Summary

This phase II trial studies how well daratumumab-based therapy works in treating patients with newly diagnosed multiple myeloma with kidney failure. Daratumumab-based therapy includes daratumumab, bortezomib, dexamethasone, and thalidomide or lenalidomide. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Bortezomib is a drug that prevents myeloma cells from getting rid of their waste products, leading to being targeted for death. Dexamethasone is a steroid that is commonly used, either alone or in combination with other drugs, to treat multiple myeloma. Lenalidomide and thalidomide may stop the growth of multiple myeloma by blocking the growth of new blood vessels necessary for tumor growth. Giving daratumumab, bortezomib, dexamethasone, and thalidomide or lenalidomide may be a good way to treat patients with newly diagnosed multiple myeloma with kidney failure.

Objectives

PRIMARY OBJECTIVE:
I. To determine the proportion of patients with newly diagnosed myeloma and acute kidney injury (AKI) who have renal function recovery following 2 cycles (6 weeks) of treatment with a daratumumab-based induction regimen.

SECONDARY OBJECTIVES:
I. Overall response rate at the end of 2 and 4 cycles of therapy.
II. Adverse event profile of the combination in patients with AKI.
III. Pharmacokinetic parameters of maximum concentration (Cmax), area under the curve (AUC), time to maximum concentration (tmax), clearance, and half life (t1/2) of daratumumab in combination treatment in the AKI population.
IV. Global assessment of renal function at cycle initiation including creatinine clearance (CrCl).
V. Timeline of changes in pharmacodynamic markers of light chains, urine paraprotein, and serum paraprotein measures.

OUTLINE:
Patients receive daratumumab intravenously (IV) weekly of cycles 1-3 and on day 1 only of cycle 4, bortezomib subcutaneously (SC) on days 1, 4, 8, and 11, and dexamethasone IV or orally (PO) on days 1-4 of cycle 1 and on day 1 of cycles 2-4 and PO on days 8 and 15 of all cycles. Beginning cycle 2, patients may also receive lenalidomide PO daily on days 1-14 or thalidomide PO once daily (QD) on days 1-21. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Eligibility

1. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
2. Creatinine clearance < 30 mL/min by Cockcroft-Gault (C-G), 24 hour urine collection or the Modification of Diet in Renal Disease (MDRD) methods. The same method used for inclusion will be used for renal response assessment
3. Documented multiple myeloma as defined by the International Myeloma Working Group (IMWG) 2014 criteria including: Clonal bone marrow plasma cells >= 10%. In addition, the patient must meet one of the criteria in day (d)1 or d2: * Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically (one or more of the following): ** Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal (ULN) or > 2.75 mmol/L (>11 mg/dL) ** Renal insufficiency: creatinine clearance (CrCl) < 30 mL/min ** Anemia: hemoglobin value of > 2 g/dL below the lower limit of normal, or a hemoglobin value < 10 g/L ** Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed tomography (CT), or magnetic resonance imaging (MRI)
4. Measurable disease as defined by any of the following: * Serum M-protein level >= 1.0 g/dL or urine M-protein level >= 200 mg/24 hours. * IgA, IgD, IgE, or IgM multiple myeloma: serum M-protein level >= 0.5 g/dL or urine M-protein level >= 200 mg/24 hours; or * Light chain multiple myeloma without measurable disease in the urine: serum Ig free light chain (FLC) >= 10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
5. Prior treatment to stabilize the patient with steroids up to 160 mg IV equivalents of dexamethasone is allowed
6. Prior treatment to stabilize the patient with bortezomib up to 2 doses of 1.3 mg/m^2 each dosing equivalent is allowed
7. Subject agrees to refrain from blood donations during therapy on study and for 8 weeks after therapy is completed
8. Female patients who: * Are postmenopausal for at least 2 years before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) * Are planning to donate eggs during the period of study and up to 3 months after the last dose of study drug * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and again within 24 hours of starting study drugs
9. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) * Agree to no sperm donation during the period of study and up to 3 months after the last dose of study drug

Treatment Sites in Georgia