A Study of Melphalan Flufenamide (Melflufen)-Dex or Pomalidomide-dex for RRMM Patients Refractory to Lenalidomide
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Melflufen; Pomalidomide; Dexamethasone
Intervention description: Intravenous infusion; Oral capsules; Oral tablets
Intervention MeSH terms: Dexamethasone; Dexamethasone acetate; Melphalan; Pomalidomide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 495.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Refractory Multiple Myeloma; Relapsed Multiple Myeloma; Melphalan flufenamide (Melflufen); Pomalidomide; Dexamethasone

Summary:

      This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled
      patients with RRMM following 2-4 lines of prior therapy and who were refractory to
      lenalidomide in the last line of therapy as demonstrated by disease progression on or within
      60 days of completion of the last dose of lenalidomide. Patients received either
      melflufen+dex or pomalidomide+dex.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female, age 18 years or older

          2. A prior diagnosis of multiple myeloma with documented disease progression requiring
             further treatment at time of screening

          3. Measurable disease defined as any of the following:

               -  Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis.

               -  ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis

               -  Serum free light chain ≥ 10 mg/dL AND abnormal serum kappa to lambda free light
                  chain ratio

          4. Received 2-4 prior lines of therapy, including lenalidomide and a PI, either
             sequential or in the same line, and is refractory (relapsed and refractory or
             refractory) to both the last line of therapy and to lenalidomide (≥ 10 mg)
             administered within 18 months prior to randomization. Refractory to lenalidomide is
             defined as progression while on lenalidomide therapy or within 60 days of last dose,
             following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per
             cycle.

          5. Life expectancy of ≥ 6 months

          6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

          7. Females of child bearing potential (FCBP) must have a negative serum or urine
             pregnancy test prior to start of treatment. Participants must agree to ongoing
             pregnancy testing. All patients must be willing to comply with all requirements of the
             USA pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or the
             pomalidomide Pregnancy Prevention Plan (PPP).

          8. Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent.

          9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula
             (QTcF) interval of ≤ 470 msec Fridericia Formula.

         10. The following laboratory results must be met during screening and also immediately
             before study drug administration on Cycle 1 Day 1:

               -  Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3 (1.0 x 10^9/L)

               -  Platelet count ≥ 75,000 cells/mm^3 (75 x 10^9/L)

               -  Hemoglobin ≥ 8.0 g/dl

               -  Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with
                  Gilberts syndrome, that have been reviewed and approved by the medical monitor.

               -  Aspartate transaminase (AST /SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x
                  ULN.

               -  Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45
                  mL/min.

         11. Must be able to take antithrombotic prophylaxis.

         12. Must have, or be willing to have an acceptable central catheter. (Port a cath,
             peripherally inserted central catheter [PICC-line], or central venous catheter)
             (Insertion only required if randomized to Arm A).

        Exclusion Criteria:

          1. Primary refractory disease (i.e. never responded (≥ MR) to any prior therapy)

          2. Evidence of mucosal or internal bleeding or platelet transfusion refractory

          3. Any medical conditions that, in the Investigator's opinion, would impose excessive
             risk to the patient or would adversely affect his/her participating in this study.

          4. Prior exposure to pomalidomide

          5. Known intolerance to IMiDs.

          6. Known active infection requiring parenteral or oral anti-infective treatment within 14
             days of randomization.

          7. Other malignancy diagnosed or requiring treatment within the past 3 years with the
             exception of adequately treated basal cell carcinoma, squamous cell skin cancer,
             carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in
             active surveillance.

          8. Pregnant or breast-feeding females

          9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or
             confuse compliance or follow-up evaluation

         10. Known human immunodeficiency virus or active hepatitis C viral infection

         11. Active hepatitis B viral infection (defined as HBsAg+).

               -  Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-,
                  Anti-HBs+, Anti-HBc-).

               -  Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the
                  discretion of the investigator after consideration of risk of reactivation.

         12. Concurrent symptomatic amyloidosis or plasma cell leukemia

         13. POEMS syndrome

         14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple
             myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. IMiDs, PIs
             and or corticosteroids within 2 weeks prior to randomization. Other investigational
             therapies and monoclonal antibodies within 4 weeks of randomization. Prednisone up to
             but no more than 10 mg orally q.d. or its equivalent for symptom management of
             comorbid conditions is permitted but dose should be stable for at least 7 days prior
             to randomization

         15. Residual side effects to previous therapy > grade 1 prior to randomization (Alopecia
             any grade and/or neuropathy grade 2 without pain are permitted)

         16. Prior peripheral stem cell transplant within 12 weeks of randomization

         17. Prior allogeneic stem cell transplantation with active graft-versus-host-disease.

         18. Prior major surgical procedure or radiation therapy within 4 weeks of the
             randomization

         19. Known intolerance to steroid therapy