| Eligibility |
Inclusion Criteria:
1. Has a diagnosis of MM based on standard criteria as follows:
Major criteria:
- Plasmacytomas on tissue biopsy.
- Bone marrow plasmacytosis (greater than 30% plasma cells).
- Monoclonal immunoglobulin (Ig) spike on serum electrophoresis IgG greater than
3.5 g/dL or IgA greater than 2.0 g/dL; kappa or lambda light chain excretion
greater than 1 g/day on 24-hour urine protein electrophoresis.
Minor criteria:
- bone marrow plasmacytosis (10% to 30% plasma cells)
- monoclonal immunoglobulin present but of lesser magnitude than given under major
criteria
- lytic bone lesions
- normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600
mg/dL
Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:
- any 2 of the major criteria
- major criterion 1 plus minor criterion 2, 3, or 4
- major criterion 3 plus minor criterion 1 or 3
- minor criteria 1, 2, and 3, or 1, 2, and 4
2. Patient must meet one of the following:
- Currently, patient has progressive MM that has progressed while receiving twice
weekly carfilzomib 27mg/m2 alone or as part of their last carfilzomib-containing
combination regimen
- Currently, the patient is not in CR and plateaued (as defined by unchanged
disease markers for at least 8 weeks) while treated with carfilzomib (twice
weekly 27 mg/m2) and dexamethasone with or without lenalidomide or pomalidomide
- Patients who were previously receiving a carfilzomib (twice weekly 27 mg/m2)
containing regimen and are currently receiving carfilzomib (twice weekly 27mg/m2)
and dexamethasone maintenance therapy with or without lenalidomide or
pomalidomide and are not in CR and have plateaued
3. Patient must have received at least one full cycle of carfilzomib at a dose of twice
weekly 27mg/m2 prior to showing evidence of PD or plateauing from their last
carfilzomib-containing regimen.
4. Patient must have previously received treatment with an immunomodulatory agents
lenalidomide or pomalidomide to be eligible for the study (applicable only for
subjects who qualify via inclusion criteria 2B or 2C).
5. There is no limit to the number of prior lines of therapy that a patient may have
received.
6. Measurable disease, as defined by one or more of the following (assessed within 14
days prior to first dose):
- Serum M-protein = 0.5 g/dL, or
- Urine M-protein = 200 mg/24 hours, or
- Only in patients who do not meet a or b, then use serum free light chain (SFLC) >
100 mg/L (involved light chain) and an abnormal ?/? ratio
7. Age = 18 years.
8. Life expectancy = 6 months.
9. Eastern Cooperative Oncology Group (ECOG) performance status = 2.
10. Adequate hepatic function within 14 days prior to first dose, with bilirubin < 1.5 ×
the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) < 3 × ULN.
11. LVEF = 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of
evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
12. Absolute neutrophil count (ANC) = 1000/mm3 within 14 days prior to first dose.
Screening ANC is to be independent of granulocyte colony stimulating factor support
for = 1 week and pegylated granulocyte colony stimulating factor for = 2 weeks.
13. Hemoglobin = 8.0 g/dL within 14 days prior to enrollment. Use of erythropoietic
stimulating factors and red blood cell (RBC) transfusions per institutional guidelines
is allowed; however, most recent RBC transfusion must have been at least 7 days prior
to obtaining screening hemoglobin.
14. Platelet count = 75,000/mm3 (= 50,000/mm3 if myeloma involvement in the bone marrow is
> 50%) within 14 days prior to first dose. Patients must not have received platelet
transfusions for at least 7 days prior to obtaining the screening platelet count.
15. Calculated or measured creatinine clearance (CrCl) of = 30 mL/min within 14 days prior
to first dose. Calculations are based on a standard formula, such as the Cockcroft and
Gault: [(140 - Age) × Mass (kg) / (72 × Creatinine mg/ dL)]; multiply result by 0.85
if female.
16. Written informed consent in accordance with federal, local, and institutional
guidelines.
17. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within the 7 days prior to study drug administration and a negative urine pregnancy
test within the 3 days prior to the first study drug administration
18. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 highly
effective methods of contraception during the study and for 30 days following the last
dose of study treatment including a male condom.
Exclusion Criteria:
1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes)
2. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
3. Waldenström's macroglobulinemia
4. Amyloidosis
5. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to
first dose
6. Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within
28 days prior to first dose
7. Treatment with bortezomib (Velcade®), thalidomide, pomalidomide (Pomalyst®) or
lenalidomide (Revlimid®) within 21 days prior to first dose
8. Focal radiation therapy within 7 days prior to first dose. Radiation therapy to an
extended field involving a significant volume of bone marrow within 21 days prior to
enrollment (i.e., prior radiation must have been to < 30% of the bone marrow)
9. Immunotherapy within 21 days prior to first dose
10. Major surgery within 21 days prior to first dose
11. Active congestive heart failure (New York Heart Association [NYHA] Classes III to IV),
symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
intervention. Myocardial infarction within 6 months prior to first dose.
Echocardiogram or MUGA evidence of left ventricular ejection fraction (LVEF) below
institutional normal within 28 days prior to enrollment
12. Acute active infection requiring systemic antibiotics, antiviral (except antiviral
therapy directed at HBV), or antifungal agents within 14 days prior to first dose
13. Known human immunodeficiency virus (HIV) seropositivity
14. Known active hepatitis B or C virus infection (except for patients with HBV receiving
and responding to HBV antiviral therapy: these patients are allowed)
15. Patients with known cirrhosis
16. Second malignancy within the past 3 years, except:
- Adequately treated basal cell or squamous cell skin cancer
- Carcinoma in situ of the cervix
- Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA)
over 12 months
- Breast carcinoma in situ with full surgical resection
- Treated medullary or papillary thyroid cancer
17. Patients with myelodysplastic syndrome
18. Significant neuropathy (Grades 3 to 4) within 14 days prior to first dose
19. Peripheral neuropathy with pain = G2 within 14 days prior to first dose
20. Patients with baseline hepatic impairment
21. Women who are pregnant and/or breast feeding
22. Known hypersensitivity to dexamethasone
23. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize
carfilzomib)
24. Hypersensitivity to any of the required concomitant drugs or supportive treatments,
including hypersensitivity to antiviral drugs.
25. Prior participation in any Onyx-sponsored Phase 3 trial
26. Ongoing graft-versus-host disease
27. Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14
days prior to enrollment
28. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
29. Any other clinically significant medical disease or psychiatric condition that, in the
Investigator's opinion, may interfere with protocol adherence or a patient's ability
to give informed consent.
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