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Daratumumab and Lenalidomide in Treating Patients with Minimal Residual Disease Positive Multiple Myeloma after Induction Therapy with or without High-Dose Chemotherapy with Stem Cell Support

Trial Status: Active

This phase II trial studies how well daratumumab and lenalidomide work in treating patients with minimal residual disease positive multiple myeloma after initial chemotherapy (induction therapy) with or without high-dose chemotherapy with stem cell transplant (stem cell support). Immunotherapy with daratumumab, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Lenalidomide works against cancer cells partly by impacting the functioning of the immune system. Giving daratumumab and lenalidomide may work better in treating patients with MRD positive multiple myeloma.

Inclusion Criteria

  • Multiple Myeloma according to the International Myeloma Working Group definition (2) i.e.: clonal bone marrow plasma cells >= 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events and/or one or more of the biomarkers for malignancy at the time of diagnosis: * Myeloma defining events: ** Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL) ** Renal insufficiency: creatinine clearance < 40 mL per minimum (min) or serum creatinine > 177 umol/L (> 2 mg/dL) ** Anemia: hemoglobin value of > 20 g/L below the lower limit of normal, or a hemoglobin value < 100 g/L ** Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT * Biomarkers of malignancy: ** Clonal bone marrow plasma cell percentage >= 60% ** Involved: uninvolved serum free light chain ratio >= 100 ** > 1 focal lesions on magnetic resonance imaging (MRI) studies
  • A very good partial response (VGPR) or better after induction therapy with/without consolidative chemotherapy and/or high-dose therapy/autologous stem cell transplantation (HDT/ASCT). * Very good partial response (VGPR): ** Serum and urine M-component detectable by immunofixation but not on electrophoresis or ** >= 90% or greater reduction in serum M-component plus urine M-component < 100 mg per 24 hours (h) * Complete response (CR): ** Negative immunofixation of serum and urine and ** Disappearance of any soft tissue plasmacytomas and ** < 5% plasma cells in bone marrow * Stringent complete response (sCR) ** CR as defined above plus ** Normal free light chain ratio and ** Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence * MRD positive by flow cytometry
  • Additionally, patients who were previously MRD negative for >= 3 months after induction therapy with/without consolidative HDT/ASCT and have turned MRD positive (by flow cytometry) within the last 3 months and do not have any evidence of progressive disease are eligible.
  • Patients must be on standard of care lenalidomide maintenance therapy for at least 6 months at the time of study enrollment.
  • Patient can be receiving bisphosphonate therapy per the treating oncologist's discretion.
  • Creatinine clearance >= 45 ml/min using the Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. If the calculated creatinine clearance (CrCl) based on Cockcroft-Gault method, MDRD, or CKD-EPI is < 45 mL/min, patient will have a 24 hour (hr) urine collection to measure CrCl.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
  • Male or female patient who accepts and is able to use recognized effective contraception (oral contraceptives, intrauterine contraceptive device [IUCD], barrier method of contraception in conjunction with spermicidal jelly) throughout the study when relevant.
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L. No transfusion or growth factor support for one week prior to labs.
  • Hemoglobin >= 8 g/dL. No transfusion or growth factor support for one week prior to labs.
  • Platelet count >= 75 x 10^9/L. No transfusion or growth factor support for one week prior to labs.
  • Adequate hepatic function, with bilirubin < 1.5 x the upper limit of normal (ULN)
  • Adequate hepatic function, with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN

Exclusion Criteria

  • Patients with a diagnosis of multiple myeloma (MM) not achieving a VGPR or better to the most recent therapy.
  • Patients with a diagnosis of MM who are MRD negative by flow cytometry
  • Patients must not have measurable disease at the time of enrollment. Measurable disease is defined as follows- * Serum monoclonal protein > 0.5 gm/dL * Urine monoclonal protein > 200 mg/24 hours * Involved serum free light chain > 10 mg/dL
  • Pregnant or lactating females.
  • Uncontrolled hypertension or diabetes.
  • Has significant cardiovascular disease with New York Heart Association (NYHA) class 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.
  • Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance of study requirements.
  • Active infection requiring treatment within two weeks prior to first dose.
  • Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy.
  • Major surgery within 1 month prior to enrollment.
  • Previous therapy with daratumumab or other anti-CD38 monoclonal antibodies.
  • 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.
  • 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 (ie, 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).

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Sham Mailankody
Phone: 646-608-3712

PRIMARY OBJECTIVE:

I. To determine the rate of minimal residual disease (MRD) negativity by the completion of 6 months of daratumumab therapy.

SECONDARY OBJECTIVES:

I. To assess the rate of sustained MRD negativity in the bone marrow.

II. To determine duration of MRD negativity.

III. To compare MRD techniques of multi-parametric flow cytometry with next-generation

sequencing and mass spectrometry.

IV. To determine progression-free and overall survival.

EXPLORATORY STUDIES:

I. The gene panel MyType (or comparable next generation sequencing panel) will explore whether any mutations appear to be associated with response to therapy or toxicity associated with therapy.

II. MyType will (or comparable next generation sequencing panel) also be evaluated using samples at the time of progression of disease and will be compared to the pre-treatment baseline samples to explore whether pathways leading to emergence of resistance to the drug regimen can be identified.

OUTLINE:

Patients receive daratumumab intravenously (IV) on days 1, 8, 15, and 22 of cycles 1-2, then on days 1 and 15 of cycles 3-6. Patients also receive lenalidomide orally (PO) daily on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After 6 cycles, patients may continue lenalidomide maintenance as standard of care treatment.

After completion of study treatment, patients are followed up at 1 month, 1 year, and 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Sham Mailankody

  • Primary ID 18-048
  • Secondary IDs NCI-2018-00871
  • Clinicaltrials.gov ID NCT03490344