Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone in Transplant-ineligible NDMM Patients

Phase 2

Completed

• Conditions: Myeloma, Plasma-Cell; Myeloma-Multiple; Myeloma Multiple; Plasma Cell Myeloma
• Interventions: Drug: Carfilzomib; Drug: Daratumumab; Drug: Lenalidomide; Drug: Dexamethasone

• Registration Number: NCT04065789
• Lead Sponsor: Tel-Aviv Sourasky Medical Center

Brief Summary

Patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve at least a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group \[IMWG\] criteria), will be treated with a quadruple regimen comprised of: Daratumumab 16 mg/Kg weekly during cycles 1-2, q14 days during cycles 3-6, thereafter monthly (1st dose cycle 1 may be split over 2 days); Once-weekly intravenous (IV) administration of Carfilzomib on days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days, alongside concomitant treatment with twice-weekly IV or oral dexamethasone 20mg administered on Days 1-2, 8-9, 15-16, and 22-23 of a 28-day cycle, for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; and oral Lenalidomide 25 mg, administered on days 1-21 of a 28-day cycle. On treatment days that require both Carfilzomib and Daratumumab infusions, Carfilzomib will be administrated prior to Daratumumab administration. All patients will undergo frailty assessment based on IMWG recommendations, and will be classified as fit, intermediate-fit and frail. Frail patients will receive Lenalidomide dose adjustment to 15 mg (throughout the study, from cycle 1 and on), and dexamethasone at 10 mg x 2/week cycles 1-2 followed by 10 mg/week for subsequent cycles. The quadruple regimen will be administered for 18 cycles, followed by long-term follow-up in which patients will receive standard of care treatment with Lenalidomide/dexamethasone (Rd) treatment, unless disease progression, the physician decides otherwise, the patient suffers from unacceptable toxicity, withdraws consent, or dies (whichever occurs first).

Detailed Description

Patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve at least a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group \[IMWG\] criteria), will be treated with a quadruple regimen comprised of: Daratumumab 16 mg/Kg weekly during cycles 1-2, q14 days during cycles 3-6, thereafter monthly (1st dose cycle 1 may be split over 2 days); Once-weekly intravenous (IV) administration of Carfilzomib on days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days, alongside concomitant treatment with twice-weekly IV or oral dexamethasone 20mg administered on Days 1-2, 8-9, 15-16, and 22-23 of a 28-day cycle, for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; and oral Lenalidomide 25 mg, administered on days 1-21 of a 28-day cycle. On treatment days that require both Carfilzomib and Daratumumab infusions, Carfilzomib will be administrated prior to Daratumumab administration. All patients will undergo frailty assessment based on IMWG recommendations, and will be classified as fit, intermediate-fit and frail. Frail patients will receive Lenalidomide dose adjustment to 15 mg (throughout the study, from cycle 1 and on), and dexamethasone at 10 mg x 2/week cycles 1-2 followed by 10 mg/week for subsequent cycles. The quadruple regimen will be administered for 18 cycles, followed by long-term follow-up in which patients will receive standard of care treatment with Lenalidomide/dexamethasone (Rd) treatment, unless disease progression, the physician decides otherwise, the patient suffers from unacceptable toxicity, withdraws consent, or dies (whichever occurs first). All patients will be required to receive either thromboprophylaxis or anticoagulation therapy in parallel. Patients will receive prophylaxis to herpes zoster and pneumocystis infection according to institutional guidelines, as well as proton pump inhibitors on dexamethasone treatment days only, according to institutional guidelines.

Patients will be assessed for response, to be determined by multiple myeloma (MM) biomarker profiling, on day 1 of cycle 2 and then every 56 ±4 days thereafter, irrespective of treatment delays or the timing of treatment cycles. Disease status will be followed until confirmed progressive disease (PD).

Long-term follow-up for disease status (only in cases where patients discontinued treatment prior to PD or patients completing all 18 cycles without signs of PD) and for survival (after reaching PD) will continue after treatment discontinuation until the patient has withdrawn consent for further participation, is lost to follow-up, has died, or the sponsor makes a decision to terminate the study. For patients who discontinued treatment before completing 18 cycles , without PD occurred, disease response assessments shall be performed every 56 days (±4 days), according to the original scheduled days of assessment, until disease progression. Patients completing all 18 cycles without signs of PD will be followed-up for disease response every 84±7 days. Follow-up for survival will be performed approximately every 3 months, or as needed, for all surviving patients until study closure. For any patient who is lost to follow-up, the study site will attempt to ascertain survival information via public database search.

The control group in this study (Historical Control) will consist of 144 consecutive patients from a subset of participating centers and will include transplant ineligible NDMM diagnosed between 2011 to 2017 with failure to respond to a bortezomib based induction (as defined in the prospective trial). Control group patients must meet the protocol inclusion and exclusion criteria.

Study Timeline

• Study Start: 2018-05-02
• Study First Submitted: 2019-07-31
• Study First Submitted QC: 2019-08-21
• Study First Posted: 2019-08-22
• Primary Completion: 2021-08-27
• Study Completion: 2021-11-12
• Status Verified: 2022-01
• Last Update Submitted: 2022-01-26
• Last Update Posted: 2022-01-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 41

Inclusion Criteria

1. Diagnosed with multiple myeloma and started induction therapy within 6 months prior to study entry

2. Received bortezomib-based induction therapy, with corticosteroids, with or without alkylators

3. Determined by investigator to be transplant-ineligible

4. Failed to achieve a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group [IMWG] criteria)

5. Measurable disease at time of enrolment including:

   • Serum M-protein ≥ 0.5 g/dL, or
   • Urine M-protein ≥ 200 mg/24 hour, or
   • Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa/lambda ratio, or
   • In patients with immunoglobulin A (IgA) type MM, whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA), qIgA ≥ 750 mg/dL (0.75 g/dL)

6. Male/female, ≥ 18 years of age

7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2

8. Adequate hepatic function within 28 days prior to treatment initiation, with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN

9. Left ventricular ejection fraction ≥ 40%

10. Absolute neutrophil count (ANC) ≥ 1500/mm3 within 28 days prior to enrollment, and reconfirmed within 7 days prior to first dose. Screening ANC should be independent of growth factor support for ≥ 1 week.

11. Hemoglobin ≥ 8.0 g/dL within 28 days prior to treatment initiation, and reconfirmed within 7 days prior to first dose. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days of obtaining Screening hemoglobin.

12. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is > 50%) within 28 days prior of treatment initiation, and reconfirmed within 7 days prior to first dose. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the Screening platelet count.

13. Calculated or measured creatinine clearance (CrCL) of ≥ 30 mL/min within 28 days prior to treatment initiation. Calculation should be based on standard formula such as the Cockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female.

14. Written informed consent in accordance with local regulations

15. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to treatment initiation and agree to use an effective method of contraception throughout the treatment period and for 3 months following last dose. Female of childbearing potential is defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

16. Male patients must use an effective barrier method of contraception during the treatment period and for 3 months following the last dose, if sexually active with a FCBP -

Exclusion Criteria

1. Prior therapy with any immunomodulatory drug (IMiD) or with Carfilzomib

2. Any unresolved Grade 2 or higher toxicity from bortezomib based induction treatment

3. Multiple myeloma of immunoglobulin M (IgM) subtype

4. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome

5. Plasma cell leukemia or circulating plasma cells ≥ 2 × 10e9/L

6. Waldenström macroglobulinemia

7. Patients with known amyloidosis

8. Focal radiation therapy within 7 days prior to treatment initiation; radiation therapy to an extended field, involving a significant volume of bone marrow, within 21 days prior to enrollment (i.e., prior radiation must have been to less than 30% of the bone marrow)

9. Major surgery (excluding kyphoplasty) within 28 days prior to treatment initiation

10. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention; myocardial infarction within 4 months prior to treatment initiation

11. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to treatment initiation

12. Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen [SAg] and core antibody receiving and responding to antiviral therapy directed at hepatitis B; these patients are allowed).

13. Patients with known cirrhosis

14. Second malignancy within the past 3 years except:

    A. Adequately treated basal cell or squamous cell skin cancer B. Carcinoma in situ of the cervix C. Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA) over 12 months D. Breast carcinoma in situ with full surgical resection E. Treated medullary or papillary thyroid cancer

15. Patients with myelodysplastic syndrome

16. Female patients who are pregnant or lactating

17. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize Carfilzomib)

18. Patients with hypersensitivity to Carfilzomib,

19. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment

20. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to treatment initiation

21. Subject has either one of the following:

    1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal.
    2. Known moderate or severe persistent asthma, within the past 2 years, uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.

22. Patients who discontinued bortezomib due to bortezomib related adverse events.

23. Any other clinically significant medical disease or psychiatric condition that, in the investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent

24. Any prior treatment with investigational anti-MM drugs -

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Carfilzomib,Daratumumab,revlimid and dexamethasone	Daratumumab	Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone
Carfilzomib,Daratumumab,revlimid and dexamethasone	Lenalidomide	Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone
Carfilzomib,Daratumumab,revlimid and dexamethasone	Carfilzomib	Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone
Carfilzomib,Daratumumab,revlimid and dexamethasone	Dexamethasone	Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone

Primary Outcome Measures

Name	Time	Method
Proportion of patients who experience any AE incidence, grade > 2 drug-elicited toxicities, peripheral neuropathy events (Grade 2 or higher).	from screening through month 20	Determined by adverse events, vital signs and clinical laboratory parameters in relation to study intervention.

Secondary Outcome Measures

Name	Time	Method
PFS	From treatment initiation to the earlier of disease progression or death due to any cause. Up to 2 years from last patient enrollment	Progression Free Survival (PFS)
Overall response rate (ORR)	From Screening and up to 2 years from last patient enrollment	The fraction of patients who experience a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) per IMWG 2016 criteria.
Time to progression (TTP)	From initiation of treatment and up to 2 years from last patient enrollment	From initiation of treatment to documented PD
Changes in Global Health Status and Quality of Life	From Screening and up to 2 years from last patient enrollment	The European Organization for Research and Treatment of Cancer \[EORTC\] Quality of Life Questionnaire Module QLQ-C30 will be used to evaluate Global Health Status/QoL. Questionnaire Module QLQ-C30 include 30 questions score scale is starting from minimum of 1 and up to a maximum of 7. In most items (1-28) Higher values represent a worse outcome.The exceptions are the items contributing to the global health status / QoL - 2 items (29-30) In which Higher values represent a better outcome .; It incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease.
Changes in Frailty Status	From Screening and up to 4 month from last patient enrollment	Frailty assessment, for this study will be based only on 4 components : age, the Charlson Comorbidity Scoring System, the Katz Index of Independence in Activities of Daily Living and the Lawton Instrumental Activities of Daily Living Scale.; All above 4 components are summed up and combined into one MM Frailty score - The score system (range 0-5, higher values represent a worse outcome), identifies 3 groups of patients: fit (score=0) intermediate-fitness (score=1) frail (score≥2)
Clinical benefit response (CBR) rate	From initiation of treatment and up to 2 years from last patient enrollment	Defined as ORR or minimal response (MR)
OS	From treatment initiation to date of death (whatever the cause). Up to 2 years from last patient enrollment	Overall Survival (OS)
Duration of response (DOR)	From initiation of treatment and up to 2 years from last patient enrollment	Time of first evidence of PR or better to confirmation of PD or death due to any cause
Disease control rate (DCR),	From initiation of treatment and up to 2 years from last patient enrollment	Defined as ORR or minimal response (MR) or stable disease (SD) lasting at least 8 weeks.

Trial Locations

Locations (14)

Hematology Department Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

Soroka Medical Center; 🇮🇱 Be'er Sheva, Israel

Kaplan Medical center; 🇮🇱 Reẖovot, Israel

Shaare Zedek medical Center; 🇮🇱 Jerusalem, Israel

Rabin Medical Center; 🇮🇱 Petah tikva, Israel

Assuta Medical Center; 🇮🇱 Tel Aviv, Israel

Haemek Medical Center; 🇮🇱 Afula, Israel

Barzilai Medical Center; 🇮🇱 Ashkelon, Israel

Carmel Medical center; 🇮🇱 Haifa, Israel

Hadassah Ein-Karem Medical Center; 🇮🇱 Jerusalem, Israel

Bnai-Zion Medical Center; 🇮🇱 Haifa, Israel

Rambam medical Center; 🇮🇱 Haifa, Israel

Meir Medical Center; 🇮🇱 Kfar Saba, Israel

Ziv Medical Center; 🇮🇱 Zefat, Israel