Denosumab for Smoldering Multiple Myeloma
Denosumab for Smoldering Multiple Myeloma
This study will assess the safety and tolerability of denosumab in smoldering multiple
 myeloma subjects as well to see if denosumab can reduce subjects' risk of getting multiple
 myeloma.
This is an open label, Phase II trial of denosumab 120mg subcutaneous (SC) for patients with
 smoldering multiple myeloma (SMM). Subjects will be recruited from the James P. Wilmot Cancer
 Center, University of Rochester in Rochester, New York. Patients seen in the inpatient or
 outpatient setting with histologically confirmed SMM will be evaluated for this study.

 20 patients will be treated as follows: Denosumab: day 1 = 120mg SC every 4 weeks for 12
 cycles. Cycles will be 28 days in length. Patients will be followed after completion of the
 study per standard of care for progression free survival for an additional 2 years after the
 last dose of denosumab. All patients will take daily vitamin D and calcium supplements of at
 least 1200mg elemental calcium and 800IU of vitamin D unless documented hypercalcemia
 develops on study. Pre-existing hypocalcemia must be corrected prior to initiating therapy
 with denosumab. Serum vitamin D levels will be checked during screening and should be
 repleted to a total 25-hydroxyvitamin D level ≥30ng/mL.
Inclusion Criteria:

 1. Patient has confirmed SMM according to the definition of the International Myeloma
 Working Group (IMWG) definition: serum M-protein ≥3 g/dL or BMPC >10% but less than
 60%, or both, along with normal organ and marrow function (CRAB) within 4 weeks prior
 to baseline. C: Absence of hypercalcemia, evidenced by a calcium ≤11 mg/dL. R: Absence
 of renal failure, evidenced by a creatinine ≤ 2.0mg/dL A: Absence of anemia, evidenced
 by a hemoglobin ≥10 g/dL.

 B: Absence of lytic bone lesions per IMWG recommendations:

 One of either PET-CT, low-dose whole-body CT (LDWBCT) or MRI of the whole body or
 spine. Increased uptake on PET-CT alone is not adequate for the diagnosis of multiple
 myeloma; evidence of underlying osteolytic bone destruction is needed on the CT
 portion of the examination.

 2. One of the risk factors below that portends for an increased risk of progression to
 MM:

 -  An abnormal free light chain ratio

 -  M-spike ≥ 4 g/dL

 -  ≥ 50% bone marrow plasma cells

 -  Immunoparesis ≥ 20% less than the institutional normal standard of the uninvolved
 immunoglobulins

 3. Serum calcium or albumin-adjusted serum calcium ≥ 2.1 mmol/L (8.4 mg/dL) and ≤
 2.9mmol/L (11.5 mg/dL) (Reference range 8.5-10.8 mg/dL)

 4. Able to tolerate daily supplementation of calcium and vitamin D

 5. Must have a vitamin D level ≥ 30 ng/mL after repletion

 6. Participants must have normal organ as defined below:

 -  Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN); patients
 diagnosed with Gilbert's syndrome can enroll with a total bilirubin > 2 after
 review of the principal investigator

 -  AST(SGOT) ≤2.5 × institutional ULN

 -  ALT(SGPT) ≤2.5 × institutional ULN

 7. Age ≥ 18 years.

 8. ECOG PS ≤1

 9. Life expectancy greater than 12 months

 10. 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.

 11. Ability to understand and the willingness to sign a written informed consent document.

 -Patient is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations including follow
 up.

 12. Statement on Inclusion of Women and Minorities - Men and women of all ethnicities and
 racial backgrounds are eligible for this study.

 Exclusion Criteria:

 1. Prior administration of denosumab.

 2. Any history of IV bisphosphonate use prior to or during the study

 3. Prescription oral fluorides or bisphosphonate usage > 3 months within the past 2 years

 4. Systemic corticosteroids > 10mg prednisone per day

 5. Known secondary cause for osteopenia or osteoporosis

 6. Patient has symptomatic MM, as defined by any of the following:

 -  Lytic lesions or pathologic fractures.

 -  Anemia (hemoglobin <10 g/dL)

 -  Hypercalcemia (corrected serum calcium > 11.0 mg/dL)

 -  Renal insufficiency (creatinine > 2.0 mg/dL).

 -  Clonal bone marrow plasma cells > 60%

 -  An involved serum free light chain (kappa or Lambda) > 100mg/L with the ratio of
 the involved/uninvolved free light chains also > 100 mg/L

 -  One or more osteolytic lesions on radiography, but more than one lesion is
 required if < 10% marrow plasma cells. From MRI imaging, there must be more than
 one lesion of > 5mm in size.

 7. Other: symptomatic hyperviscosity, amyloidosis, plasma cell leukemia, POEMS syndrome
 (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein)

 8. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

 9. Active dental or jaw condition that requires oral surgery, including tooth extraction.

 10. Non-healed dental/oral surgery, including tooth extraction.

 11. Planned invasive dental procedures during the course of study.

 12. Evidence of any of the following conditions per subject self-report or medical chart
 review:

 -  Any prior invasive malignancy within 3 years of enrollment that may affect
 outcome of study

 -  Any non-invasive malignancy not treated with curative intent or with known active
 disease within 3 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) requiring IV
 anti-infective therapy

 13. Subject is pregnant or breast feeding, or planning to become pregnant within 5 months
 after the end of treatment.

 14. 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.

 15. Clinically significant hypersensitivity to denosumab or any components of denosumab
 120mg.

 16. Known sensitivity to any of the products to be administered during the study (e.g.,
 calcium, or vitamin D).

 17. Subject is receiving or is less than 14 days since ending other experimental drug (no
 marketing authorization for any indication).

 18. 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.