Ibrutinib, Lenalidomide, and Dexamethasone in Treating Patients With Multiple Myeloma Ineligible for Transplant

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of ibrutinib that can be combined with
lenalidomide and dexamethasone in relapsed multiple myeloma (MM) patients. (Phase I) II. To
estimate the overall response rate (ORR) including partial response (PR) or better of the
combination of ibrutinib, lenalidomide, and dexamethasone in subjects with newly diagnosed MM
who are not candidates for high dose chemotherapy and autologous stem cell transplantation
(ASCT). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of this regimen in relapsed MM patients. (Phase I) II. To
evaluate the progression free survival (PFS) of the combination of ibrutinib, lenalidomide,
and dexamethasone in MM patients. (Phase II) III. To evaluate the safety profile of this
regimen in untreated MM patients. (Phase II) IV. To evaluate the duration of response for
patients treated with this 3-drug regimen. (Phase II) V. To evaluate overall survival (OS)
for patients treated with this 3-drug regimen. (Phase II)

TERTIARY OBJECTIVES:

I. To explore compliance to treatment. II. To assess effects of treatment on patient-reported
quality of life (QoL) measures.

III. To determine the role of members of the BTK signalosome in achievement or lack thereof
of response to ibrutinib.

IV. To explore biologic effects of ibrutinib on microenvironment in MM and correlate with
response to treatment.

V. To evaluate pharmacodynamic measures including receptor occupancy for BTK prior to
introducing lenalidomide in patients treated with ibrutinib and dexamethasone.

VI. To evaluate the impact of ibrutinib on platelet aggregation.

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

PHASE I: Patients receive ibrutinib orally (PO) on days 1-28, lenalidomide PO on days 1-21,
and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24
courses in the absence of disease progression or unacceptable toxicity. Beginning course 25,
patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22.
Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive ibrutinib and dexamethasone as in phase I and lenalidomide PO on
days 1-21 beginning course 2. Beginning course 25, patients receive lenalidomide and
dexamethasone as in phase I.

After completion of study treatment, patients are followed up every 3 months, then every 6
months for up to 3 years.

Inclusion Criteria:

- Diagnosis

- Phase I: confirmed diagnosis of relapsed or refractory multiple myeloma

- Phase II: confirmed diagnosis of active multiple myeloma and must be newly
diagnosed

- NOTE: all tests for establishing disease status must be completed =< 28 days
prior to registration

- Measurable disease =< 28 days prior to registration, defined by at least one of the
following:

- Serum monoclonal protein >= 1.0 g/dL

- > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis

- Serum immunoglobulin free light chain > 10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio

- Monoclonal bone marrow plasmacytosis > 30% (evaluable disease)

- Prior treatment

- Phase I: exposure to 2-3 prior lines of therapy or no therapeutic options

- Phase II: previously untreated for symptomatic MM

- EXCEPTION: =< 7 days with pulse steroids or localized radiation therapy, without
curative intent, for a myeloma-related complication prior to registration is
allowed, as considered necessary by the treating physician

- Myeloma Frailty Score:

- NOTE: this will include calculating a frailty score (based on age, activities of
daily living, instrumental activities of daily living and Charlson comorbidity
index)

- Phase I: "intermediate fitness" or "frail"; NOTE: no "fit" patients will be
included in the phase 1 portion of the trial which is being done to
determine the MTD of the 3-drug combination

- Phase II: transplant-ineligible as per their treating physician; NOTE: all
the patients with "intermediate fitness" or "frail" status will be
considered transplant-ineligible; other reasons to consider transplant
ineligibility may include, but are not limited to: financial constraints or
patient preference; in case such patients have a frailty score of "fit", it
should be duly noted by the treating physician

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2

- Absolute neutrophil count (ANC) >= 1,000 cell/mm^3 without growth factor support

- Platelets >= 50,000 cells/mm^3 for patients who have bone marrow

- Plasmacytosis < 50% or >= 30,000 cells/mm^3 for patients who have bone marrow
plasmacytosis of >= 50%

- Calculated or measured creatinine clearance >= 30 ml/min

- Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome

- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN

- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 X ULN

- Provide informed written consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Persons able to become pregnant must be willing to adhere to the scheduled pregnancy
testing as required in the REVLIMID Risk Evaluation and Mitigation Strategy (REMS)
program

- Willing to be registered into the mandatory REVLIMID REMS program, and willing and
able to comply with the requirements of the REVLIMID REMS program

- Ability to complete study-related (QoL, pill diary) questionnaire(s) by themselves or
with assistance

- Willing to provide bone marrow aspirate and core, and blood samples for correlative
research purposes

Exclusion Criteria:

- Non-secretory MM or known amyloid light-chain (AL) amyloidosis

- Clinically significant active infection requiring intravenous antibiotics =< 14 days
prior to registration

- >= grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

- Other prior malignancy; EXCEPTIONS:

- Adequately treated basal cell or squamous cell skin cancer

- Any in situ cancer

- Adequately treated stage I or II cancer from which the patient is currently in
complete remission, or

- Any other cancer from which the patient has been disease-free for >= at least
three years prior to registration

- Concurrent therapy considered to be investigational; NOTE: patients must not be
planning to receive any radiation therapy (except localized radiation for palliative
care that must be completed prior to starting cycle 1, day 1)

- Any of the following:

- Pregnant women

- Nursing women (lactating females are eligible provided that they agree not to
breast feed while taking lenalidomide)

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Requires treatment with a strong cytochrome (CYP) 3A4/5 inhibitor

- Major surgery =< 4 weeks prior to registration

- History of stroke/intracranial hemorrhage =< 6 months prior to registration

- Requires use of therapeutic anticoagulation prior to registration

- NOTE: thromboprophylaxis with any agent is permitted

- History of clinically significant bleeding or known platelet or coagulation disorder

- Clinically significant cardiac illness including New York Heart Association (NYHA)
class III or class IV heart failure, unstable angina pectoris, myocardial infarction
within the past 6 months, or >= grade 3 cardiac arrhythmias noted =< 14 days prior to
registration

- Hepatic impairment:

- Phase I: any currently active, clinically significant hepatic impairment
(Child-Pugh class A, B, or C according to the Child Pugh classification)

- Phase II: currently active, clinically significant hepatic impairment Child-Pugh
class B or C according to the Child Pugh classification

- Known human immunodeficiency virus (HIV) positive (+) patients; EXCEPTION: if they
meet the following additional criteria =< 28 days prior to registration:

- CD4 cells >= 500/mm^3

- Viral load of < 50 copies HIV messenger (m) ribonucleic acid (RNA)/mm^3 if on
combination antiretroviral therapy (cART) or < 10,000 copies HIV mRNA if not on
cART • No zidovudine or stavudine as part of cART

- Known hepatitis B or hepatitis C infection; EXCEPTION: if viral load < 800,000 IU/L

- Phase I: active dermatologic disease >= grade 3