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

This is a randomized, 2-arm phase II, placebo-controlled, multi-center study, where the investigators aim to evaluate whether the reported benefits of denosumab, delay of SRE and decrease in myeloma growth promotion, reduce the risk of progression of high-risk SMM and of early 'SLiM CRAB' myeloma into active, symptomatic CRAB positive myeloma or serological progression. In addition, tolerability of long-term treatment will be assessed.

The aim of this study is to evaluate whether the transition of early Multiple Myeloma (High Risk Smouldering Multiple Myeloma SMM or "Ultra High Risk" SMM) or SLiM CRAB positive multiple myeloma to a symptomatic multiple myeloma (MM) can be reduced or delayed by the administration of denosumab.

With the exception of clinical studies, there are currently no standardized treatment options for SMM. Ultra-high risk SMM is already part of early active myeloma and is therefore in some cases treated according to a standard myeloma protocol (Revlimid-Dexamethasone, Velcade melphalan prednisone, melphalan prednisone thalidomide, or others). However, most practitioners recommend a wait-and-see strategy, since depending on the initial situation within two years only 58-95% of patients develop an 'active' MM and 5-42% of the patients had a stable disease and therefore do not necessarily have to be treated immediately.

Denosumab is a human monoclonal antibody (IgG2) which binds to RANKL with high affinity and specificity. RANKL (receptor activator of NF-κB Ligand) is a protein that is responsible for the formation, function and survival of osteoclasts (cell type responsible for bone resorption) Increased osteoclast activity, stimulated by RANKL, is a key mediator of the bone resorption in bone metastases and MM. Thus the activity of denosumab is resulting in a reduced number and function of osteoclasts and thus decreases the bone resorption and tumor-induced bone destruction.

After an initial phase of about 14 days (screening), the patients will be randomized 1:1 in one of the two study groups (arm A: denosumab or arm B: placebo). The study is double-blinded. The planned duration of therapy is 3 years. Patients receive denosumab or placebo every 4 weeks for 6 months, then every 3 months until a total of 3 years or progression.

After completion of the therapy, an observation and follow-up phase is carried out with patient visits every 3 months until the end of the treatment.

Eligibility Criteria:
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