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.
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
- 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
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
12. Statement on Inclusion of Women and Minorities - Men and women of all ethnicities and
racial backgrounds are eligible for this study.
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
- 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
- Active infection with Hepatitis B virus or Hepatitis C virus
- Known infection with human immunodeficiency virus (HIV) requiring IV
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
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.