Allogeneic Hematopoietic Stem Cell Transplantation With Ixazomib for High Risk Multiple Myeloma (BMT CTN 1302)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Allogeneic HSCT; Fludarabine; Melphalan; Bortezomib; Ixazomib; Placebo
Intervention description: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11.; Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3.; Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3.; Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3.; Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.; Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Intervention MeSH terms: Fludarabine; Bortezomib; Melphalan; Ixazomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 57.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Multiple Myeloma; Allogeneic Transplant; Maintenance Therapy; Anti-Myeloma Agents; Hematologic Disorders

Summary:

      This study is designed to compare progression-free survival (PFS) from randomization among
      patients randomized on the BMT CTN 1302 protocol, "Multicenter Phase II, Double-blind Placebo
      Controlled Trial of Maintenance Ixazomib after Allogeneic Hematopoietic Stem Cell
      Transplantation for High Risk Multiple Myeloma". It is hypothesized that Ixazomib maintenance
      therapy will result in improved PFS in patients with high-risk multiple myeloma following
      Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) compared to placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must meet one of the following disease criteria:

             a. Patients with high risk multiple myeloma in partial response (PR) or better with no
             prior progression and are ≤ 24.0 months after autologous hematopoietic cell
             transplantation (HCT) (single or planned tandem), or are ≤ 24.0 months after
             initiation of systemic anti-myeloma therapy for patients without prior autologous HCT;
             or

             i. High risk is defined by the presence of any one of the following detected at any
             time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics,
             hypodiploidy, abnormality in chromosome 1(1q amplification or 1p deletion), t(4;14),
             t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or
             conventional karyotyping; high risk criteria based on commercially available gene
             expression profiling (GEP)

             b. Patients with high risk multiple myeloma (see criterion 2.a.i. above) in very good
             partial response (VGPR) or better with 1 prior progression which occurred ≤ 24.0
             months after autologous HCT (single or planned tandem), or ≤ 24.0 months after
             initiation of systemic anti-myeloma therapy for patients without prior autologous HCT;
             or

             i. Patients with one prior progression without measurable monoclonal paraprotein at
             the time of disease progression or relapse (< 1.0 g/dl in serum or < 200 mg/24hrs in
             urine) may be considered to have met VGPR criteria if < 5% plasma cells in bone marrow
             and ≥ 90% decrease in the difference between involved and uninvolved free light chain
             (FLC) levels from baseline (time of progression/relapse).

             ii. In patients with immunoglobulin G (IgG) kappa multiple myeloma (MM) receiving
             daratumumab: International Myeloma Working Group criteria for VGPR may not be achieved
             since daratumumab is known to increase the IgG kappa spike. In such cases the FLC and
             marrow may be used to establish VGPR, as above, with prior approval from the protocol
             co-chairs.

             c. Patients with standard risk multiple myeloma in VGPR or better (see criteria 2.b.i.
             and 2.b.ii. above) at the time of enrollment with 1 prior progression ≤ 24.0 months
             from single or planned tandem autologous HCT; or d. Patients with primary plasma cell
             leukemia in VGPR or better with no prior disease progression and are ≤ 18.0 months
             after autologous HCT, or are ≤ 18.0 months after initiation of anti-myeloma therapy
             without prior autologous HCT.

          2. Patients must have a related or unrelated peripheral blood stem cell donor that meet
             one of the following criteria:

               1. A sibling donor who is a 6/6 match at HLA-A and -B (intermediate or higher
                  resolution) and -DR Beta 1 (DRB1) (at high resolution using DNA-based typing) and
                  must be willing to donate peripheral blood stem cells and meet institutional
                  criteria for donation OR

               2. A related donor (other than sibling) who is a 8/8 match for HLA-A, -B, -C (at
                  intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based
                  typing) and must be willing to donate peripheral blood stem cells and meet
                  institutional criteria for donation OR

               3. An unrelated donor who is an 8/8 match at HLA-A, -B, -C, and -DRB1 (at high
                  resolution using DNA-based typing) and must be willing to donate peripheral blood
                  stem cells and meet institutional criteria for donation.

          3. Cardiac function: Ejection fraction > 40%

          4. Estimated creatinine clearance greater than 40 mL/minute (using the Cockcroft-Gault
             formula and actual body weight)

          5. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40%
             (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%

          6. Liver function: total bilirubin < 2x the upper limit of normal and alanine
             aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit
             (Patients with Gilbert's Disease are permitted to exceed the defined bilirubin value
             of 2x the upper limit of normal, however measurements of direct bilirubin should be
             done to confirm this diagnosis).

          7. Female subjects (unless postmenopausal for at least 1 year before the screening visit,
             or surgically sterilized), agree to practice two (2) effective methods of
             contraception at the same time, or agree to practice true abstinence when this is in
             line with the preferred and usual lifestyle of the subject (Periodic abstinence [eg,
             calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not
             acceptable methods of contraception) through 90 days after the last dose of
             maintenance therapy (see Section 2.6.2 for definition of postmenopausal).

          8. Male subjects (even if surgically sterilized) must agree to one of the following:
             practice effective barrier contraception (see Section 2.6.4.1 for list of barrier
             methods), or practice true abstinence when this is in line with the preferred and
             usual lifestyle of the subject. Periodic abstinence [eg, calendar, ovulation,
             symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
             from the time of signing the informed consent through 90 days after last dose of
             maintenance therapy.

          9. Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care.

         10. Able to comply with the study visit schedule and other protocol requirements.

        Exclusion Criteria:

          1. Karnofsky Performance Score < 70%

          2. Prior allogeneic HCT

          3. Patient with purely non-secretory multiple myeloma [absence of monoclonal protein (M
             protein) in serum as measured by electrophoresis and immunofixation and the absence of
             Bence Jones protein in the urine defined by the use of conventional electrophoresis
             and immunofixation techniques and the absence of involved serum free light chain > 100
             mg/L].

          4. Planned pre-emptive/prophylactic administration of donor lymphocytes (as per section
             2.5.2)

          5. Central Nervous System (CNS) involvement with multiple myeloma defined as
             cerebrospinal fluid (CSF) positivity for plasma cells or a parenchymal CNS
             plasmacytoma

          6. Patients with uncontrolled bacterial, viral or fungal infections (currently taking
             medication and with progression or no clinical improvement) at time of enrollment.

          7. Presence of fluid collection (ascites, pleural, or pericardial effusion) that
             interferes with methotrexate clearance or makes methotrexate use contraindicated.

          8. Patients seropositive for the human immunodeficiency virus (HIV).

          9. Patient with active Hepatitis B or C determined by serology and/or nucleic acid
             amplification test (NAAT).

         10. Patients with hypersensitivity to bortezomib, boron or mannitol.

         11. Known GI disease or GI procedure that could interfere with the oral absorption or
             tolerance of MLN9708 (ixazomib) including difficulty swallowing.

         12. Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

         13. Patients with ≥ grade 2 sensory peripheral neuropathy.

         14. Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at screening must be documented by the investigator as not medically
             relevant.

         15. Female patients who are lactating or pregnant

         16. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma
             in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed.
             Cancer treated with curative intent < 5 years, which is in remission, will be reviewed
             on a case-by-case basis by the Protocol Officer or one of the Protocol Chairs.

         17. Patients with multi-organ involvement by amyloidosis or evidence of amyloidosis
             related organ dysfunction.

         18. Failure to have fully recovered (i.e., no toxicities > Grade 1 by CTCAE version 4.0)
             from the reversible effects of prior chemotherapy.

         19. Patient with serious medical of psychiatric illness likely to interfere with
             participation on this clinical study

         20. Participation in clinical trials with other investigational agents not included in
             this trial, ≤ 14.0 days of enrollment on this trial and throughout its duration.

         21. Patients who have received radiation therapy within 3 weeks before transplant.
             Enrollment of subjects who require concurrent radiotherapy (which must be localized in
             its field size) should be deferred until the radiotherapy is completed and 3 weeks
             have elapsed since the last date of therapy.

         22. Patients unable or unwilling to adhere to the study assessment schedule.