Pomalidomide and Dexamethasone With or Without Ixazomib in Treating Patients With Relapsed Multiple Myeloma

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) for combination therapy
pomalidomide/dexamethasone/ixazomib. (Phase I) II. To assess whether the combination of
pomalidomide/dexamethasone/ixazomib improves progression-free survival (PFS) relative to
pomalidomide/dexamethasone. (Phase II)

SECONDARY OBJECTIVES:

I. To determine dose-limiting toxicities (DLTs). (Phase I) II. To analyze type and grade of
all serious adverse events (SAEs). (Phase I) III. To analyze type and grade of all adverse
events (AEs). (Phase I) IV. To analyze the reason for and incidence of dose
modifications/omissions/delays. (Phase I) V. To assess preliminary evidence of clinical
efficacy. (Phase I) VI. To assess whether the overall response rate (ORR), partial response
(PR), very good partial response (VGPR), complete response (CR) or stringent CR (sCR) rate
differ with respect to treatment regimen. (Phase II) VII. To assess the clinical benefit rate
(CBR: minimal response [MR] + ORR) for pomalidomide/dexamethasone/ixazomib compared to
pomalidomide/dexamethasone. (Phase II) VIII. To assess the disease control rate (DCR: stable
disease [SD] + CBR) for pomalidomide/dexamethasone/ixazomib compared to
pomalidomide/dexamethasone. (Phase II) IX. For those patients achieving a PR or better, we
will assess whether the combination of pomalidomide/dexamethasone/ixazomib increases the
duration of response (DOR) compared to pomalidomide/dexamethasone. (Phase II) X. To assess
whether the combination of pomalidomide/dexamethasone/ixazomib improves overall survival (OS)
compared to those taking pomalidomide/dexamethasone alone. (Phase II) XI. To assess time to
next treatment (TNT) for patients taking pomalidomide/dexamethasone/ixazomib compared to
those on pomalidomide/dexamethasone. (Phase II) XII. To evaluate the safety of
pomalidomide/dexamethasone/ixazomib compared with pomalidomide/dexamethasone. (Phase II)
XIII. For patients on the pomalidomide/dexamethasone arm who opt to cross-over to the
pomalidomide/dexamethasone/ixazomib arm, assessment of response rate (ORR, CBR, DCR), DOR,
TNT, PFS and OS will be evaluated from date of cross-over. (Phase II) XIV. To determine if
baseline level of perceived fatigue and overall quality of life (QOL) is associated with OS.
(Phase II)

OUTLINE: This is a phase I, dose-escalation study of pomalidomide and ixazomib followed by a
phase II study.

After completion of study treatment, patients are followed up every 4 weeks until disease
progression and then every 3 months for 3 years.

- Histologically confirmed diagnosis of symptomatic multiple myeloma; relapsed disease
is myeloma that has previously responded to prior therapy (MR or better) and
subsequently progressed

- Patient must have measurable disease or non-measurable disease, defined as one or more
of the following holding true:

- Measurable disease:

- Serum M-protein >= 1.0 g/dL (>= 0.5 g/dL for IgA or IgM myeloma) and/or

- Urine M-protein >= 200 mg/24 hours and/or

- Involved serum free light chain level >= 10 mg/dL AND an abnormal serum free
light chain ratio

- For non-measurable disease:

- Baseline marrow burden of myeloma of at least 30%

- Progression on lenalidomide as part of first line therapy (lenalidomide-refractory
disease)

* Lenalidomide-refractory disease is defined as disease progression on or progression
within 60 days of the last dose of a lenalidomide-based treatment; patients should
have received at least 2 cycles of a lenalidomide-based regimen to be evaluable for
refractoriness; examples: 1) progression on lenalidomide maintenance therapy after
initial induction +/- consolidation; 2) initial response followed by progression on
continuous lenalidomide-dexamethasone +/- elotuzumab or daratumumab

- Pomalidomide naive disease

- Proteasome inhibitor naive or sensitive disease; proteasome inhibitor sensitive
disease is defined as a PR or better to prior proteasome inhibitor-based therapy that
is maintained for >= 60 days from the last dose of the proteasome inhibitor

* A patient who receives induction therapy with lenalidomide, bortezomib and
dexamethasone and achieves a PR or better but subsequently progresses on continued
lenalidomide or lenalidomide-dexamethasone would be eligible provided the progression
occurs 60 days or more after discontinuation of the bortezomib; similarly, ixazomib
exposure is allowed provided they meet the definition of proteasome inhibitor
sensitive disease

- 1 prior line of systemic therapy for multiple myeloma, where a line of therapy for
myeloma is defined as 1 or more planned cycles of single agent or combination therapy,
as well as a planned series of treatment regimens administered in a sequential manner
(e.g. lenalidomide, bortezomib and dexamethasone induction therapy for 4 cycles
followed by autologous stem cell transplantation and then lenalidomide maintenance
therapy would be considered 1 line of prior therapy); a new line of therapy begins
when a planned therapy is modified to include other treatment agents (alone or in
combination) as a result of disease progression, disease relapse or treatment-related
toxicity (e.g. a patient is progressing in the face of lenalidomide maintenance
therapy and has bortezomib and dexamethasone added into their regimen); a new line of
therapy also begins when a planned treatment-free interval is interrupted by the need
to start treatment due to disease relapse/progression (e.g. a patient with relapsed
myeloma achieves a partial response after a planned 8 cycles of cyclophosphamide,
bortezomib and dexamethasone, enjoys an 8-month period off therapy but then
experiences disease progression requiring re-initiation of therapy)

- Allogeneic stem cell transplantation is allowed provided the patient is >= 1 year from
transplant at time of registration, is not on immunosuppressive therapy to
treat/prevent graft-versus-host disease, has no evidence of active graft versus host
disease, and no evidence of active infection

- No other chemotherapy or radiation therapy within 14 days prior to registration

- No investigational therapy within 14 days prior to registration

- No major surgery within 28 days prior to registration

- No G-CSF (filgrastim) or GM-CSF (sargramostim) within 7 days of registration or
pegfilgrastim within 14 days of registration to meet eligibility criteria

- No platelet transfusions within 7 days of registration to meet eligibility criteria;
Note: red blood cell transfusions are allowed at any time

- A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in
the preceding 24 consecutive months)

- Women of childbearing potential:

- Must have a negative serum or urine pregnancy test with a sensitivity of at
least 25 mlU/ml no more than 14 days prior to registration and must agree to
repeat this test within 24 hours of starting pomalidomide

- Must either commit to complete abstinence from heterosexual contact or begin
TWO acceptable methods of birth control, one highly effective method and one
additional effective (barrier) method, AT THE SAME TIME, before starting
pomalidomide

- Must agree to ongoing pregnancy testing

- Must agree to not become pregnant or breast feed a child during treatment on
this protocol

- Men must practice complete abstinence or agree to use a condom during sexual
contact with a female of childbearing potential, even if they have had a
successful vasectomy

- Note: All participants must be counseled at a minimum of every 28 days about
pregnancy precautions and risks of fetal exposure

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

- Platelet count >= 50 x 10^9/L

- Calculated (Calc.) creatinine clearance >= 30 mL/min; calculated utilizing the
Cockcroft-Gault formula or 24-hour urine collection

- Total bilirubin < 1.5 x upper limits of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper
limits of normal (ULN)

- Note: G-CSF and platelet transfusions cannot be used to increase counts to meet
eligibility criteria

- Patients cannot have:

- Central nerve system involvement

- Primary refractory multiple myeloma, where primary refractory multiple myeloma is
defined as disease that is nonresponsive - patients who have never achieved a
minimal response (MR) or better - with any therapy over the course of their
disease; it includes patients who never achieve MR or better in whom there is no
significant change in M-protein and no evidence of clinical progression as well
as patients who meet criteria for true progressive disease (PD)

- Primary or secondary plasma cell leukemia

- Light-chain (AL) amyloidosis or polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy, and skin changes (POEMS) syndrome

- Known active hepatitis C based on:

- +hepatitis C virus (HCV) antibody (confirmed)

- +HCV RNA

- Liver disease with history of positive serology

- Note: patients with a prior history of hepatitis C that has been
successfully eradicated with antiviral therapy are eligible

- Known hepatitis B surface antigen positivity

- Previous hypersensitivity to any of the components of the study treatment

- Prior history of erythema multiforme with thalidomide or lenalidomide treatment

- =< grade 2 peripheral neuropathy

- Adequate cardiac function, defined as:

- No electrocardiogram (EKG) evidence of acute ischemia

- No EKG evidence of active, clinically significant conduction system abnormalities

- No EKG evidence of > grade 2 (> 480 ms) corrected QT (QTc) prolongation

- Prior to study entry, any EKG abnormality at screening not felt to put the
patient at risk has to be documented by the investigator as not medically
significant

- No uncontrolled angina or severe ventricular arrhythmias

- No clinically significant pericardial disease

- No history of myocardial infarction within 6 months prior to registration

- No class 3 or higher New York Heart Association congestive heart failure

- No strong inducers of cytochrome P450 (CYP) 3A4 or CYP1A2 or strong inhibitors of
CYP3A4 or CYP1A2 within 14 days prior to registration

- Note: Ixazomib is a substrate of CYP3A4 and CYP1A2

- Patients with human immunodeficiency virus (HIV) infection are eligible, provided they
meet the following:

- No history of acquired immunodeficiency syndrome (AIDS)-defining conditions or
other HIV related illness

- Cluster of differentiation (CD)4+ cells nadirs > 350/mm^3 within 28 days prior to
registration

- Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50
copies/mm^3 within 28 days prior to registration

- Note: HIV+ patients who enroll on this study and are assigned to treatment with
ixazomib may need to modify their anti-retroviral therapy prior to receiving
protocol therapy if they are on strong inducers or potent inhibitors of
cytochrome P450 3A4

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patients randomized to Arm 1 may opt to
switch to the 3-drug regimen following disease progression; these patients must be
re-registered to the study and meet the eligibility criteria below

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Patient must have measurable disease or
non-measurable disease after progression on pomalidomide + dexamethasone, defined as
one or more of the following holding true:

* Measurable disease:

- Serum M-protein >= 0.5 g/dL and/or

- Urine M-protein >= 200 mg/24 hours and/or

- Involved serum free light chain level >= 10 mg/dL AND an abnormal serum free
light chain ratio

* For non-measurable disease:

- Marrow burden of myeloma of at least 30%

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2):

- Women of childbearing potential:

** Must have a negative serum or urine pregnancy test within 72 hours prior to
re-registration

** Must either commit to complete abstinence from heterosexual contact or begin
TWO acceptable methods of birth control, one highly effective method and one
additional effective (barrier) method, AT THE SAME TIME, before starting
pomalidomide

** Must agree to ongoing pregnancy testing

** Must agree to not become pregnant or breast feed a child during treatment on
this protocol

- Men must practice complete abstinence or agree to use a condom during sexual
contact with a female of childbearing potential, even if they have had a
successful vasectomy

- Note: All participants must be counseled at a minimum of every 28 days about
pregnancy precautions and risks of fetal exposure

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): ECOG performance status 0-2

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Absolute neutrophil count (ANC) >= 1.0
x 10^9/L

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Platelet count >= 50 x 10^9/L

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Calc. creatinine clearance >= 30 mL/min

* Calculated utilizing the Cockcroft-Gault formula or 24-hour urine collection

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Total bilirubin < 1.5 x upper limits of
normal (ULN)

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): AST and ALT < 2.5 x upper limits of
normal (ULN)

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): Note: G-CSF and platelet transfusions
cannot be used to increase counts to meet eligibility criteria

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): =< grade 2 peripheral neuropathy

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2): No strong inducers of cytochrome P450
(CYP) 3A4 or CYP1A2 or strong inhibitors of CYP3A4 or CYP1A2 * Note: Ixazomib is a
substrate of CYP3A4 and CYP1A2