Hospital Clinic of Barcelona; Study Chair: Jesús F San Miguel, Clinica Universidad de Navarra; Study Chair: Juan Jose Lahuerta, Dr, Hospital 12 de Octubre

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2018
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): January 1, 2031

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: November 13, 2018
• First Posted (Actual): November 15, 2018

Study Record Updates

• Last Update Posted (Actual): September 14, 2022
• Last Update Submitted That Met QC Criteria: September 13, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Lenalidomide; Daratumumab; Prednisone; Melphalan; Bortezomib
• Other Study ID Numbers: GEM2017FIT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No