A Phase 2, single arm Multicenter, Study testing Mezigdomide, Carfilzomib, and Dexamethasone (480Kd) in Participants with Relapsed or Refractory Multiple Myeloma (RRMM)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-04-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To determine the progression-free survival (PFS) of mezigdomide, carfilzomib and dexamethasone (480Kd) in participants with relapsed or refractory multiple myeloma (RRMM)

Secondary objectives 11

1. Overall Survival (OS)
2. Overall Response Rate (ORR)
3. Rate of very good partial response (VGPR) or better (VGPRR)
4. Rate of complete response (CR) or better (CRR)
5. Time to Response (TTR)
6. Duration of Response (DOR)
7. Time to Progression
8. Time to Next Treatment (TTNT)
9. To evaluate minimal residual disease (MRD)
10. To evaluate safety of 480Kd in participants with RRMM
11. To evaluate cancer and multiple myeloma-related symptoms and health-related quality of life (HRQoL)

Conditions and MedDRA coding

Patients with relapsed/refractory symptomatic multiple myeloma (MM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Signed Written Informed Consent
2. Adult patients (≥18 years old)
3. ECOG Performance Status score of 0, 1, or 2
4. Participant has documented diagnosis of multiple myeloma (MM) and measurable disease, defined as any of the following:  M-protein ≥ 0.5 g/dL by serum protein electrophoresis (sPEP), or  M-protein ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) or,  For participants without measurable disease in sPEP or uPEP: serum free light chain (sFLC) levels > 100 mg/L (10 mg/dL) involved light chain and an abnormal κ/λ FLC ratio
5. Participant has received one or two prior line of anti-myeloma therapy. Note: One line can contain several phases (eg, induction, [with or without] hematopoietic stem cell transplant, (with or without) consolidation, and/or [with or without] maintenance therapy)
6. Participant must have received prior treatment with lenalidomide and an anti-CD38 monoclonal antibody.
7. Participant achieved minimal response [MR] or better to at least 1 prior anti-myeloma therapy
8. Participant must have documented disease progression during or after their last antimyeloma regimen
9. Women of childbearing potential (WOCBP) must  Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy and must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy.  Either commit to true abstinence* from heterosexual contact or agree to use, and be able to comply with, 2 forms of contraception: one highly effective, and one additional effective (barrier) contraception without interruption, 28 days prior to starting study intervention, during treatment (including dose interruptions), and for at least 28 days after the last dose of mezigdomide, or 6 months after the last dose carfilzomib, whichever is longest
10. Male participants must: • Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant woman or a WCBPFCBP while participating in the study, during dose interruptions and for at least 90 days after the last dose of mezigdomide or carfilzomib, even if he has undergone a successful vasectomy
11. Male participants must agree to refrain from donating sperm while on study intervention, during dose interruptions, and for at least 90 days following last dose of mezigdomide or carfilzomib.
12. Women must agree to refrain from donating eggs while on study intervention and for at least 28 days after last dose of mezigdomide
13. Participants must agree to refrain from donating blood while on study intervention, during dose interruptions, and for at least 28 days following the last dose of study intervention
14. All male and female participants must follow all requirements defined in the Pregnancy Prevention Plan in Appendix 11 for mezigdomide

Exclusion criteria 32

1. Participant that received >= 3 prior line of anti-myeloma therapy
2. Administration of strong CYP3A modulators; administration of proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) within 2 weeks of starting study intervention
3. Participant has impaired cardiac function or clinically significant cardiac disease, including any of the following: • Myocardial infarction within 1 year before inclusion, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure New York Heart Association Class III-IV) or pericardial disease. • Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities, including prolongation of QT interval on Screening ECG as defined by a QTc interval > 470 msec using Fridericia's QT correction formula • Left ventricular ejection fraction < 40% as assessed by transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA)
4. Participant who has had prior treatment with mezigdomide or carfilzomib
5. Participant has uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
6. Participant who has had a live vaccine within 3 months of start of study therapy
7. Participant is unable or unwilling to undergo protocol required thromboembolism or antiviral prophylaxis
8. Participant who has had any investigational agents within 28 days or 5 half-lives (whichever is shorter) of initiating study intervention (Participation in another interventional clinical trial concurrent with this study is not permitted, except for those who have completed treatment with the prior investigational agent(s) and are currently in long-term follow-up.)
9. Participant has received Plasmapheresis within the last 28 days of initiating study intervention
10. Participant has received any Major surgery (as defined by the Investigator) within 28 days of initiating study intervention.
11. Participant has received any Radiation therapy, other than local palliative therapy, for myeloma-associated bone lesions within 14 days of initiating study intervention
12. Participant with known central nervous system (CNS) involvement with myeloma
13. Participant has Use of any systemic anti-myeloma drug therapy within 14 days of initiating study intervention
14. Participant has previously received allogeneic stem cell transplant at any time or received autologous stem cell transplant within 12 weeks of initiating study treatment
15. Participant has plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant light-chain amyloidosis
16.  Participant is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, active hepatitis A, or active hepatitis C: • Known positive HIV status. • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (ie, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. • Known to be seropositive for hepatitis C virus (HCV); anti-HCV antibody positive or HCV- ribonucleic acid (RNA) quantitation positive, except in the setting of a sustained virologic response (SVR), defined as viremia at least 12 weeks after completion of antiviral therapy
17. Participant is a female who is pregnant or breastfeeding, or who intends to become pregnant during participation in the study.
18. Contraindication to investigational medicinal products (mezigdomide, carfilzomib and dexamethasone)
19. Participation in another interventional study or being in the exclusion period at the end of a previous study
20. Participant has any significant medical condition, including active or uncontrolled infection, presence of laboratory abnormality, or psychiatric illness that places the participant at an unacceptable risk for treatment-related complications, if he/she were to participate in the study
21. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days for mild or asymptomatic infections or 28 days for severe/critical illness prior to initiating study intervention (Acute symptoms must have resolved and there are no sequelae that would place the participant at a higher risk of receiving study intervention, based on Investigator assessment in consultation with the Sponsor Medical Monitor)
22. Participant has any condition that confounds the ability to interpret data from the study
23. Participant has any of the following laboratory abnormalities: • Absolute neutrophil count (ANC) < 1,000/¬µL. It is not permissible to administer GCSF to achieve minimum ANC levels within 7 days prior to screening complete blood count (CBC) (or within 14 days prior for pegfilgrastim). • Platelet count: < 75,000/¬µL for participants in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 50,000/¬µL for participants in whom ‚â• 50% of bone marrow nucleated cells are plasma cells. Platelet transfusions are not permitted within 7 days prior to screening complete blood count (CBC). • Hemoglobin < 8 g/dL (< 4.9 mmol/L). • Estimated glomerular filtration rate (eGFR) < 30 mL/min or requiring dialysis. eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD) formula (see http://mdrd.com). • Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L) • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5xx upper limit of normal (ULN) • Serum total bilirubin > 1.5 x ULN; > 3.0 mg/dL is allowed for participants with documented Gilbert's syndrome.
24. Participant with gastrointestinal disease or surgery (eg, gastric bypass surgery) that may significantly alter the absorption of CC-92480 and/or other oral study intervention.
25. Participant has prior history of malignancies, other than MM, unless the participant has been free of the disease for 5 years with the exception of the following noninvasive malignancies: • Basal cell carcinoma of the skin • Squamous cell carcinoma of the skin in situ (Stage 0) • Carcinoma in situ of the cervix • Carcinoma in situ of the breast • Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative
26. Participant has received immunosuppressive medication within the last 14 days of initiating study intervention. The following are exceptions to this criterion: • Intranasal, inhaled, or topical corticosteroids or local corticosteroid injections (eg, intra-articular injection). • Systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or the equivalent (see Table 7.7.2-1). • Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication).
27. Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: Concomitant Therapy
28. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population
29. Participant has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide (including ‚â• Grade 3 rash during prior thalidomide or lenalidomide therapy), carfilzomib or dexamethasone or the excipients contained in the formulations, or participant has any contraindications per local prescribing information
30. Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply, and BMS approval is required)
31. Participants must agree to refrain from donating blood while on study intervention, during dose interruptions, and for at least 28 days following the last dose of study intervention
32. Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The progression-free survival defined as the time from inclusion to first documentation of progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma or death due to any cause, whichever occurs first

Secondary endpoints 11

1. Overall Survival (OS) defined as the time from inclusion to time of death due to any cause
2. Overall Response Rate (ORR) defined as the percentage of participants who achieve best response of partial response (PR) or better according to the IMWG Uniform Response Criteria for Multiple Myeloma
3. Rate of very good partial response (VGPR) or better (VGPRR) defined as the percentage of participants who achieve best response of VGPR or better according to the IMWG Uniform Response Criteria for Multiple Myeloma
4. Rate of complete response (CR) or better (CRR) defined as the percentage of participants who achieve best response of CR or better according to the IMWG Uniform Response Criteria for Multiple Myeloma
5. Time to Response (TTR) defined as the time from inclusion on to the first documentation of response (PR or better)
6. Duration of Response (DOR) defined as the time from the first documentation of response (PR or better) to the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first
7. Time to Progression (TTP) defined as the time from inclusion to the first documentation of PD
8. Time to Next Treatment (TTNT) defined as the time from inclusion to the start of the next anti-myeloma treatment
9. To evaluate minimal residual disease (MRD) negativity rate in participants treated with 480Kd defined as the proportion of participants who achieve CR or better and are MRD negative (defined at a sensitivity of a minimum of 1 in 105 nucleated cells)
10. To evaluate safety of 480Kd in participants with RRMM, defined as the type, frequency, seriousness and severity of adverse events (AEs), and relationship of AEs to study treatment
11. To evaluate cancer and multiple myeloma-related symptoms and health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC QLQ-C30) and the European Quality of Life Multiple Myeloma module (EORTC QLQ-MY20) in participants treated with 480Kd

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Prof Mohamad MOHTY

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Prof Mohamad MOHTY

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Results and documents

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

Documents 17 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