<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03839459</url>
  </required_header>
  <id_info>
    <org_study_id>UMMY18121</org_study_id>
    <nct_id>NCT03839459</nct_id>
  </id_info>
  <brief_title>Denosumab for Smoldering Multiple Myeloma</brief_title>
  <official_title>Denosumab for Smoldering Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Rochester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Rochester</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will assess the safety and tolerability of denosumab in smoldering multiple&#xD;
      myeloma subjects as well to see if denosumab can reduce subjects' risk of getting multiple&#xD;
      myeloma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open label, Phase II trial of denosumab 120mg subcutaneous (SC) for patients with&#xD;
      smoldering multiple myeloma (SMM). Subjects will be recruited from the James P. Wilmot Cancer&#xD;
      Center, University of Rochester in Rochester, New York. Patients seen in the inpatient or&#xD;
      outpatient setting with histologically confirmed SMM will be evaluated for this study.&#xD;
&#xD;
      20 patients will be treated as follows: Denosumab: day 1 = 120mg SC every 4 weeks for 12&#xD;
      cycles. Cycles will be 28 days in length. Patients will be followed after completion of the&#xD;
      study per standard of care for progression free survival for an additional 2 years after the&#xD;
      last dose of denosumab. All patients will take daily vitamin D and calcium supplements of at&#xD;
      least 1200mg elemental calcium and 800IU of vitamin D unless documented hypercalcemia&#xD;
      develops on study. Pre-existing hypocalcemia must be corrected prior to initiating therapy&#xD;
      with denosumab. Serum vitamin D levels will be checked during screening and should be&#xD;
      repleted to a total 25-hydroxyvitamin D level ≥30ng/mL.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 19, 2019</start_date>
  <completion_date type="Anticipated">June 1, 2024</completion_date>
  <primary_completion_date type="Actual">September 16, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases.</measure>
    <time_frame>1 year</time_frame>
    <description>Risk Categories:&#xD;
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present&#xD;
Risk Factors:&#xD;
BM plasma cell % ≥50&#xD;
M-protein ≥ 3g/dL&#xD;
Involved/ un-involved free light chains ≥ 8</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of Subjects With Skeletal Related Events</measure>
    <time_frame>1 year</time_frame>
    <description>To be determined by the investigator</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Subjects With Disease Progression to Multiple Myeloma</measure>
    <time_frame>1 year</time_frame>
    <description>Risk Categories:&#xD;
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present&#xD;
Risk Factors:&#xD;
BM plasma cell % ≥50&#xD;
M-protein ≥ 3g/dL&#xD;
Involved/ un-involved free light chains ≥ 8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Subjects With Progression Free Survival</measure>
    <time_frame>3 year</time_frame>
    <description>time to progression or death from any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Subjects With Change in Bone Mineral Density</measure>
    <time_frame>1 year</time_frame>
    <description>baseline and each post-treatment point</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Smoldering Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Denosumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Denosumab</intervention_name>
    <description>120mg of Denosumab will be administered subcutaneously once every 4 weeks</description>
    <arm_group_label>Denosumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient has confirmed SMM according to the definition of the International Myeloma&#xD;
             Working Group (IMWG) definition: serum M-protein ≥3 g/dL or BMPC &gt;10% but less than&#xD;
             60%, or both, along with normal organ and marrow function (CRAB) within 4 weeks prior&#xD;
             to baseline. C: Absence of hypercalcemia, evidenced by a calcium ≤11 mg/dL. R: Absence&#xD;
             of renal failure, evidenced by a creatinine ≤ 2.0mg/dL A: Absence of anemia, evidenced&#xD;
             by a hemoglobin ≥10 g/dL.&#xD;
&#xD;
             B: Absence of lytic bone lesions per IMWG recommendations:&#xD;
&#xD;
             One of either PET-CT, low-dose whole-body CT (LDWBCT) or MRI of the whole body or&#xD;
             spine. Increased uptake on PET-CT alone is not adequate for the diagnosis of multiple&#xD;
             myeloma; evidence of underlying osteolytic bone destruction is needed on the CT&#xD;
             portion of the examination.&#xD;
&#xD;
          2. One of the risk factors below that portends for an increased risk of progression to&#xD;
             MM:&#xD;
&#xD;
               -  An abnormal free light chain ratio&#xD;
&#xD;
               -  M-spike ≥ 4 g/dL&#xD;
&#xD;
               -  ≥ 50% bone marrow plasma cells&#xD;
&#xD;
               -  Immunoparesis ≥ 20% less than the institutional normal standard of the uninvolved&#xD;
                  immunoglobulins&#xD;
&#xD;
          3. Serum calcium or albumin-adjusted serum calcium ≥ 2.1 mmol/L (8.4 mg/dL) and ≤&#xD;
             2.9mmol/L (11.5 mg/dL) (Reference range 8.5-10.8 mg/dL)&#xD;
&#xD;
          4. Able to tolerate daily supplementation of calcium and vitamin D&#xD;
&#xD;
          5. Must have a vitamin D level ≥ 30 ng/mL after repletion&#xD;
&#xD;
          6. Participants must have normal organ as defined below:&#xD;
&#xD;
               -  Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN); patients&#xD;
                  diagnosed with Gilbert's syndrome can enroll with a total bilirubin &gt; 2 after&#xD;
                  review of the principal investigator&#xD;
&#xD;
               -  AST(SGOT) ≤2.5 × institutional ULN&#xD;
&#xD;
               -  ALT(SGPT) ≤2.5 × institutional ULN&#xD;
&#xD;
          7. Age ≥ 18 years.&#xD;
&#xD;
          8. ECOG PS ≤1&#xD;
&#xD;
          9. Life expectancy greater than 12 months&#xD;
&#xD;
         10. Subjects with reproductive potential must be willing to use, in combination with&#xD;
             his/her partner, 2 highly effective methods of effective contraception or practice&#xD;
             sexual abstinence throughout the study and continue for 5 months after the study&#xD;
             duration. Subjects who are surgically sterile (e.g. history of bilateral tubal&#xD;
             ligation, hysterectomy) or whose sexual partner is sterile (e.g. history of vasectomy)&#xD;
             are not required to use additional contraceptive measures.&#xD;
&#xD;
         11. Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
             -Patient is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up.&#xD;
&#xD;
         12. Statement on Inclusion of Women and Minorities - Men and women of all ethnicities and&#xD;
             racial backgrounds are eligible for this study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior administration of denosumab.&#xD;
&#xD;
          2. Any history of IV bisphosphonate use prior to or during the study&#xD;
&#xD;
          3. Prescription oral fluorides or bisphosphonate usage &gt; 3 months within the past 2 years&#xD;
&#xD;
          4. Systemic corticosteroids &gt; 10mg prednisone per day&#xD;
&#xD;
          5. Known secondary cause for osteopenia or osteoporosis&#xD;
&#xD;
          6. Patient has symptomatic MM, as defined by any of the following:&#xD;
&#xD;
               -  Lytic lesions or pathologic fractures.&#xD;
&#xD;
               -  Anemia (hemoglobin &lt;10 g/dL)&#xD;
&#xD;
               -  Hypercalcemia (corrected serum calcium &gt; 11.0 mg/dL)&#xD;
&#xD;
               -  Renal insufficiency (creatinine &gt; 2.0 mg/dL).&#xD;
&#xD;
               -  Clonal bone marrow plasma cells &gt; 60%&#xD;
&#xD;
               -  An involved serum free light chain (kappa or Lambda) &gt; 100mg/L with the ratio of&#xD;
                  the involved/uninvolved free light chains also &gt; 100 mg/L&#xD;
&#xD;
               -  One or more osteolytic lesions on radiography, but more than one lesion is&#xD;
                  required if &lt; 10% marrow plasma cells. From MRI imaging, there must be more than&#xD;
                  one lesion of &gt; 5mm in size.&#xD;
&#xD;
          7. Other: symptomatic hyperviscosity, amyloidosis, plasma cell leukemia, POEMS syndrome&#xD;
             (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein)&#xD;
&#xD;
          8. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.&#xD;
&#xD;
          9. Active dental or jaw condition that requires oral surgery, including tooth extraction.&#xD;
&#xD;
         10. Non-healed dental/oral surgery, including tooth extraction.&#xD;
&#xD;
         11. Planned invasive dental procedures during the course of study.&#xD;
&#xD;
         12. Evidence of any of the following conditions per subject self-report or medical chart&#xD;
             review:&#xD;
&#xD;
               -  Any prior invasive malignancy within 3 years of enrollment that may affect&#xD;
                  outcome of study&#xD;
&#xD;
               -  Any non-invasive malignancy not treated with curative intent or with known active&#xD;
                  disease within 3 years before enrollment that may affect outcome of study&#xD;
&#xD;
               -  Major surgery or significant traumatic injury occurring within 4 weeks before&#xD;
                  enrollment&#xD;
&#xD;
               -  Active infection with Hepatitis B virus or Hepatitis C virus&#xD;
&#xD;
               -  Known infection with human immunodeficiency virus (HIV) requiring IV&#xD;
                  anti-infective therapy&#xD;
&#xD;
         13. Subject is pregnant or breast feeding, or planning to become pregnant within 5 months&#xD;
             after the end of treatment.&#xD;
&#xD;
         14. Female subject of child-bearing potential is not willing to use, in combination with&#xD;
             her partner, 2 methods of highly effective contraception during treatment and for 5&#xD;
             months after the end of treatment.&#xD;
&#xD;
         15. Clinically significant hypersensitivity to denosumab or any components of denosumab&#xD;
             120mg.&#xD;
&#xD;
         16. Known sensitivity to any of the products to be administered during the study (e.g.,&#xD;
             calcium, or vitamin D).&#xD;
&#xD;
         17. Subject is receiving or is less than 14 days since ending other experimental drug (no&#xD;
             marketing authorization for any indication).&#xD;
&#xD;
         18. Any major medical or psychiatric disorder that, in the opinion of the investigator,&#xD;
             might prevent the subject from completing the study or interfere with the&#xD;
             interpretation of the study results.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brea Lipe</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Rochester Wilmot Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Rochester</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>February 11, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <results_first_submitted>January 19, 2023</results_first_submitted>
  <results_first_submitted_qc>January 19, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 15, 2023</results_first_posted>
  <last_update_submitted>January 19, 2023</last_update_submitted>
  <last_update_submitted_qc>January 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Rochester</investigator_affiliation>
    <investigator_full_name>Brea Lipe</investigator_full_name>
    <investigator_title>Associate Professor - Department of Medicine , Hematology/Oncology</investigator_title>
  </responsible_party>
  <keyword>Smoldering Multiple Myeloma</keyword>
  <keyword>Denosumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
    <mesh_term>Smoldering Multiple Myeloma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Denosumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 15, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/59/NCT03839459/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 21, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/59/NCT03839459/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Denosumab</title>
          <description>Denosumab: 120mg of Denosumab will be administered subcutaneously once every 4 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>progression of disease</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Denosumab</title>
          <description>Denosumab: 120mg of Denosumab will be administered subcutaneously once every 4 weeks</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>30-39</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>40-49</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60-69</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>70-79</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>80-89</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases.</title>
        <description>Risk Categories:&#xD;
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present&#xD;
Risk Factors:&#xD;
BM plasma cell % ≥50&#xD;
M-protein ≥ 3g/dL&#xD;
Involved/ un-involved free light chains ≥ 8</description>
        <time_frame>1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Denosumab</title>
            <description>Denosumab: 120mg of Denosumab will be administered subcutaneously once every 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases.</title>
          <description>Risk Categories:&#xD;
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present&#xD;
Risk Factors:&#xD;
BM plasma cell % ≥50&#xD;
M-protein ≥ 3g/dL&#xD;
Involved/ un-involved free light chains ≥ 8</description>
          <units>proportion of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Subjects With Skeletal Related Events</title>
        <description>To be determined by the investigator</description>
        <time_frame>1 year</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Subjects With Disease Progression to Multiple Myeloma</title>
        <description>Risk Categories:&#xD;
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present&#xD;
Risk Factors:&#xD;
BM plasma cell % ≥50&#xD;
M-protein ≥ 3g/dL&#xD;
Involved/ un-involved free light chains ≥ 8</description>
        <time_frame>1 year</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Subjects With Progression Free Survival</title>
        <description>time to progression or death from any cause, whichever occurs first.</description>
        <time_frame>3 year</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Subjects With Change in Bone Mineral Density</title>
        <description>baseline and each post-treatment point</description>
        <time_frame>1 year</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Denosumab</title>
          <description>Denosumab: 120mg of Denosumab will be administered subcutaneously once every 4 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Kidney infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear and labyrinth disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Adrenal insufficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Endocrine disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dental caries</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Oral hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nail infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Injury, poisoning and procedural complications - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hemoglobin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hepatobiliary disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Investigations - Other</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Buttock pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Osteoporosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Amnesia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Brea Lipe, MD</name_or_title>
      <organization>University of Rochester Medical Center</organization>
      <phone>(585) 275-4099</phone>
      <email>Brea_Lipe@URMC.Rochester.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03839459
org study id: UMMY18121
nct id: NCT03839459
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases.
time frame: 1 year
description: Risk Categories:
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present
Risk Factors:
BM plasma cell % ≥50
M-protein ≥ 3g/dL
Involved/ un-involved free light chains ≥ 8
measure: Proportion of Subjects With Skeletal Related Events
time frame: 1 year
description: To be determined by the investigator
measure: Proportion of Subjects With Disease Progression to Multiple Myeloma
time frame: 1 year
description: Risk Categories:
Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present
Risk Factors:
BM plasma cell % ≥50
M-protein ≥ 3g/dL
Involved/ un-involved free light chains ≥ 8
measure: Proportion of Subjects With Progression Free Survival
time frame: 3 year
description: time to progression or death from any cause, whichever occurs first.
measure: Proportion of Subjects With Change in Bone Mineral Density
time frame: 1 year
description: baseline and each post-treatment point
arm group label: Denosumab
arm group type: Experimental
intervention type: Drug
intervention name: Denosumab
description: 120mg of Denosumab will be administered subcutaneously once every 4 weeks
arm group label: Denosumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Brea Lipe
role: Principal Investigator
affiliation: University of Rochester Wilmot Cancer Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Rochester
investigator full name: Brea Lipe
investigator title: Associate Professor - Department of Medicine , Hematology/Oncology
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Smoldering Multiple Myeloma
mesh term: Denosumab
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 