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

Sponsor

PETHEMA Foundation (Other)

Overall Status

Recruiting

CT.gov ID

NCT03742297

Collaborator

(none)

300

Enrollment

Locations

Arms

156

Anticipated Duration (Months)

4.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Newly Diagnosed Multiple Myeloma	Drug: Lenalidomide. Drug: Carfilzomib Drug: Bortezomib Drug: Daratumumab Drug: Dexamethasone Drug: Prednisone Drug: Melphalan	Phase 3

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:

no further treatment or
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:

To compare the above mentioned induction strategies in terms of PFS at the end of the different treatment phases (induction, consolidation and maintenance).
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
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 Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 22, 2018

Anticipated Primary Completion Date :

Oct 22, 2023

Anticipated Study Completion Date :

Oct 22, 2031

Arms and Interventions

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: Lenalidomide. Lenalidomide Drug: Bortezomib Bortezomib Drug: Dexamethasone Dexamethasone Drug: Prednisone Prednisone 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: Lenalidomide. Lenalidomide Drug: Carfilzomib Carfilzomib Drug: Dexamethasone Dexamethasone
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: Lenalidomide. Lenalidomide Drug: Carfilzomib Carfilzomib Drug: Daratumumab Daratumumab Drug: Dexamethasone Dexamethasone

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: Lenalidomide.

Lenalidomide

Drug: Bortezomib

Bortezomib

Drug: Dexamethasone

Dexamethasone

Drug: Prednisone

Prednisone

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: Lenalidomide.

Lenalidomide

Drug: Carfilzomib

Carfilzomib

Drug: Dexamethasone

Dexamethasone

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: Lenalidomide.

Lenalidomide

Drug: Carfilzomib

Carfilzomib

Drug: Daratumumab

Daratumumab

Drug: Dexamethasone

Dexamethasone

Outcome Measures

Primary Outcome Measures

Efficacy in terms of numbers of compleat responses [18 months]
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,

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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%.

Contacts and Locations

Locations

	Site	City	Country
1	Complejo Hospitalario Universitario A Coruña	A Coruña	Spain
2	Complejo Hospitalario Universitario de Albacete	Albacete	Spain
3	Hospital General Universitario de Alicante	Alicante	Spain
4	Hospital Universitari Germans Trias i Pujol (ICO Badalona)	Badalona	Spain
5	Hospital Clinic i Provincial de Barcelona	Barcelona	Spain
6	Hospital de la Santa Creu i Sant Pau	Barcelona	Spain
7	Hospital Universitari Vall d´Hebron	Barcelona	Spain
8	ICO L´Hospitalet	Barcelona	Spain
9	Hospital Universitario de Cruces	Bilbao	Spain
10	Hospital General de Ciudad Real	Ciudad Real	Spain
11	Complejo Hospitalario de Cáceres	Cáceres	Spain
12	Complejo Hospitalario Regional Reina Sofía	Córdoba	Spain
13	Hospital de Cabueñes	Gijón	Spain
14	Hospital Universitari Dr. Josep Trueta (ICO Girona)	Girona	Spain
15	Hospital Universitario Virgen de las Nieves	Granada	Spain
16	Hospital de Especialidades de Jerez de la Frontera	Jerez De La Frontera	Spain
17	Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín	Las Palmas De Gran Canaria	Spain
18	Complejo Asistencial Universitario de León	León	Spain
19	Hospital Universitari Arnau de Vilanova de Lleida	Lleida	Spain
20	Hospital San Pedro	Logroño	Spain
21	Complejo Hospitalario Lucus Augusti	Lugo	Spain
22	Hospital 12 de octubre	MAdrid	Spain
23	Hospital clínico San Carlos	Madrid	Spain
24	Hospital Ramón y Cajal	Madrid	Spain
25	Hospital Universitario 12 de Octubre	Madrid	Spain
26	Hospital Universitario de Fuenlabrada	Madrid	Spain
27	Hospital Universitario de la Princesa	Madrid	Spain
28	Hospital Universitario Fundación Jiménez Díaz	Madrid	Spain
29	Hospital Universitario Infanta Leonor	Madrid	Spain
30	Hospital Universitario La Paz	Madrid	Spain
31	Hospital Universitario Madrid Sanchinarro	Madrid	Spain
32	HU Gregorio Marañón	Madrid	Spain
33	Hospital San Joan de Deu (Althaia)	Manresa	Spain
34	Hospital Clínico Universitario Virgen de la Arrixaca	Murcia	Spain
35	Hospital General Universitario Morales Meseguer	Murcia	Spain
36	Hospital General Universitario Santa Lucía	Murcia	Spain
37	Hospital Costa del Sol	Málaga	Spain
38	Hospital Virgen de la Victoria	Málaga	Spain
39	Complejo Hospitalario Universitario de Ourense	Ourense	Spain
40	Hospital Universitario Central de Asturias	Oviedo	Spain
41	Complejo Asistencial de Palencia	Palencia	Spain
42	Hospital Son Llatzer	Palma De Mallorca	Spain
43	Hospital Universitario Son Espases	Palma De Mallorca	Spain
44	Clinica Universitaria de Navarra	Pamplona	Spain
45	Complejo Hospitalario de Navarra	Pamplona	Spain
46	Complejo Hospitalario de Pontevedra	Pontevedra	Spain
47	Hospital de Sabadell (Parc Taulí)	Sabadell	Spain
48	Hospital Universitario de Salamanca	Salamanca	Spain
49	Hospital Universitario de Donostia	San Sebastián	Spain
50	Complejo Hospitalario Universitario Nuestra Señora de la Candelaria	Santa Cruz De Tenerife	Spain
51	Hospital Universitario Marqués de Valdecilla	Santander	Spain
52	Complejo Hospitalario Universitario de Santiago	Santiago De Compostela	Spain
53	Hospital General de Segovia	Segovia	Spain
54	H. Universitario Virgen de Rocío	Sevilla	Spain
55	Hospital Nuestra Señona de Valme	Sevilla	Spain
56	Hospital Universitari Joan XXIII de Tarragona	Tarragona	Spain
57	Hospital Universitario de Canarias	Tenerife	Spain
58	Complejo Hospitalario de Toledo (Virgen de la Salud)	Toledo	Spain
59	Hospital Clínico Universitario de Valencia	Valencia	Spain
60	Hospital Universitari i Politecnic la Fe	Valencia	Spain
61	Hospital Universitario Dr. Peset Aleixandre	Valencia	Spain
62	Complejo Hospitalario Universitario de Vigo	Vigo	Spain
63	Hospital Txagorritxu	Vitoria	Spain
64	Hospital Clínico Lozano Blesa	Zaragoza	Spain
65	Hospital Universitario Miguel Servet	Zaragoza	Spain