Denosumab in Treating Patients with Multiple Myeloma with Kidney Insufficiency
This phase II trial studies how well denosumab works in treating patients with multiple myeloma with kidney insufficiency. Immunotherapy with monoclonal antibodies, such as denosumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread
- Subjects must have documented multiple myeloma as defined by the criteria below: * Clonal bone marrow plasma cells >= 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following calcium, renal failure, anemia, bone lesions (CRAB) features and myeloma-defining events (MDEs) * Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: ** 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 minute or serum creatinine > 177 umol/L (> 2 mg/dL) ** Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L ** Bone lesions: one or more osteolytic lesion on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)/CT * Any one or more of the following biomarkers of malignancy (MDEs) ** 60% or greater clonal plasma cells on bone marrow examination ** Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L (a patient’s “involved” free light chain – either kappa or lambda – is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range) ** More than one focal lesion on magnetic resonance imaging (MRI) that is at least 5 mm or greater in size
- Creatinine clearance < 30 mL/min, not eligible for bisphosphonate; estimated glomerular filtration rate will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and/or the Cockcroft-Gault equation
- Serum calcium or albumin-adjusted serum calcium >= 2.1 mmol/L (8.4 mg/dL) and =< 2.9 mmol/L (11.5 mg/dL) (reference range 8.5-10.8 mg/dL)
- Able to tolerate daily supplementation of calcium and vitamin D
- Must have a vitamin D level >= 30 ng/mL after repletion
- Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)
- Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x institutional ULN
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
- Plan to receive anti-myeloma therapies
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Life expectancy greater than 6 months
- Subjects with reproductive potential must be willing to use, in combination with his/her partner, 2 highly effective methods of effective contraception or practice sexual abstinence throughout the study and continue for 5 months after the study duration; subjects who are surgically sterile (e.g. history of bilateral tubal ligation, hysterectomy) or whose sexual partner is sterile (e.g. history of vasectomy) are not required to use additional contraceptive measures
- Ability to understand and the willingness to sign a written informed consent document
- Prior administration of denosumab
- Active intravenous (IV) bisphosphonate use in the last 3 months
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- Plasma cell leukemia
- Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
- Active dental or jaw condition that requires oral surgery, including tooth extraction
- Non-healed dental/oral surgery, including tooth extraction
- Planned invasive dental procedures during the course of study
- Evidence of any of the following conditions per subject self-report or medical chart review * Any prior invasive malignancy within 5 years of enrollment that may affect outcome of study * Any non-invasive malignancy not treated with curative intent or with known active disease within 5 years before enrollment that may affect outcome of study * Major surgery or significant traumatic injury occurring within 4 weeks before enrollment * Active infection with hepatitis B virus or hepatitis C virus * Known infection with human immunodeficiency virus (HIV) * Active infection requiring IV anti-infective therapy
- Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment
- Female subject of child-bearing potential is not willing to use, in combination with her partner, 2 methods of highly effective contraception during treatment and for 5 months after the end of treatment
- Clinically significant hypersensitivity to denosumab or any components of denosumab 120 mg
- Known sensitivity to any of the products to be administered during the study (e.g., calcium, or vitamin D)
- Subject is receiving or is less than 14 days since ending other experimental drug (no marketing authorization for any indication)
- Any major medical or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
Locations & Contacts
Contact: Ajay Kumar Nooka
Contact: Jacob Peter Laubach
Contact: Jacob Peter Laubach
Contact: Elizabeth (Betsy) K. O'Donnell
Contact: Andrew Jenho Yee
Contact: Robb Scott Friedman
Contact: Brea C. Lipe
Contact: Ehsan Malek
Trial Objectives and Outline
I. To assess the effect of denosumab 120 mg every 4 weeks (Q4W) on serum c-terminal telopeptide (sCTX) levels in multiple myeloma (MM) patients with renal insufficiency, defined as a creatinine clearance (CrCl) < 30 mL/min.
I. To assess the safety and tolerability of denosumab in MM patients with renal insufficiency.
II. To assess the incidence of hypocalcemia in patients with renal insufficiency receiving denosumab.
III. To assess the effect of denosumab on bone mineral density.
IV. To assess the effect of denosumab on urinary n-terminal telopeptide (uNTX).
V. To evaluate the proportions of subjects who have a documented skeletal-related event (SRE).
I. To assess the effect of denosumab on bone turnover markers which may include osteocalcin and procollagen 1 n-terminal propeptide (P1NP).
Patients receive denosumab subcutaneously (SC) on day 1. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks for 2 years.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Elizabeth (Betsy) K. O'Donnell
Secondary IDs NCI-2016-01375
Clinicaltrials.gov ID NCT02833610