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

  • End date
    Oct 22, 2031
  • participants needed
  • sponsor
    PETHEMA Foundation
Updated on 24 March 2021


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).


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-melfaln-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

Condition Newly Diagnosed Multiple Myeloma
Treatment prednisone, melphalan, Dexamethasone, Bortezomib, Daratumumab, Carfilzomib, Lenalidomide.
Clinical Study IdentifierNCT03742297
SponsorPETHEMA Foundation
Last Modified on24 March 2021


Yes No Not Sure

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
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
mg/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
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%
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