This is a registration, open-label phase 1 study of the combination of ibrutinib/lenalidomide:/dexamethasone in women and men with relapsed/refractory multiple myeloma.

The study will be completed in two parts: Dose escalation and dose expansion.

Dose Escalation Starting doses of ibrutinib and lenalidomide will be assigned at the time of registration. A minimum of 2 or a maximum of 6 patients will be accrued to a given dose level. Doses will not be escalated in any individual patient.

If none of the first 3 patients treated at a given dose level develops a dose limiting toxicity during the first cycle of treatment, enrollment to the dose level will be closed and enrollment will reopen at next higher dose level. If there are no other higher dose levels to be tested, three additional patients will be enrolled at the current dose level to confirm maximum tolerated dose. If one of the first 3 patients treated at a given dose level develops a dose limiting toxicity during the first cycle of treatment, three additional patients will be enrolled onto the current dose level. If, at any time in the enrollment of these 3 additional patients, a patient develops a dose limiting toxicity, enrollment will be closed to this dose level. Enrollment will be re-opened to the next lower dose level if fewer than 6 patients have been treated at that dose level. If none of these 3 additional patients develops a dose limiting toxicity during the first cycle of treatment, enrollment to this dose level will be closed and enrollment will reopen at next higher dose level. If there are no other higher dose levels to be tested, this will be considered the maximum tolerated dose.

Patients will return to the clinic every 28 days for physical exams, laboratory assessments and review of side effects.

Patients who do not have disease progression and have not experienced unacceptable toxicities will be eligible to continue protocol treatment at their current dose level until disease progression, unacceptable toxicity, or refusal. Those patients who have not experienced progression of disease but have unacceptable toxicity may be eligible for re-treatment at a lower dose.

Part 2: Dose Expansion Once the maximum tolerated dose has been established or determined, 4-10 additional patients will be treated at the maximum tolerated dose of lenalidomide and ibrutinib at the same schedule as above. Dexamethasone will be given at the same dose as in the dose escalation portion of the study.

Patients who discontinue treatment for protocol defined reasons will go to survival follow-up. Once a patient has entered the survival follow-up phase of the trial, his/her therapy is at the discretion of the treating physician. Patients' charts will be reviewed for progression and survival endpoints during visits with treating physicians.

Inclusion Criteria:

1. Men and women ≥ 18 years

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Appendix I).

3. Symptomatic multiple myeloma (MM) (as defined by revised IMWG criteria) with measurable disease, defined here as having at least one of the following:

   • Serum monoclonal protein ≥ 0.5 g/dL
   • ≥200 mg of monoclonal protein in the urine on 24 hour electrophoresis
   • Serum immunoglobulin free light chain (FLC): involved FLC ≥ 10 mg/dL (≥ 100 mg/L) AND abnormal serum immunoglobulin kappa to lambda free light chain ratio.

4. At least 1 prior therapy with demonstrated disease progression following the most recent line of treatment.

5. Progression of disease within 60 days of completion of last therapeutic regimen or the failure to achieve minimal response while on last treatment (according to IMWG).

   • Patients should not have progressed on lenalidomide at a dose of more than 10mg

6. No prior treatment with ibrutinib or any other protein kinase inhibitory drug or drug targeting the b-cell receptor (BCR) signal transduction pathway.

7. Patients with prior daratumumab and allogeneic stem cell transplant are included.

8. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN, except if on anticoagulation for medical reasons in which case INR should be ≤ 3

9. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to registration, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screen and enrollment defined as:

   • Absolute neutrophil count (ANC) ≥1000/mm3 independent of growth factor support.
   • Transfusion independent platelet counts ≥75,000/mm3 (or ≥50,000/mm3 if bone marrow involvement is ≥50%).
   • Hemoglobin level ≥ 8 g/dL, independent of transfusion support.

10. Biochemical values must be within the following limits within 7 days prior to registration

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN).
    • Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
    • Serum creatinine ≤ 2 x ULN or GFR > 30 ml/min based on either the estimated Glomerular Filtration Rate (Crockcoft Gault) or measured GFR from 24-hour urine sample. Study participants with GFR 30-50 ml/min will be treated according to manufacturer's instruction with lenalidomide 10mg rather than 25 mg.

11. Ability to understand and willingness to sign a written informed consent form (ICF).

12. Ability to adhere with the study visit schedule and other protocol procedures.

13. A negative pregnancy test will be required for all women of child bearing potential within 7 days prior to registration. Breast feeding is not permitted.

14. Fertility requirements

    • Female patients with child bearing potential must have a negative pregnancy test at least 7 days before starting treatment drugs.
    • Male subject must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.
    • Female patients must be either post-menopausal, free from menses ≥ 2yrs, surgically sterilized, willing to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from sexual activity starting from screening and for 90 days after lenalidomide treatment
    • Female patients of childbearing potential must agree to comply with the fertility and pregnancy test requirements dictated by the Rev-Assist program.

15. Willingness to provide blood and tissue samples for correlative research purposes

Exclusion Criteria:

1. Prior history of: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, osteosclerotic myeloma, Crow-Fukase syndrome, primary amyloidosis or plasma cell leukemia.

2. Radiotherapy within 21 days of registration. However, if the radiation portal was localized to single lesion or fracture site and covered by ≤ 5% of the bone marrow reserve (by investigator estimate), the subject may be enrolled irrespective of the end date of radiotherapy.

3. Prior chemotherapy:

   • Alkylators (e.g. melphalan, cyclophosphamide) ≤ 21 days prior to registration and/or monoclonal antibody ≤ 6 weeks prior to first administration of study treatment.
   • Anthracyclines ≤ 21 days prior to registration.
   • High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide), or proteasome inhibitors (bortezomib or carfilzomib) ≤ 14 days prior to registration.

4. No concomitant high dose corticosteroids (concurrent use of corticosteroids). EXCEPTION: Patients may be on chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc.

5. Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration or baseline QTcF of > 470.

6. Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction.

7. History of prior malignancy, with the exception of the following:

   • Malignancy treated with curative intent and with no known active disease present for more than 3 years prior to registration and felt to be at low risk for recurrence by treating physician;
   • Adequately treated non melanoma skin cancer or lentigo maligna without current evidence of disease; or
   • Adequately treated breast or cervical carcinoma in situ without current evidence of disease.

8. Peripheral neuropathy Grade > 2 on clinical examination within 14 days prior to registration.

9. Uncontrolled diabetes mellitus.

10. Currently active systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).

11. Use of antibiotics for treatment of infection within 14 days prior to registration

12. Recent infection requiring systemic treatment that was completed within 14 days of registration.

13. Known infection with human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.

    Note: Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result within 14 days prior to registration.

14. History of stroke or intracranial hemorrhage within 6 months prior to registration.

15. Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or patient who requires continuous treatment with a strong CYP3A inhibitor (Appendix II).

16. Currently active, clinically significant hepatic impairment (Child-Pugh class B or C) according to the Child Pugh classification (Appendix III).

17. Lactating or pregnant

18. Major surgery within 4 weeks prior to registration

19. Known bleeding disorders (e.g. von Willebrand's disease or hemophilia).

20. Allergies and adverse drug reactions: history of allergy to study drug components

21. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

22. Any life-threatening illness, medical condition, or organ systemic dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.

23. Unresolved toxicities from prior anti-cancer therapy, defined as not having resolved to CTCAE Version 5.0, Grade 0 or 1, with the exception of alopecia.