Inclusion Criteria:
1. Age >=18 years
2. Patients must have a known diagnosis of multiple myeloma with evidence of measurable
disease, AND have evidence of disease progression based on IMWG criteria:
- Serum M-protein >= 0.5 g/dL, or urine M-protein >= 200 mg/24 hours. OR
- In the absence of measurable M-protein, serum immunoglobulin free light chain >=
10 mg/dL, and abnormal serum immunoglobulin kappa lambda free light chain ratio
3. Relapsed from or refractory to 2 or more different prior therapies, including
immunomodulatory drugs (IMiDs; e.g., thalidomide, lenalidomide) and proteasome
inhibitors, chemotherapy-based regimens, monoclonal antibodies, or autologous stem
cell transplantation (ASCT)
- Relapse is defined as progression of disease after an initial response (minimal
response (MR) or better) to previous treatment, more than 60 days after cessation
of treatment
- Refractory disease is defined as < 25% reduction in M-protein or progression of
disease during treatment or within 60 days after cessation of treatment
4. Prior exposure to daratumumab, with most recent dose being at least 6 months prior to
trial enrollment
5. Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)
6. Demonstrates adequate organ function as defined below within 7 days of first dose of
drug:
- Absolute neutrophil count >= 1,500/microliter (mcL)
- Platelets >= 75,000/mcL
- Total bilirubin within normal institutional limits, unless elevated due to
Gilbert's syndrome and direct bilirubin is within normal limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT))
=< 3 x institutional upper limit of normal
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =<
3 x institutional upper limit of normal
- Creatinine =< 1.5 x within institutional upper limit or normal OR creatinine
clearance glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2, calculated
using the Cockcroft-Gault equation, unless data exists supporting safe use at
lower kidney function values, no lower than 30 mL/min/1.73 m^2
7. Life expectancy of at least 3 months
8. Women of childbearing potential must have at least one negative highly sensitive serum
(beta-human chorionic gonadotropin (beta-hCG)) during screening, within one week prior
to the first dose of any component of study treatment
9. Before enrollment, a woman must be either:
- Not of childbearing potential defined as:
- Postmenopausal:
- A postmenopausal state is defined as no menses for 12 months without an
alternative medical cause. A high follicle stimulating hormone level (>
40 IU/L or milli-international units per milliliter (mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in
women not using hormonal contraception or hormonal replacement therapy,
however in the absence of 12 months of amenorrhea, a single follicle
stimulating hormone measurement is insufficient
- Permanently sterile
- Permanent sterilization methods include hysterectomy, bilateral
salpingectomy, bilateral tubal occlusion/ligation procedures, and
bilateral oophorectomy OR
- Of childbearing potential and
- Practicing 2 highly effective user-independent methods of contraception
(failure rate of < 1% per year when used consistently and correctly
- Examples of highly effective user-independent methods of contraception
include:
- Implantable progesterone-only hormone contraception associated
with inhibition of ovulation; intrauterine device (IUD);
intrauterine hormone-releasing system (IUS); vasectomized partner;
sexual abstinence (sexual abstinence is considered a highly
effective method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated with the
study drug. The reliability of sexual abstinence needs to be
evaluated in relation to the duration of the study and the
preferred and usual lifestyle of the subject.)
- Typical use failure rates may differ from those when used consistently
and correctly. Use should be consistent with local regulations
regarding the use of contraceptive methods for subjects participating
in clinical studies
- Hormonal contraception may be susceptible to interaction with the study
drug, which may reduce the efficacy of the contraceptive method
- Agrees to remain on a highly effective method for 4 weeks before the
first dose of any component of study treatment, throughout the study
(including during dose interruptions), and for 4 weeks following
discontinuation of azacitidine, and for 3 months after last daratumumab
dose
- Note: If the risk of pregnancy changes (e.g., a woman who is not
heterosexually active becomes active), a woman must begin a highly
effective method of contraception, as described throughout the
inclusion criteria
- If reproductive status is questionable, additional evaluation
should be considered
- Agrees to not breast feed for the duration of the study (including
during dose interruptions), and for 4 weeks following discontinuation
of azacitidine, and for 3 months after last daratumumab dose
10. Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study (including during dose interruptions), and for 4 weeks
following discontinuation of azacitidine, and if receiving daratumumab, for 3 months
after the last dose
11. Due to the teratogenicity of azacitidine and the lack of adequate reproductive
toxicity data for daratumumab, in addition to the user independent highly effective
method of contraception, a male or female condom with or without spermicide,
diaphragm, or cervical cap is required. Male condom and female condom should not be
used together (due to risk of failure with friction)
12. During the study (including during dose interruptions), and for 4 weeks following
discontinuation of azacitidine, and for 3 months after the last daratumumab dose, in
addition to the user independent highly effective method of contraception (even if he
has undergone a successful vasectomy), a man
- Who is sexually active with a woman of childbearing potential must agree to use a
barrier method of contraception (i.e., latex or synthetic condom with spermicidal
foam/gel/film/cream/suppository)
- Who is sexually active with a woman who is pregnant must use a latex or synthetic
condom
- Must agree not to donate sperm
13. Willing and able to adhere to the prohibitions and restrictions specified in this
protocol and referenced in the informed consent form (ICF)
14. Must sign an ICF (or their legally acceptable representative must sign) indicating
that he or she understands the purpose of, and procedures required for, the study and
is willing to participate in the study
Exclusion Criteria:
1. Diagnosed or treated for malignancy (either solid tumor or hematologic) other than
multiple myeloma, except:
- Malignancy treated with curative intent and with no known active disease before
enrollment
- Adequately treated non-melanoma skin cancer, lentigo maligna or in situ
malignancies (including but not limited to, cervical, breast) with no
evidence of disease
2. Received daratumumab therapy less than 6 months prior to trial enrollment
3. Primary refractory to prior daratumumab
4. Subject is:
- Seropositive for human immunodeficiency virus (HIV)
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg
negative but positive for antibodies to hepatitis B core antigen (anti-HBc)
and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened
using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus
(HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be
excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV
vaccination (anti-HBs positivity as the only serologic marker) AND a known
history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
- Seropositive for hepatitis C (except in the setting of a sustained virologic
response (SVR), defined as aviremia at least 12 weeks after completion of
antiviral therapy)
5. Known chronic obstructive pulmonary disease with a forced expiratory volume in 1
second (FEV1) < 50% of predicted normal to minimize daratumumab-related pulmonary
toxicities
- Note: FEV1 testing is required for subjects suspected of having chronic
obstructive pulmonary disease and asthma. Subjects must be excluded if FEV1 < 50%
of predicted normal
6. Known moderate or severe persistent asthma within the past 2 year or currently has
uncontrolled asthma of any classification
- Note: Subjects who currently have controlled intermittent asthma or controlled
mild persistent asthma are allowed in the study. FEV1 testing is required for
subjects suspected of having asthma
7. Concurrent medical condition or disease (e.g., active systemic infection) that is
likely to interfere with study procedures or results, or that in the opinion of the
investigator would constitute a hazard for participating in this study
8. Clinically significant cardiac disease, including:
- Myocardial infarction within 6 months before cycle 1, day -7, or unstable or
uncontrolled disease/condition related to or affecting cardiac function (e.g.,
unstable angina, congestive heart failure, New York Heart Association class
III-IV)
- Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE) version 5.0 grade 2 or higher) or
clinically significant electrocardiogram (ECG) abnormalities
- Screening 12-lead electrocardiogram (ECG) showing a baseline corrected QT
interval (QTc) > 470 msec.
9. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human
proteins, daratumumab or its excipients (refer to investigator's brochure), or known
sensitivity to mammalian-derived products
10. Concurrent plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and/or skin
changes), or light chain amyloidosis
11. Known or suspected of not being able to comply with the study protocol (e.g., because
of alcoholism, drug dependency, or psychological disorder) or the subject has any
condition for which, in the opinion of the investigator, participation would not be in
the best interest of the subject (e.g., compromise their well-being) or that could
prevent, limit, or confound the protocol-specified assessments
12. Contraindications to the use of daratumumab, azacitidine or dexamethasone per local
prescribing information
13. Taken any disallowed therapies before the planned first dose of study drug
14. Received any therapy to treat cancer (including radiation, chemotherapy, biologics,
cellular therapies, and/or steroids at doses > 20 mg) or undergone a major surgical
procedure within 14 days, or within 5 half-lives of an anticancer drug, prior to the
first dose of study treatment, whichever is longer (with the exception of palliative
radiotherapy for symptomatic management but not on measurable extramedullary
plasmacytoma).
15. Participated in an interventional clinical trial(s) and received an investigational
drug (including investigational vaccines) or used an invasive investigational medical
device within 4 weeks before cycle 1, day -7 or 5 pharmacokinetic half-lives,
whichever is longer.
16. Had major surgery within 2 weeks before cycle 1, day -7, or will not have fully
recovered from surgery, or has surgery planned during the time the subject is expected
to participate in the study or within 2 weeks after the last dose of study drug
administration. Note: Subjects with planned surgical procedures to be conducted under
local anesthesia may participate. Kyphoplasty is not considered a major surgery.
