Summary

This randomized phase II trial studies how well ixazomib citrate and dexamethasone or ixazomib citrate, dexamethasone, and lenalidomide work based on the expression of a gene called nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) in treating patients with multiple myeloma that has returned after a period of improvement (recurrent) or does not respond to treatment (refractory). Ixazomib citrate may stop the growth of cancer cells by blocking enzymes called proteasomes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stimulate the immune system against cancer cells and may also prevent the growth of new blood vessels that tumors need to grow. It is not yet known whether ixazomib citrate and dexamethasone, or ixazomib citrate, dexamethasone, and lenalidomide are more effective in treating multiple myeloma.

Objectives

PRIMARY OBJECTIVES:
I. To test whether the NFKB2 rearrangement can guide the selection of treatment (ixazomib [ixazomib citrate] plus dexamethasone [Id] or ixazomib plus lenalidomide and dexamethasone [IRd]) by conducting the following 3 comparisons:
Ia. To compare the response rate at 4 cycles between patients treated with Id and patients treated with IRd and confirm the lack of significant difference in overall response.
Ib. To compare the response rate at 4 cycles between non-rearranged and rearranged NFKB2 treated with Id and confirm that NFKB2 rearrangement is associated with reduce response rate.
Ic. To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated with Id or IRd and confirm that adding lenalidomide increases the response rate in this population.

SECONDARY OBJECTIVES:
I. To determine time to treatment failure (TTF).
II. To determine the frequency and severity adverse events (AE) in IRd treated cohort.
III. To identify novel transcribed mutations associated with Id and IRd resistance in patients with multiple myeloma (MM).
IV. To determine the prevalence of NFKB2 rearrangement in relapsed/refractory MM patients screened in the study.
V. To determine the prevalence of NFKB2 rearrangement according to the type of previous therapies received in all patients screened in the study.
VI. To determine the toxicity profile of the study drugs according to the presence of NFKB2 rearrangement.
VII. Delineate transcribed mutations associated with relapse or refractoriness to Id or IRd treatment by ribonucleic acid (RNA)-sequencing.

OUTLINE:
ARM A (UNMUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and dexamethasone PO on days 1, 8, 15, and 22.

Patients with mutated NFKB2 rearrangement are randomized in to 1 of 2 treatment arms.

ARM B (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib citrate and dexamethasone as in arm A.

ARM C (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib citrate and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.

In all arms, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients may proceed to autologous stem cell transplant after 4 cycles of treatment.

After completion of study, patients are followed up monthly.

Eligibility

1. 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
2. Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and again within 24 hours of starting lenalidomide and ixazomib and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide through 90 days after the last dose of study drug; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy from the time of signing the informed consent form through 90 days after the last dose of study drug; in the event that the male patients choose to agree to practice true abstinence, this must follow the timelines detailed above; all patients assigned to the lenalidomide treatment group must be registered in and must comply with all requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months
3. Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis
4. The patient has confirmed relapsed or refractory MM
5. For patients that relapse following a response to prior treatment with bortezomib or carfilzomib, six months must have elapsed since the last dose of treatment
6. The patient has received 1 to 3 prior lines of therapy; by definition, a single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy; radiotherapy, bisphosphonate, or a single short course of steroids (i.e., less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy
7. Patients must have measurable disease defined by at least 1 of the following measurements: * Serum M-protein >= 1.0 g/dL (>= 10 g/L) for an immunoglobulin (Ig)G myeloma, >= 0.1 g/dL for an IgD myeloma or 0.5 g/dL (>= 5g/L) for an IgA myeloma * Urine light chain >= 200 mg/24 hours * Serum free light chain >= 10 mg/dL provided the free light chain (FLC) ratio is abnormal * Patients with oligo- or non-secretory disease must have bone marrow involvement with at least 30% plasmacytosis on aspiration
8. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2
9. Absolute neutrophil count (ANC) >= 1,000/mm^3
10. Platelet count >= 75,000/mm^3; in the case that platelets are between 50,000 -75,000, the patient can be enrolled if the plasma cell count in the bone marrow is superior to >= 50%; to meet this hematological eligibility no transfusion support and hematological growth factor are not allowed within 7 days before study enrollment
11. Total bilirubin =< 1.5 x the upper limit of the normal range (ULN)
12. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
13. Serum creatinine =< 2.5 mg/dL or a calculated creatinine clearance >= 50 mL/min

Treatment Sites in Georgia