Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients

Inclusion Criteria:

* Age ≥ 18 years
* Able to provide written informed consent in accordance with federal, local, and institutional guidelines
* Must meet criteria of high-risk smoldering MM or early "SLiM CRAB" MM based on the criteria described below:

  * High-risk SMM is defined here according to the revised Mayo Clinical criteria (2 out of 3 criteria must be fulfilled):

    * Bone marrow clonal plasma cells \> 20%
    * Serum M protein \> 2.0g/dL
    * Serum-free light chain ratio \> 20, measured with "Binding site Kit"
  * Early 'SLiM CRAB' multiple myeloma

    * Patients must present with only one of the following features
    * Bone marrow clonal plasma cells ≥ 60%, or
    * Serum FLC ratio ≥ 100 (kappa-LC leading) or ≤ 0.01 (lambda-LC leading), measured with "Binding site Kit", or
    * \>1 Focal bone lesion of ≥5mm (not associated with osteolysis, detected by PET-CT or whole-body low-dose CT (WBLDCT))
* Time from diagnosis of high-risk SMM or SLIM CRAB positive, early MM to study enrollment: \<5 years

Exclusion Criteria:

* ECOG \>3
* Active, symptomatic MM (fulfilling CRAB-criteria)
* Non-secretory MM, extramedullary plasmacytoma, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
* MGUS
* Hypocalcemia (can be corrected by drug intervention before start of treatment)
* Second malignancy within the past 5 years except:

  * Adequately treated basal cell or squamous cell skin cancer
  * Carcinoma in situ of the cervix
  * Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA over 12 months)
  * Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
  * Treated medullary or papillary thyroid cancer
  * Similar condition with an expectation of \> 95% five-year disease-free survival
* Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
* Patients with known active or latent tuberculosis
* Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection (subjects with past hepatitis B virus \[HBV\] infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti-HBc\] antibody test are eligible; subjects positive for hepatitis C virus \[HCV\] antibody are eligible only if polymerase chain reaction \[PCR\] is negative for HCV RNA.)
* Participation in another interventional study within the 28 days prior to randomization
* Any other clinically significant medical disease or social condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent, be compliant with study procedures, or provide accurate information.
* Prior administration of denosumab
* Prior exposure to any experimental or approved anti-myeloma agent
* Use of oral bisphosphonates with a cumulative exposure of more than 1 year (washout period for allowed bisphosphonate exposure 1 month)
* More than 1 previous dose of IV bisphosphonate or teriparatide administration (washout period for allowed bisphosphonate exposure 1 month)
* Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
* Active dental or jaw condition which requires oral surgery, including tooth extraction
* Subject is pregnant or breastfeeding, or planning to become pregnant within 7 months after the end of treatment
* Female subject of childbearing potential is not willing to use, in combination with her partner, a highly effective and in addition an effective method of contraception during treatment and for 5 months after the end of treatment
* Known sensitivity to denosumab (including all components of the formulation) or any of the products to be administered during the study (eg, mammalian derived products, calcium, or vitamin D)
* Subject is receiving or is less than 30 days since ending other experimental devices or drugs (no marketing authorization for any indication).
* Subject will not be available for follow-up assessment