Comparison of Pomalidomide and Dexamethasone With or Without Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma Previously Treated With Lenalidomide and a Proteasome InhibitorDaratumumab/Pomalidomide/Dexamethasone vs Pomalidomide/Dexamethasone
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Daratumumab; Pomalidomide; Dexamethasone
Intervention description: Daratumumab will be given at a dose of 16 mg/kg administered as an IV infusion (Dara IV) or 1800 mg subcutaneously (Dara SC) at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Subjects will receive pre-infusion medications before infusions to mitigate potential IRRs.; Pomalidomide will be administered at full dose of 4 mg orally (PO) on Days 1 through 21 of each 28-day cycle.; Dexamethasone will be administered at a dose of 40 mg (20 mg for patients ≥75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle.
Intervention MeSH terms: Dexamethasone; Daratumumab; Pomalidomide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Masking: Single (Participant)
Masking description: Masking: Open Label
Enrollment: 304.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the effects of the addition of daratumumab to
      pomalidomide and dexamethasone in terms of progression-free survival in subjects with
      relapsed or refractory Multiple Myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Males and females at least 18 years of age.

          2. Voluntary written informed consent before performance of any study-related procedure.

          3. Subject must have measurable disease of MM as defined by the criteria below:

               -  IgG multiple myeloma: Serum M protein level ≥1.0 g/dL or urine M-protein level
                  ≥200 mg/24 hours, or

               -  IgA, IgD, IgE, IgM multiple myeloma: Serum M-protein level ≥0.5 g/dL or urine
                  M-protein level ≥200 mg/24 hours; or

               -  Light chain multiple myeloma, for subjects without measurable disease in the
                  serum or urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and
                  abnormal serum immunoglobulin kappa lambda FLC ratio.

          4. Subjects must have received prior antimyeloma treatment. The prior treatment must have
             included both a PI- and lenalidomide-containing regimens. The subject must have had a
             response (ie, PR or better based on the investigator's determination of response as
             defined by the modified IMWG criteria) to prior therapy.

          5. Subjects must have documented evidence of PD based on the investigator's determination
             of response as defined by the modified IMWG criteria on or after the last regimen.

          6. Subjects who received only 1 line of prior treatment must have demonstrated PD on or
             within 60 days of completion of the lenalidomide containing regimen (ie, lenalidomide
             refractory).

          7. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.

          8. Willingness and ability to participate in study procedures.

          9. For subjects experiencing toxicities resulting from previous therapy, the toxicities
             must be resolved or stabilized to ≤Grade 1.

         10. Any of the following laboratory test results during Screening:

               1. Absolute neutrophil count ≥1.0 × 109/L;

               2. Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L); (transfusions are not permitted to
                  reach this level);

               3. Platelet count ≥75 × 109/L in subjects in whom <50% of bone marrow nucleated
                  cells are plasma cells and platelet count ≥50 x 109/L in subjects in whom ≥50% of
                  bone marrow nucleated cells are plasma cells;

               4. Alanine aminotransferase (ALT) level ≤2.5 times the upper limit of normal (ULN);

               5. Aspartate aminotransferase (AST) level ≤2.5 x ULN;

               6. Total bilirubin level ≤1.5 x ULN, (except for Gilbert Syndrome: direct bilirubin
                  ≤1.5 × ULN);

               7. Creatinine clearance ≥30 mL/min

               8. Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized
                  calcium ≤ 6.5 mg/dL (≤1.6 mmol/L).

         11. Reproductive Status

               1. Women of childbearing potential (WOCBP) must have 2 negative serum or urine
                  pregnancy tests, one 10-14 days prior to start of study treatment and one 24
                  hours prior to the start of study treatment. Females are not of reproductive
                  potential if they have been in natural menopause for at least 24 consecutive
                  months, or have had a hysterectomy and/or bilateral oophorectomy.

               2. Women must not be breastfeeding.

               3. WOCBP must agree to follow instructions for methods of contraception for 4 weeks
                  before the start of study treatment, for the duration of study treatment, and for
                  3 months after cessation of daratumumab or 4 weeks after cessation of
                  pomalidomide, whichever is longer.

               4. Males who are sexually active must always use a latex or synthetic condom during
                  any sexual contact with females of reproductive potential, even if they have
                  undergone a successful vasectomy. They must also agree to follow instructions for
                  methods of contraception for 4 weeks before the start of study treatment, for the
                  duration of study treatment, and for a total of 3 months post-treatment
                  completion.

               5. Male subjects must not donate sperm for up to 90 days post-treatment completion.

               6. Female subject must not donate eggs for up to 90 days post-treatment completion.

               7. Azoospermic males and WOCBP who are not heterosexually active are exempt from
                  contraceptive requirements. However, WOCBP will still undergo pregnancy testing
                  as described in this section.

        Highly effective methods of contraception have a failure rate of < 1% when used
        consistently and correctly. Subjects must agree to the use of 2 methods of contraception,
        with 1 method being highly effective and the other method being additionally effective.

        Because of the embryo-fetal risk of pomalidomide, all subjects must adhere to the
        pomalidomide pregnancy prevention program applicable in their region. Investigators should
        comply with the local label for pomalidomide for specific details of the program.

        Exclusion Criteria:

          1. Previous therapy with any anti-CD38 monoclonal antibody.

          2. Previous exposure to pomalidomide.

          3. Subject has received antimyeloma treatment within 2 weeks or 5 pharmacokinetic
             half-lives of the treatment, whichever is longer, before the date of randomization.
             The only exception is emergency use of a short course of corticosteroids (equivalent
             of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before
             Cycle 1, Day 1 (C1D1).

          4. Previous allogenic stem cell transplant; or autologous stem cell transplantation
             (ASCT) within 12 weeks before C1D1.

          5. History of malignancy (other than MM) within 3 years before the date of randomization
             (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of
             the cervix or breast, or other non-invasive lesion that in the opinion of the
             investigator, with concurrence with the sponsor's medical monitor, is considered cured
             with minimal risk of recurrence within 3 years).

          6. Clinical signs of meningeal involvement of MM.

          7. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1
             second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for
             subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of
             predicted normal.

          8. Clinically significant cardiac disease, including:

               1. Myocardial infarction within 6 months, before C1D1 or unstable or uncontrolled
                  condition (eg, unstable angina, congestive heart failure, New York Heart
                  Association Class III-IV).

               2. Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Grade
                  3 or higher) or clinically significant electrocardiogram (ECG) abnormalities.

               3. Electrocardiogram showing a baseline QT interval as corrected QTc >470 msec.

          9. Known active hepatitis A, B, or C.

         10. Known HIV infection.

         11. Gastrointestinal disease that may significantly alter the absorption of pomalidomide.

         12. Subject has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard
             differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy,
             organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.

         13. Any concurrent medical or psychiatric condition or disease (eg, active systemic
             infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that
             is likely to interfere with the study procedures or results or that, in the opinion of
             the investigator, would constitute a hazard for participating in this study.

         14. Ongoing ≥ Grade 2 peripheral neuropathy.

         15. Subject had ≥Grade 3 rash during prior therapy.

         16. Subject has had major surgery within 2 weeks before randomization, or has not fully
             recovered from an earlier surgery, or has surgery planned during the time the subject
             is expected to participate in the study or within 2 weeks after the last dose of study
             drug administration. Note: subjects with planned surgical procedures to be conducted
             under local anesthesia may participate. Kyphoplasty or vertebroplasty are not
             considered major surgery.

         17. Pregnant or nursing women.