This is a registration, open-label phase 1 study of the combination of
ibrutinib/lenalidomide:/dexamethasone in women and men with relapsed/refractory multiple
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
Part 2: Dose Expansion Once the maximum tolerated dose has been established or determined, 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.
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 2 prior therapies 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).
6. Patients can have received prior lenalidomide but cannot be refractory to the agent.
Disease considered refractory to prior lenalidomide- containing regimens is defined
- Disease that is nonresponsive while on therapy or progresses within 60 days of
last therapy. Nonresponsive disease is defined as either failure to achieve
minimal response or development of progressive disease while on treatment
- Patients who experience disease progression on lenalidomide maintenance at a dose
< 10 mg are eligible to participate
7. No prior treatment with ibrutinib or any other protein kinase inhibitory drug or drug
targeting the b-cell receptor (BCR) signal transduction pathway.
8. Patients with prior daratumumab and allogeneic stem cell transplant are included.
9. 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
10. 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.
11. Biochemical values must be within the following limits within 7 days prior to
- 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.
12. Ability to understand and willingness to sign a written informed consent form (ICF).
13. Ability to adhere with the study visit schedule and other protocol procedures.
14. 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.
15. 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.
16. Willingness to provide blood and tissue samples for correlative research purposes
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
- 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
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
8. Peripheral neuropathy Grade > 2 on clinical examination within 14 days prior to
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
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
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.