Study to evaluate the efficacy of 3 different treatments, followed by maintenance treatment, in older adult patients, between 65 and 80 years old, in good general health and newly diagnosed multiple myeloma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion PETHEMA

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Oct 2018 → ongoing

Decision date (initial)

2024-10-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516905-22-00

EudraCT number

2017-000044-18

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Compare the efficacy in terms of immunphenotypic complete response at 18 months of the standard treatment in Spain for patients with newly diagnosed multiple myeloma that are ineligible for bone marrow transplant (VMP followed by Rd) with experimental KRd treatment (carfilzomib, lenalidomide, dexamethasone, alone or in combination with daratumumab) as induction therapy for 18 cycles in a selected patient population in good general health with newly diagnosed multiple myeloma.

Secondary objectives 6

1. Compare Progression Free Survival (PFS) from the date of first randomization to progression and/or death, between the experimental treatment arm and the control arm, midway through induction therapy (9 cycles) at the end of induction (18 cycles), post-consolidation, and yearly for at least 5 years. SLP2, TTP, and OS will also be compared to conventional response (stringent CR, CR, VGPR, and PR).
2. Correlate the elimination kinetics of minimal residual disease (MRD) with PFS midway through induction therapy (9 cycles), at the end of induction (18 cycles and primary endpoint), at post-consolidation and yearly during maintenance for the first five years to evaluate what time represents the optimal surrogate response marker for PFS.
3. Based on assessment of MRD by next generation flow cytometry (NGF). a. 3.a Compare the efficacy of 9 cycles of VMP to 9 cycles of the experimental combination without alkylating agent: carfilzomib plus lenalidomide-dexamethasone (KRd) (with/without daratumumab). b. 3.b Investigate capacity of consolidation with daratumumab-lenalidomide to reduce MRD levels in patients treated in the control group, as well as those who receive KRd without daratumumab. We will also evaluate whether, with this short consolidation, we can manage without a prolonged induction therapy with KRd+daratumumab. c. 3.c Investigate the capacity of maintenance therapy to preserve the response obtained after consolidation both in patients who are MRD-negative and who are MRD-positive.
4. Correlate immunphenotypic response with standard response and classical survival assessment criteria: a. 4.a Standard response categories: Stringent CR, CR, VGPR, PR b. 4.b Time from randomization to disease progression or when the third line of thearpy begins. SLP2. c. 4.c Overall survival (OS).
5. Evaluate the evolution of quality of life based on questionnaires EQ-5D/5L, QLQ-C30 and MY20 at initiation, and at 6, 12, and 18 months during induction therapy, after consolidation, and every 6 months during maintenance.
6. Evaluate safety in each treatment arm and each phase of treatment.

Conditions and MedDRA coding

Multiple myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patients with newly diagnosed multiple myeloma that need to initiate treatment in accordance with that published in 2014 by the IMWG
2. Aged between 65 and 80 years old, inclusive.
3. Patient in good overall health, assessed by the health status scale (Geriatric Assessment in Hematology GHA scale, appendix 11). (0-94 points GAH scale) [2]. Patients with a score of ≤42 will be included.
4. Signed informed consent
5. Patients must have measurable disease, defined as: a. For secretory multiple myeloma, measurable disease is defined as the presence of quantifiable M-protein ≥0.5 g/dl, or excretion of free light chains in urine 200 mg/24h or greater. b. For oligo-secretory or non-secretory multiple myeloma, the level of involved plasma free light chains must be ≥10 mg/dl (≥100 mg/L, with an abnormal ratio of free light chains).
6. Functional status ≤2 as defined by Eastern Cooperative Oncology Group (ECOG) (see appendix 6).
7. Life expectancy greater than 3 months.
8. Adequate organ function: a. Platelet count ≥ 50,000/mm3, hemoglobin ≥ 8 g/dl and absolute neutrophil count ≥ 1,000/mm3. The lowest values will be permitted only if they are due to BM infiltration. b. Aspartate transaminase (AST) and alanine aminotransferase ≤ 2.5 times above the upper limit of normal. c. Total bilirubin: ≤ 2 time above the upper limit of normal. d. Serum creatinine ≤ 2 mg/dl. e. Calcium ≤14mg/dl or corrected plasma calcium ≤14mg/dl in patients whose albumin levels are out of range (see appendix 9).
9. In their judgement, the investigator feels that the patient is able to comply with all of the protocol requirements.
10. Left ventricle ejection fraction ≥ 40%.
11. Male patients that receive lenalidomide must agree to use condoms each time they have sexual relations with a pregnant woman or a woman able to become pregnant during the time they are taking the study drug, even if said male patients have undergone a successful vasectomy. If not, they must agree to practice total abstinence (if this is part of the patient’s choice of or normal lifestyle). This commitment must be maintained including during periods when administration of the investigational drug is interrupted and for at least 30 days after treatment has ended. In addition, male patients that receive treatment with lenalidomide must agree not to donate semen or sperm during treatment with the study drug, including during periods of dose interruptions, for at least 90 days after the end of treatment. NOTE: Keeping in mind the age of patients that will be included in this clinical trial (between 65 and 80, inclusive), there is no possibility that women of childbearing potential will be participating. For this reason the pregnancy prevention program (appendix 12) has been modified as a result.

Exclusion criteria 16

1. Patients older than 81 or younger than 65.
2. Patients who are not in good general health according to the GAH scale (appendix 11) (>43 points on the GAH scale).
3. Patients who have previously received anti-myeloma treatment, with the exception of steroid pulses in the event of emergency, administration of bisphosphonates or analgesic radiotherapy, or due to the presence of plasmacytomas that caused an emergency.
4. Male patients who do not commit to using a condom during sexual relations with pregnant women or women of childbearing potential, even if said male patients have undergone as successful vasectomy. If not, the must agree to practice total abstinence (if this is part of the patient’s choice of or normal lifestyle).
5. Left ventricle ejection fraction ≥ 40%.
6. Previous medical history of disease other than multiple myeloma (except basal or squamous cell carcinoma, cervical or breast carcinoma in situ, unless the patient has been disease-free for ≥ 5 years.
7. Other relevant diseases or adverse medical conditions: a. Myocardial infarction in the 6 months prior to enrolment in the trial. b. Functional class III-IV s per the NYHA, heart failure, uncontrolled angina, uncontrolled ventricular arrhythmia or acute ischemia detected by electrocardiogram or conduction system anomalies. c. History of significant neurological or psychiatric diseases. d. Active infection. e. Significant non-malignant liver disease (for example cirrhosis, active chronic hepatitis). f. Uncontrolled arterial hypertension. g. Any serious medical condition or psychiatric disorder that might interfere with the patient's understanding of the informed consent form.
8. Positive for Human Immunodeficiency Virus (HIV) or hepatitis B surface antigen, or active hepatitis C virus infection.
9. Limitation in the patient’s capacity to comply with the treatment or follow-up protocol.
10. Uncontrolled endocrine disease (for example diabetes mellitus, hypo- or hyperthyroidism). These diseases have required relevant changes in medication in the last month or have required hospitalization of the patient in the last 3 months.
11. Patients with ≥ Grade 2 peripheral neuropathy in the 14 days prior to inclusion in the study.
12. Known hypersensitivity to any of the study drugs or their excipients.
13. Patients treated with any other study drug in the 30 days prior to inclusion.
14. Patients with diffuse infiltrative lung disease and/or pericardial effusion.
15. Patients that are unable or unwilling to undergo anti-thrombotic therapy.
16. Patients with severe chronic obstructive pulmonary disease (CPOD) or asthma with forced expiratory volume in the first minute (VEF1) less than 50%.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The difference between each experimental arm and the control group in terms of immunphenotypic complete response (MRD negative by cytometry) after 18 cycles of induction therapy. Evaluation will be carried out using next generation flow cytometry through a study developed by the EuroFlow Consortium in accordance with response guidelines recently proposed by the IMWG [3].

Secondary endpoints 8

1. Difference between each experimental arm and the control group in terms of the probability of Progression Free Survival from the date of randomization until progression or death, midway through induction (9 cycles) at the end of induction (18 cycles), post-consolidation, and yearly during maintenance. As well, differences in terms of of probability of SLP2, TTP, OS and proportions of standard response (stringent CR, CR, VGPR and PR).
2. Kinetics of MRD elimination after: a. 9 cycles (midway through induction). b. 18 cycles (end of induction, primary endpoint). c. post-consolidation d. yearly during maintenance therapy, for at least five years.
3. The evaluation of MRD using NGF will allow us to evaluate: a. 3.a The difference between each experimental group and the control group in terms of proportion of immunphenotypic complete response (MRD negativity by cytometry) after 9 cycles of induction therapy.
4. The evaluation of MRD using NGF will allow us to evaluate: 3.b Reduction in MRD levels in patients treated in the control group, as well as in patients who receive KRd without daratumumab between the end of induction therapy and the end of consolidation therapy In addition, the difference in the levels of MRD between the two above-mentioned arms at the end of short consolidation therapy (22 months) and the KRd+ daratumumab arm at the end of a prolonged period of induction therapy (18 months).
5. The evaluation of MRD using NGF will allow us to evaluate:3 .c Difference, evaluated yearly after the start of maintenance therapy, in preservation of response obtained after consolidation in both patients with negative MRD and those with positive MRD.
6. Correlation of classic efficacy/survival criteria with immunphenotypic response: a. Standard response categories: Stringent CR, CR, VGPR, PR b. Time from randomization to second disease progression or the moment when the third line of treatment is initiated. SLP2. c. Overall Survival
7. Difference in the quality of life scores in the questionnaires EQ-5D/5L, QLQ-C30 and MY20 between initiation and months 6, 12, and 18 during induction therapy, after consolidation, and every 6 months during maintenance.
8. Counts and proportions of treatment-related adverse effects for each treatment arm and in each treatment phase.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion PETHEMA

Sponsor organisation

Fundacion PETHEMA

Address

Oficinas 3 4 5, Calle De Santa Balbina 2 Calle De Santa Balbina 2

City

Madrid

Postcode

28023

Country

Spain

Scientific contact point

Organisation

Fundacion PETHEMA

Contact name

Juan José Lahuerta

Public contact point

Organisation

Fundacion PETHEMA

Contact name

Juan José Lahuerta

Third parties 6

Locations

1 EU/EEA country · 56 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications