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About
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).
Full 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.
Enrollment
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Volunteers
Inclusion criteria
Diagnosed with multiple myeloma and started induction therapy within 6 months prior to study entry
Received bortezomib-based induction therapy, with corticosteroids, with or without alkylators
Determined by investigator to be transplant-ineligible
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)
Measurable disease at time of enrolment including:
Male/female, ≥ 18 years of age
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2
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
Left ventricular ejection fraction ≥ 40%
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.
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.
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.
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.
Written informed consent in accordance with local regulations
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).
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
Prior therapy with any immunomodulatory drug (IMiD) or with Carfilzomib
Any unresolved Grade 2 or higher toxicity from bortezomib based induction treatment
Multiple myeloma of immunoglobulin M (IgM) subtype
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome
Plasma cell leukemia or circulating plasma cells ≥ 2 × 10e9/L
Waldenström macroglobulinemia
Patients with known amyloidosis
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)
Major surgery (excluding kyphoplasty) within 28 days prior to treatment initiation
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
Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to treatment initiation
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).
Patients with known cirrhosis
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
Patients with myelodysplastic syndrome
Female patients who are pregnant or lactating
Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize Carfilzomib)
Patients with hypersensitivity to Carfilzomib,
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
Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to treatment initiation
Subject has either one of the following:
Patients who discontinued bortezomib due to bortezomib related adverse events.
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
Any prior treatment with investigational anti-MM drugs -
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41 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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