<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/NCT03836014</url>
  </required_header>
  <id_info>
    <org_study_id>D20180138</org_study_id>
    <secondary_id>2016-002129-12</secondary_id>
    <nct_id>NCT03836014</nct_id>
  </id_info>
  <brief_title>Study Comparing Continuous Versus Fixed Duration Therapy With Daratumumab, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma</brief_title>
  <acronym>CONFIRM</acronym>
  <official_title>A Multi-center Phase III Randomized Study Comparing Continuous Versus Fixed Duration Therapy With Daratumumab, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of&#xD;
      care has improved the outcome for patients with multiple myeloma (MM) over the past 10 years.&#xD;
      However, most patients (&gt;85%) still eventually relapse around 3-4 years after diagnosis, and&#xD;
      ultimately die of their disease, despite salvage therapies. Relapse can occur even when&#xD;
      complete remission is achieved after first-line therapy.&#xD;
&#xD;
      Currently, daratumumab (Dara) is approved by the american FDA and EMA in combination with&#xD;
      lenalidomide (Len) and dexamethasone (Dex) or bortezomib and Dex for the treatment of MM&#xD;
      patients who have received at least one prior therapy. Therefore, the Dara-Len-Dex&#xD;
      combination is likely to become the most widely used standard of care regimen for MM at the&#xD;
      time of first relapse.&#xD;
&#xD;
      However, although approval of the latter combination is meant for until disease progression&#xD;
      (PD) (&quot;continuous therapy&quot;) (CT), the actual optimal duration of relapse treatment is still&#xD;
      unknown. Of note, many experts advocate that a &quot;fixed duration&quot; of therapy should be favored,&#xD;
      especially if one can show that CT does not translate into a significant overall survival&#xD;
      (OS) benefit. As a matter of fact, given the extremely high cost of such novel agents (&gt;100&#xD;
      KEuros/year/patient), the pharmacoeconomic consequences of a &quot;continuous&quot; versus &quot;fixed&quot;&#xD;
      duration therapy are also of utmost importance.&#xD;
&#xD;
      Based on this background, the investigator propose to conduct a non-inferiority phase III&#xD;
      randomized, multicenter, open label trial for treatment of MM at first relapse, comparing the&#xD;
      Dara-Len-Dex combination administered continuously until PD, versus a fixed duration of 24&#xD;
      months. The choice of this duration is justified by the currently available evidence with&#xD;
      respect to achievement of a plateau in terms of deep disease response, patients' compliance,&#xD;
      and physicians' preference according to different surveys. The primary objective of this&#xD;
      study is to estimate the OS rate at 4 years after diagnosis of relapse and initiation of&#xD;
      salvage therapy. The primary endpoint is OS at 4 years after randomization. The analysis will&#xD;
      be performed on both per-protocol and intent-to-treat sets of patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      MM is a B cells malignancy, and is one of the most frequent primary neoplasms of the bone&#xD;
      marrow. The fundamental pathology is an expansion of a single clone of plasma cells that&#xD;
      produce monoclonal immunoglobulin (M-proteins) and replace normal bone marrow. Although the&#xD;
      etiology of myeloma is not known, several studies have shown that myeloma cells acquire&#xD;
      certain genetic changes that allow for uncontrolled growth, migration, and protection from&#xD;
      apoptosis.&#xD;
&#xD;
      The incidence of MM in Europe is 6.0 cases per 100,000 per year, with a median age at&#xD;
      diagnosis between 63 and 70 years; the mortality is 4.1 cases per 100,000 per year.&#xD;
&#xD;
      Dara is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope&#xD;
      on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor&#xD;
      cells that express high levels of CD38, such as plasma cells from patients with MM. This&#xD;
      target is distinct from those of other approved agents for MM therapy. Darashowed promising&#xD;
      efficacy alone and with Len and Den in a phase 1-2 study involving patients with relapsed or&#xD;
      refractory MM. Subsequently, a phase 3 trial randomized 569 MM patients to receive Len and&#xD;
      Den (Len-Dex; control group) or in combination with Dara (Dara-Len-Dex group) With a median&#xD;
      follow-up of 25.4 months, progression-free survival was significantly prolonged in the&#xD;
      Dara-Len-Dex group (median not reached versus 17.5 months in the control group; HR, 0.41; 95%&#xD;
      CI, 0.31-0.53; P &lt;0.0001). A significantly higher rate of overall response was observed in&#xD;
      the Dara-Len-Dex group than in the control group (93% vs. 76%, P&lt;0.0001), as was a higher&#xD;
      rate of complete response or better (51% vs. 21%, P&lt;0.0001). Furthermore, the rates of&#xD;
      treatment discontinuation owing to adverse events were low and similar in the two groups.&#xD;
&#xD;
      The investigator propose to conduct a non-inferiority phase III randomized, multicenter, open&#xD;
      label trial for treatment of MM at first relapse, comparing the Dara-Len-Dex combination&#xD;
      administered continuously until PD, versus a fixed duration of 24 months. The choice of this&#xD;
      duration is justified by the currently available evidence with respect to achievement of a&#xD;
      plateau in terms of deep disease response, patients' compliance, and physicians' preference&#xD;
      according to different surveys. As a matter of fact, given the extremely high cost of such&#xD;
      novel agents (&gt;100 KEuros/year/patient), the pharmacoeconomic consequences of a &quot;continuous&quot;&#xD;
      versus &quot;fixed&quot; duration therapy are also of utmost importance.&#xD;
&#xD;
      Dosage, route of administration and administration schedule of the medications prescribed are&#xD;
      in accordance with the FDA and EMEA authorization in MM first relapse. Only the duration of&#xD;
      combination is compared. One group of patient will receive the Dara-Len-Dex combination until&#xD;
      PD in accordance with the FDA and EMEA authorization in MM first relapse (standard of care).&#xD;
      The experimental group will receive the Dara-Len-Dex combination for up to 24 months. This&#xD;
      shorter duration of treatment (24 months) is justified by the currently available evidence&#xD;
      with respect to achievement of a plateau in terms of deep disease response, patients'&#xD;
      compliance, and physicians' preference according to different surveys.&#xD;
&#xD;
      The aim of the current protocol is to investigate whether a fixed duration of treatment (24&#xD;
      months) with the Dara-Len-Dex combination is not inferior to the continuous administration of&#xD;
      the combination until PD. In this study some patients may have a similar OS while receiving a&#xD;
      shorter duration of treatment. This study may allow to deliver a shorter duration of therapy&#xD;
      for the treatment of MM at first relapse.&#xD;
&#xD;
      The foreseeable risks are those of an earlier relapse in patients receiving a fixed duration&#xD;
      of Dara-Len-Dex combination compare to the situation where they would have received the&#xD;
      treatment until PD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 25, 2019</start_date>
  <completion_date type="Anticipated">July 2026</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>overall survival</measure>
    <time_frame>4 years after randomization</time_frame>
    <description>Overall survival (OS) is defined as the time between randomization and death due to any cause. Patients, who die, regardless of the cause of death, will be considered to have had an event even if they were lost to follow-up for an extended time. All subjects who are lost to follow-up prior to the end of the trial or who are withdrawn from the trial will be censored at the last available date the subject is known to be alive</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rate</measure>
    <time_frame>Within the 4 years after randomization</time_frame>
    <description>Best response rate obtain at any time within 4 years after randomization. Assessment of the International Myeloma Working Group uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall response rate (ORR)</measure>
    <time_frame>assessed monthly from Randomization until PD, (approximately up to 3 years).</time_frame>
    <description>disease evaluation will be assessed monthly until disease progression. ORR and will be calculated as the number of responders (at least partial response PR) divided by the number of subjects in the ITT population</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>at 4 years after randomization and initiation of salvage therapy</time_frame>
    <description>PFS will be calculated as the months between the randomization and disease progression based on IMWG criteria or death on study, whichever occurred earlier. Disease evaluation will be assessed monthly until disease progression or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events.</measure>
    <time_frame>within the 4 years after randomization</time_frame>
    <description>Descriptive statistics of cumulative dose, relative dose intensity, dose reduction and reason for dose reduction will be presented by treatment arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life (QoL)</measure>
    <time_frame>within the 4 years after randomization</time_frame>
    <description>Evaluation by EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life (QoL)</measure>
    <time_frame>within the 4 years after randomization</time_frame>
    <description>Evaluation by EQ-5D 5L (EuroQol - five dimension - five levels).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incremental cost-effectiveness ratios</measure>
    <time_frame>during the 4 years after randomization</time_frame>
    <description>expressed in cost per quality adjusted life year (QALY) gained, in cost per Life Year Gained, and in cost per progression free year gained</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">436</enrollment>
  <condition>Multiple Myeloma in Relapse</condition>
  <arm_group>
    <arm_group_label>Fixed duration therapy for 24 months.</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Daratumumab, Lenalidomide, Dexamethasone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Continuous therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Daratumumab, Lenalidomide, Dexamethasone</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Daratumumab/Lenalidomide/Dexamethasone for 24 months</intervention_name>
    <description>Conditioning regimen: 16 mg/kg IV :&#xD;
Weekly (Cycles 1 and C2)&#xD;
Every two weeks (C3 to C6)&#xD;
Monthly from C7 up to 24 months in total (Arm 1)&#xD;
Infusion reaction prophylaxis :&#xD;
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion&#xD;
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion&#xD;
Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion.&#xD;
Lenalidomide:&#xD;
Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle up to 24 months in total (Arm 1)&#xD;
Dexamethasone:&#xD;
Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle up to 24 months in total (Arm 1)</description>
    <arm_group_label>Fixed duration therapy for 24 months.</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Daratumumab/Lenalidomide/Dexamethasone until progression</intervention_name>
    <description>Conditioning regimen: 16 mg/kg IV :&#xD;
Weekly (Cycles 1 and C2)&#xD;
Every two weeks (C3 to C6)&#xD;
Monthly from C7 until disease progression (Arm 2).&#xD;
Infusion reaction prophylaxis :&#xD;
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion&#xD;
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion&#xD;
Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion.&#xD;
Lenalidomide:&#xD;
Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle until disease progression (Arm 2).&#xD;
Dexamethasone:&#xD;
Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle until disease progression (Arm 2).</description>
    <arm_group_label>Continuous therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients (≥ 18 years old)&#xD;
&#xD;
          2. Documented MM in relapse according to standard criteria and requiring initiation of a&#xD;
             first line salvage therapy.&#xD;
&#xD;
          3. Subject must have received one prior line of therapy for MM.&#xD;
&#xD;
          4. Subject must have achieved a response (PR or better) to the prior regimen.&#xD;
&#xD;
          5. Subject must have an ECOG Performance Status score of 0, 1, or 2.&#xD;
&#xD;
          6. For subjects experiencing toxicities resulting from previous therapy (including&#xD;
             peripheral neuropathy), the toxicities must have been resolved or stabilized.&#xD;
&#xD;
          7. Signed informed consent&#xD;
&#xD;
          8. Affiliation to a social security system or equivalent (recipient or assign)&#xD;
&#xD;
          9. Effective method of contraception for the duration of treatment and 3 months after the&#xD;
             last dose for women of childbearing age and men with a partner of childbearing age:&#xD;
&#xD;
               -  Progestin-only pill associated with inhibition of ovulation&#xD;
&#xD;
               -  Hormonal methods of contraception, including oral contraceptive pills containing&#xD;
                  a combination of estrogen + progesterone, vaginal ring, injectables, implants and&#xD;
                  intrauterine devices (IUDs)&#xD;
&#xD;
               -  non-hormonal IUD&#xD;
&#xD;
               -  Bilateral tubal occlusion&#xD;
&#xD;
               -  Vasectomized partner with documented azoospermia 90 days after procedure and who&#xD;
                  received a medical assessment of surgical success&#xD;
&#xD;
               -  Intrauterine hormone release system (IUS)&#xD;
&#xD;
               -  Complete Abstinence: Complete abstinence is defined as the complete avoidance of&#xD;
                  heterosexual intercourse. Complete abstinence is an acceptable form of&#xD;
                  contraception for all study drugs and must be used throughout the duration of the&#xD;
                  study and for the duration of time as specified above. It is not necessary to use&#xD;
                  any other method of contraception when complete abstinence is elected. Acceptable&#xD;
                  alternate methods of highly effective contraception must be discussed in the&#xD;
                  event that the subject chooses to forego complete abstinence.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of refractoriness or intolerance to lenalidomide and/or daratumumab (or&#xD;
             another anti CD38 monoclonal antibody). If previously treated with a lenalidomide or&#xD;
             daratumumab-containing regimen, the subject is excluded if he or she:&#xD;
&#xD;
               -  Discontinued due to any severe adverse event related to prior lenalidomide and/or&#xD;
                  daratumumab (or another anti CD38 monoclonal antibody) treatment, or&#xD;
&#xD;
               -  If, at any time point, the subject was refractory to any dose of lenalidomide&#xD;
                  and/or daratumumab (or another anti CD38 monoclonal antibody). Refractoriness to&#xD;
                  lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) is&#xD;
                  defined either as:&#xD;
&#xD;
                    -  Subjects whose disease progressed within 60 days of lenalidomide and/or&#xD;
                       daratumumab (or another anti CD38 monoclonal antibody) administration; or&#xD;
&#xD;
                    -  Subjects whose disease is nonresponsive while on lenalidomide and/or&#xD;
                       daratumumab (or another anti CD38 monoclonal antibody). Nonresponsive&#xD;
                       disease is defined as either failure to achieve at least a minimal response&#xD;
                       or development of progressive disease while on lenalidomide and/or&#xD;
                       daratumumab (or another anti CD38 monoclonal antibody).&#xD;
&#xD;
          2. Subject has received an allogenic stem cell transplant (regardless of timing).&#xD;
&#xD;
          3. Subjects planning to undergo a stem cell transplant prior to progression of disease on&#xD;
             this study, ie, these subjects should not be enrolled in order to reduce disease&#xD;
             burden prior to transplant.&#xD;
&#xD;
          4. Subject has a history of malignancy (other than MM) within 3 years before the date of&#xD;
             randomization (exceptions are squamous and basal cell carcinomas of the skin,&#xD;
             carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator&#xD;
             is considered cured with minimal risk of recurrence within 3 years).&#xD;
&#xD;
          5. Subject has known MM meningeal involvement.&#xD;
&#xD;
          6. Subject has plasma cell leukemia (&gt;2.0 × 109/L circulating plasma cells by standard&#xD;
             differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy,&#xD;
             organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.&#xD;
&#xD;
          7. Subject has any concurrent medical condition or disease (eg, active systemic&#xD;
             infection) that is likely to interfere with study procedures or results, or that, in&#xD;
             the opinion, of the investigator would constitute a hazard for participating in this&#xD;
             study.&#xD;
&#xD;
          8. Subject has known uncontrolled chronic obstructive pulmonary disease (COPD)&#xD;
&#xD;
          9. Subject has clinically significant cardiac disease.&#xD;
&#xD;
         10. Subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis&#xD;
             B or hepatitis C.&#xD;
&#xD;
         11. Creatinine clearance ≤30 mL/min (MDRD method) (lenalidomide dose adjustment will be&#xD;
             considered for subjects with creatinine clearance 30-60 mL/min).&#xD;
&#xD;
         12. Hypersensitivity to the active substance or to any of the excipients&#xD;
&#xD;
         13. Pregnancy or lactation women&#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>Mohamad Mohty, PU-PH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Saint Antoine Hospital - Hematology Department</name>
      <address>
        <city>Paris</city>
        <zip>75012</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <last_update_submitted>February 28, 2023</last_update_submitted>
  <last_update_submitted_qc>February 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Multiple myeloma</keyword>
  <keyword>Relapse</keyword>
  <keyword>daratumumab,</keyword>
  <keyword>lenalidomide</keyword>
  <keyword>dexamethasone</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>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>Lenalidomide</mesh_term>
    <mesh_term>Daratumumab</mesh_term>
    <mesh_term>BB 1101</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03836014
org study id: D20180138
secondary id: 2016-002129-12
nct id: NCT03836014
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of
      care has improved the outcome for patients with multiple myeloma (MM) over the past 10 years.
      However, most patients (>85%) still eventually relapse around 3-4 years after diagnosis, and
      ultimately die of their disease, despite salvage therapies. Relapse can occur even when
      complete remission is achieved after first-line therapy.

      Currently, daratumumab (Dara) is approved by the american FDA and EMA in combination with
      lenalidomide (Len) and dexamethasone (Dex) or bortezomib and Dex for the treatment of MM
      patients who have received at least one prior therapy. Therefore, the Dara-Len-Dex
      combination is likely to become the most widely used standard of care regimen for MM at the
      time of first relapse.

      However, although approval of the latter combination is meant for until disease progression
      (PD) ("continuous therapy") (CT), the actual optimal duration of relapse treatment is still
      unknown. Of note, many experts advocate that a "fixed duration" of therapy should be favored,
      especially if one can show that CT does not translate into a significant overall survival
      (OS) benefit. As a matter of fact, given the extremely high cost of such novel agents (>100
      KEuros/year/patient), the pharmacoeconomic consequences of a "continuous" versus "fixed"
      duration therapy are also of utmost importance.

      Based on this background, the investigator propose to conduct a non-inferiority phase III
      randomized, multicenter, open label trial for treatment of MM at first relapse, comparing the
      Dara-Len-Dex combination administered continuously until PD, versus a fixed duration of 24
      months. The choice of this duration is justified by the currently available evidence with
      respect to achievement of a plateau in terms of deep disease response, patients' compliance,
      and physicians' preference according to different surveys. The primary objective of this
      study is to estimate the OS rate at 4 years after diagnosis of relapse and initiation of
      salvage therapy. The primary endpoint is OS at 4 years after randomization. The analysis will
      be performed on both per-protocol and intent-to-treat sets of patients.
MM is a B cells malignancy, and is one of the most frequent primary neoplasms of the bone
      marrow. The fundamental pathology is an expansion of a single clone of plasma cells that
      produce monoclonal immunoglobulin (M-proteins) and replace normal bone marrow. Although the
      etiology of myeloma is not known, several studies have shown that myeloma cells acquire
      certain genetic changes that allow for uncontrolled growth, migration, and protection from
      apoptosis.

      The incidence of MM in Europe is 6.0 cases per 100,000 per year, with a median age at
      diagnosis between 63 and 70 years; the mortality is 4.1 cases per 100,000 per year.

      Dara is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope
      on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor
      cells that express high levels of CD38, such as plasma cells from patients with MM. This
      target is distinct from those of other approved agents for MM therapy. Darashowed promising
      efficacy alone and with Len and Den in a phase 1-2 study involving patients with relapsed or
      refractory MM. Subsequently, a phase 3 trial randomized 569 MM patients to receive Len and
      Den (Len-Dex; control group) or in combination with Dara (Dara-Len-Dex group) With a median
      follow-up of 25.4 months, progression-free survival was significantly prolonged in the
      Dara-Len-Dex group (median not reached versus 17.5 months in the control group; HR, 0.41; 95%
      CI, 0.31-0.53; P <0.0001). A significantly higher rate of overall response was observed in
      the Dara-Len-Dex group than in the control group (93% vs. 76%, P<0.0001), as was a higher
      rate of complete response or better (51% vs. 21%, P<0.0001). Furthermore, the rates of
      treatment discontinuation owing to adverse events were low and similar in the two groups.

      The investigator propose to conduct a non-inferiority phase III randomized, multicenter, open
      label trial for treatment of MM at first relapse, comparing the Dara-Len-Dex combination
      administered continuously until PD, versus a fixed duration of 24 months. The choice of this
      duration is justified by the currently available evidence with respect to achievement of a
      plateau in terms of deep disease response, patients' compliance, and physicians' preference
      according to different surveys. As a matter of fact, given the extremely high cost of such
      novel agents (>100 KEuros/year/patient), the pharmacoeconomic consequences of a "continuous"
      versus "fixed" duration therapy are also of utmost importance.

      Dosage, route of administration and administration schedule of the medications prescribed are
      in accordance with the FDA and EMEA authorization in MM first relapse. Only the duration of
      combination is compared. One group of patient will receive the Dara-Len-Dex combination until
      PD in accordance with the FDA and EMEA authorization in MM first relapse (standard of care).
      The experimental group will receive the Dara-Len-Dex combination for up to 24 months. This
      shorter duration of treatment (24 months) is justified by the currently available evidence
      with respect to achievement of a plateau in terms of deep disease response, patients'
      compliance, and physicians' preference according to different surveys.

      The aim of the current protocol is to investigate whether a fixed duration of treatment (24
      months) with the Dara-Len-Dex combination is not inferior to the continuous administration of
      the combination until PD. In this study some patients may have a similar OS while receiving a
      shorter duration of treatment. This study may allow to deliver a shorter duration of therapy
      for the treatment of MM at first relapse.

      The foreseeable risks are those of an earlier relapse in patients receiving a fixed duration
      of Dara-Len-Dex combination compare to the situation where they would have received the
      treatment until PD.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: overall survival
time frame: 4 years after randomization
description: Overall survival (OS) is defined as the time between randomization and death due to any cause. Patients, who die, regardless of the cause of death, will be considered to have had an event even if they were lost to follow-up for an extended time. All subjects who are lost to follow-up prior to the end of the trial or who are withdrawn from the trial will be censored at the last available date the subject is known to be alive
measure: Response rate
time frame: Within the 4 years after randomization
description: Best response rate obtain at any time within 4 years after randomization. Assessment of the International Myeloma Working Group uniform response criteria
measure: overall response rate (ORR)
time frame: assessed monthly from Randomization until PD, (approximately up to 3 years).
description: disease evaluation will be assessed monthly until disease progression. ORR and will be calculated as the number of responders (at least partial response PR) divided by the number of subjects in the ITT population
measure: Progression free survival (PFS)
time frame: at 4 years after randomization and initiation of salvage therapy
description: PFS will be calculated as the months between the randomization and disease progression based on IMWG criteria or death on study, whichever occurred earlier. Disease evaluation will be assessed monthly until disease progression or death.
measure: Incidence of adverse events.
time frame: within the 4 years after randomization
description: Descriptive statistics of cumulative dose, relative dose intensity, dose reduction and reason for dose reduction will be presented by treatment arm.
measure: Quality of Life (QoL)
time frame: within the 4 years after randomization
description: Evaluation by EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30)
measure: Quality of Life (QoL)
time frame: within the 4 years after randomization
description: Evaluation by EQ-5D 5L (EuroQol - five dimension - five levels).
measure: Incremental cost-effectiveness ratios
time frame: during the 4 years after randomization
description: expressed in cost per quality adjusted life year (QALY) gained, in cost per Life Year Gained, and in cost per progression free year gained
arm group label: Fixed duration therapy for 24 months.
arm group type: Experimental
description: Daratumumab, Lenalidomide, Dexamethasone
arm group label: Continuous therapy
arm group type: Active Comparator
description: Daratumumab, Lenalidomide, Dexamethasone
intervention type: Combination Product
intervention name: Daratumumab/Lenalidomide/Dexamethasone for 24 months
description: Conditioning regimen: 16 mg/kg IV :
Weekly (Cycles 1 and C2)
Every two weeks (C3 to C6)
Monthly from C7 up to 24 months in total (Arm 1)
Infusion reaction prophylaxis :
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion
Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion.
Lenalidomide:
Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle up to 24 months in total (Arm 1)
Dexamethasone:
Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle up to 24 months in total (Arm 1)
arm group label: Fixed duration therapy for 24 months.
intervention type: Combination Product
intervention name: Daratumumab/Lenalidomide/Dexamethasone until progression
description: Conditioning regimen: 16 mg/kg IV :
Weekly (Cycles 1 and C2)
Every two weeks (C3 to C6)
Monthly from C7 until disease progression (Arm 2).
Infusion reaction prophylaxis :
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion
Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion.
Lenalidomide:
Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle until disease progression (Arm 2).
Dexamethasone:
Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle until disease progression (Arm 2).
arm group label: Continuous therapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mohamad Mohty, PU-PH
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
facility: 
country: France
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Recurrence
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: Lenalidomide
mesh term: Daratumumab
mesh term: BB 1101
mesh term: Antibodies, Monoclonal
sharing ipd: Undecided