Treatment with carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with high-risk smoldering Multiple Myeloma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Nov 2018 → ongoing

Decision date (initial)

2024-09-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Amgen · Celgene

External identifiers

EU CT number

2024-511334-12-00

EudraCT number

2017-000555-10

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To assess MRD negativity rate by NGF after 9 cycles for all eligible ITT patients of KRd versus Rd in patients with high-risk SMM

Secondary objectives 12

1. To assess MRD (NGF) negativity rate after 4 cycles of induction treatment
2. To assess MRD (NGF) negativity rate after completion of maintenance treatment
3. To assess correlation of MRD (NGF) negativity rate with PFS
4. To assess overall response rate (ORR) after 4 and 9 cycles induction treatment and after maintenance
5. To determine progression-free survival (PFS)
6. To determine progression-free survival-2 (PFS2)
7. To determine duration of response (DOR)
8. To determine overall survival (OS)
9. To assess correlation of MRD (NGF) negativity rate with PFS, PFS2, DOR and OS
10. To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone)
11. To evaluate safety (type, frequency, and severity of adverse events (AE) and relationship of AE to study drug, serious AE (SAEs)
12. To evaluate disease heterogeneity in relation to clinical outcomes (molecular profiling on bone marrow samples)

Conditions and MedDRA coding

Smoldering Multiple Myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma based on the 2014 International Myeloma Working Group Criteria: Serum M-protein ≥3 g/dl or urinary monoclonal protein >500 mg per 24 hours and/or Absence of CRAB symptoms and myeloma defining events
2. Patient is capable of giving informed consent
3. Patients must have high risk Smoldering Multiple Myeloma based on the Mayo Clinic and/or the PETHEMA criteria
4. Measurable disease
5. Age >18 years
6. WHO/ECOG performance status <=2
7. Patients must have normal organ and marrow function
8. Patients must be willing and capable to use adequate contraception during and after the therapy (all men, all premenopausal women) Patients must be able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Plan
9. Females of childbearing potential must have a negative serum or urine pregnancy test within 10 - 14 days prior to entry and again within 24 hours of starting lenalidomide treatment
10. Written informed consent
11. Calculated Creatinine Clearance ≥ 50 ml/min

Exclusion criteria 20

1. Patients with symptomatic multiple myeloma (i.e. having myeloma defining events)
2. Amyloid Light-chain (AL) amyloidosis
3. Patients who are receiving any other investigational agents.
4. Concurrent systemic treatment or prior therapy within 4 weeks for SMM
5. Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy
6. History of allergic reactions attributed to immunomodulatory agents and proteasome inhibitors.
7. Hypersensitive reaction to active substances or any excipients of the IMPs
8. Uncontrolled hypertension or diabetes
9. Pregnant or lactating females.
10. Significant cardiovascular disease with NYHA grade III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia
11. Active hepatitis B or C infection
12. Known or suspected HIV infection
13. Incidence of gastrointestinal disease that would prevent absorption
14. Patients with gastric or duodenal ulcers
15. Significant neuropathy ≥Grade 3 or grade 2 with pain within 14 days of enrollment
16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection.
17. History of other malignancy (apart from basal cell carcinoma of the skin, or in situ cervix carcinoma) except if the patient has been free of symptoms and without active therapy during at least 5 years
18. Major surgery within 1 month prior to enrollment
19. Pre-existing pulmonary, cardiac or renal impairement that prevents hydration measures
20. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MRD negativity rate by NGF after cycle 9 for all eligible ITT patients; eligible patients who achieve a MRD negativity after cycle 9 will be considered as a success. All other eligible randomized ITT patients will be considered as a failure, including patients going off-protocol before cycle 9, whatever the cause.

Secondary endpoints 12

1. MRD negativity rate evaluated by means of next generation flow cytometry (cut off 10-5) after cycle 4
2. MRD negativity rate evaluated by means of next generation flow cytometry (cut off 10-5) after completion of maintenance
3. Correlation of MRD (NGF) negativity rate with PFS
4. Overall response rate (ORR; i.e. at least partial response (PR)) after 9 cycles induction treatment
5. Progression-free survival (PFS), defined as time from study entry to progression or death, whichever comes first
6. Progression-free survival-2 (PFS2), defined at time from randomization to progression after second-line treatment or death, whichever comes first
7. Duration of response (DOR), defined as time from response to progression or death, whichever comes first
8. Overall survival (OS), defined as time from study entry to death from any cause. Patients still alive at the date last contact will be censored
9. Correlation of MRD (NGF) negativity rate with PFS, PFS2, DOR and OS
10. Toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone)
11. Safety (type, frequency, and severity of adverse events (AE) and relationship of AE to study drug, serious AE (SAEs)
12. Disease heterogeneity in relation to clinical outcomes (molecular profiling on bone marrow samples)

Investigational products

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

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

A. Broijl

Public contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

HOVON

Third parties 1

Locations

2 EU/EEA countries · 8 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 11 files

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

Application history

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