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Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of Newly Diagnosed Multiple Myeloma

Trial Status: Active

This phase II trial compares the safety and activity of the combination of carfilzomib, lenalidomide, and dexamethasone (KRD), or carfilzomib, lenalidomide, dexamethasone and daratumumab (KRD+DARA) with the usual treatment composed of lenalidomide, bortezomib and dexamethasone (VRD) for the treatment of newly diagnosed multiple myeloma. Immunotherapy with daratumumab, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Carfilzomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells. It may also prevent the growth of new blood vessels that tumors need to grow. Anti-inflammatory drugs such as dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. This study will measure the amount of myeloma cells that remain in the body after treatment with the study drugs, described as minimal residual disease (MRD). Studies show that having no remaining multiple myeloma cells or a low number of these cells (MRD negativity) is associated with better clinical outcomes. This study compares the results of the usual treatment (VRD) with those of KRD or KRD+DARA to see which treatment is safer and results in more patients achieving MRD negativity.

Inclusion Criteria

  • Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria: * Clonal plasma cells in the bone marrow * Measurable disease within the past 4 weeks defined by any one of the following: * Serum monoclonal protein >= 1.0 g/dL * Urine monoclonal protein >= 200 mg/24 hour * Involved serum immunoglobulin free light chain >= 10 mg/dL AND abnormal kappa/lambda ratio
  • Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following: * Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) above upper limit of normal or >= 2.75 mmol/L (11 mg/dL) * Anemia: hemoglobin value < 10 g/dL or > 2 g/dL below lower limit of normal * Bone disease: >= 1 lytic lesions on skeletal X-ray, computed tomography (CT), or positron emission tomography (PET)-CT. For patients with 1 lytic lesion, bone marrow should demonstrate >= 10% clonal plasma cells * Clonal bone marrow plasma cell percentage >= 60% * Involved/un-involved serum free light chain ratio >= 100 and involved free light chain >= 100 mg/L * > 1 focal lesion on magnetic resonance imaging study (lesion must be > 5 mm) in size
  • Creatinine clearance >= 60 ml/min. Creatinine clearance (CrCl) can be measured or estimated using Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic Kidney Disease (CKD)-Epidemiology (EPI) formulae
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) >= 1.0 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible
  • Hemoglobin >= 8 g/dL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible
  • Platelet count >= 75 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible
  • Bilirubin < 1.5 x the upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN
  • All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (Coumadin) or alternative anti-coagulant
  • All study participants must be registered into the mandatory electronic Risk Evaluation and Mitigation Strategy (eREMS) program and be willing and able to comply with the requirements of REMS
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy * A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Exclusion Criteria

  • Patients receiving > 1 cycle of prior treatment or concurrent systemic treatment for multiple myeloma: * Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted * Bisphosphonates are permitted * Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted * Prior treatment with radiotherapy is permitted * Prior treatment for smoldering myeloma is permitted with a washout period of 2 weeks from last dose. Smoldering patients previously treated with carfilzomib are excluded * Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 2 weeks from last dose (on a trial or outside a trial) are eligible
  • Plasma cell leukemia
  • Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome
  • Amyloidosis
  • Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal (note that FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 < 50% of predicted normal)
  • Pregnant or lactating females. Because there is a potential risk for adverse events nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide. These potential risks may also apply to other agents used in this study
  • Uncontrolled hypertension or diabetes
  • Active hepatitis B or C infection
  • Subject is: * Seropositive for human immunodeficiency virus (HIV) * Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects 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: Subjects 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 * Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
  • Has significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, ejection fraction (EF) =< 40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed during screening evaluation
  • Pulmonary hypertension
  • Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption of oral agents
  • Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
  • Significant neuropathy >= grade 3 or grade 2 neuropathy with pain at baseline
  • Contraindication to any concomitant medication, including antivirals or anticoagulation
  • Major surgery within 3 weeks prior to first dose

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Carl Ola Landgren
Phone: 212-639-5126

PRIMARY OBJECTIVE:

I. To compare the rates of minimal residual disease (MRD) negativity for patients who receive bortezomib, lenalidomide, dexamethasone (VRD) (Arm A) to patients who receive carfilzomib, lenalidomide, and dexamethasone (KRD) (Arm B) and for patients who receive VRD (Arm A) to patients who received KRD + daratumumab (DARA) (Arm C).

SECONDARY OBJECTIVES:

I. To compare overall survival, progression-free survival, and event-free survival in patients achieving partial response (PR) or less within the first 4 cycles of therapy, across the treatment arms (Arm A versus [vs] Arm B, Arm A vs Arm C).

II. To compare the rates of PR or better, very good partial response (VGPR) or better, complete response (CR) and stringent complete response (sCR) across the treatment arms (Arm A vs Arm B, Arm A vs Arm C).

III. To compare the rate of MRD-negativity as a best response after the completion of eight cycles of therapy across the treatment arms (Arm A vs Arm B, Arm A vs Arm C).

IV. To compare the rate of MRD-negativity 12 months after randomization across the treatment arms (Arm A vs Arm B, Arm A vs Arm C).

V. To compare the safety and tolerability of the three treatment arms.

VI. To compare clonoSEQ next generation sequencing (NGS)-MRD in bone marrow versus blood.

EXPLORATORY OBJECTIVES:

I. To explore clinical outcomes by cytogenetic risk groups.

II. With the myTYPE gene panel, explore whether any mutations appear to be associated with response to therapy or toxicity.

III. With the myTYPE gene panel, evaluate the samples collected at the time of disease progression or during an ongoing response and compare them to the pre-treatment baseline samples to explore whether pathways leading to emergence of resistance to the drug regimen can be identified.

IV. To obtain and store biosamples for future testing, and store leftover samples for future studies of potential biomarkers of prognosis and outcome.

V. To explore associations of symptom burden of lenalidomide-related diarrhea (including, but not limited to, grade and duration of diarrhea) and the potential role of the gut microbiota in the pathoetiology of lenalidomide-related diarrhea (Memorial Sloan Kettering [MSK] patients only).

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A (VRD): Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4, 8, and 11, dexamethasone orally (PO) or IV on days 1, 4, 8, and 11, and lenalidomide PO on days 1-14. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

ARM B (KRD): Patients receive carfilzomib IV over 30 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1, 2, 8, 15 and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2 and days 1, 8, and 15 of subsequent cycles, and lenalidomide PO on days 2-21 of cycle 1 and days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

ARM C (KRD+DARA): Patients receive daratumumab IV on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6 and day 1 of subsequent cycles. Patients also receive carfilzomib IV over 30 minutes on days 2, 8, and 15 of cycle 1, and days 1, 8, and 15 of subsequent cycles, dexamethasone PO or IV on days 1, 2, 8, 15 and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2 and days 1, 8, and 15 of subsequent cycles, and lenalidomide PO on days 2-21 of cycle 1 and days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Response assessment is measured after 4 cycles of therapy. Patients with progressive disease receive no additional study treatment.

In all arms, patients who are MRD positive and do not have progressive disease after 4 cycles of therapy, undergo autologous stem cell transplantation (ASCT) after 8 cycles of treatment, then receive lenalidomide for 2 years, and patients who are MRD negative receive lenalidomide for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up until the end of maintenance therapy for a total of 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Carl Ola Landgren

  • Primary ID 19-339
  • Secondary IDs NCI-2020-01093
  • Clinicaltrials.gov ID NCT04268498