| Eligibility |
Inclusion Criteria:
1. Males or females, age 18 years or older.
2. ECOG performance status score of 0, 1 or 2.
3. Life expectancy of at least 3 months
4. Measurable disease according to the IMWG criteria defined below (These baseline
laboratory studies for determining eligibility must be obtained during the screening
period within 28 days prior to start of study drug):
1. Serum monoclonal paraprotein (M-protein) = 10 g/L (if IgG) or =5g/L (if IgA, D, E
or M).
2. Urine M-protein = 200 mg/24 h.
3. Serum free light chains (FLC) assay: Involved FLC level = 100 mg/L and an
abnormal serum free light chain ratio (< 0.26 or > 1.65)
5. Received at least 3 prior lines of therapy including a proteasome inhibitor (=2 cycles
or 2 months of treatment) and an IMiD (=2 cycles or 2 months of treatment) in any
order or in combination during the course of treatment or subjects whose disease is
double refractory to a PI and an IMiD. For subjects who have received more than 1 type
of PI, their disease must be refractory to the most recent one. Similarly, for those
who have received more than 1 type of IMID, their disease must be refractory to the
most recent one.
**A single line of therapy may consist of 1 or more agents, and may include induction,
hematopoietic stem cell transplantation, and maintenance therapy (refer to Appendix
2). Radiotherapy, bisphosphonate, or a single short course of steroids (i.e. less than
or equal to the equivalent of dexamethasone 40 mg/day for 4 days) would not be
considered prior lines of therapy.
6. Have achieved at least a minimal response (MR) or better to at least one previous line
of therapy as per IMWG response criteria.
7. The following laboratory results must be met within 10 days of first study drug
administration:
1. ANC = 1.0 x 109/L
2. Hemoglobin = 80 g/L
3. Platelets = 70 x 109/L (or =50 x 109/L if = 50% plasmacytosis in bone marrow)
4. Calculated or measured CrCl = 30 mL/min
5. AST and ALT = 3.0 x ULN
6. Total bilirubin = 2 x ULN unless known to have Gilbert's disease
7. Corrected serum calcium = 3.5 mmol/L
8. Have signed the informed consent documents indicating that the subject understands the
purpose of the procedures required for the study and is willing to participate and
adhere to the study protocol.
9. Females with child-bearing potential (FCBP†) must agree to use 2 reliable forms of
contraception* simultaneously or practice complete abstinence from heterosexual
contact for at least 28 days before starting study drug, while participating in the
study (including during dose interruptions), and for at least 3 months after study
treatment discontinuation.
†Females of childbearing potential (FCBP): a female of childbearing potential is a
sexually mature woman who: 1) has not undergone a hysterectomy or bilateral
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive
months).
* The two methods of birth control used may be selected from the following categories,
but the two methods cannot be selected from any one category: barrier method: i.e.,
condom (male or female) or diaphragm with spermicide; hormonal: i.e., contraceptive
pill, patch; intrauterine device (IUD); vasectomy; or tubal ligation.
10. Females must agree to abstain from breastfeeding during study participation and 90
days after study drug discontinuation.
11. Males must agree to use a latex condom during any sexual contact with FCBP while
participating in the study and for 3 months following discontinuation from this study,
even if he has undergone a successful vasectomy.
12. Males must also agree to refrain from donating semen or sperm during the treatment
phase and for 3 months after discontinuation from this study treatment.
13. All subjects must agree to refrain from donating blood while on study therapy and for
28 days after discontinuation from this study treatment.
Exclusion Criteria:
1. Prior exposure to daratumumab (or other anti-CD38 monoclonal antibody).
2. History of prior allogeneic stem cell transplantation and showing evidence of active
graft-versus-host disease or graft-versus-host disease that requires immunosuppressive
therapy.
3. Chemotherapy or other anti-myeloma therapy within 14 days prior to the first dose of
study drug.
4. Treatment-related toxicity that has not recovered =Grade 1 unless deemed to be
irreversible (an example of an irreversible toxicity would include steroid induced
cataracts).
5. Subjects who have received steroids within 2 weeks prior to starting study treatment
or who have not recovered from side effects of such therapy. Concomitant therapy
medications that include corticosteroids are allowed if subject receive = 10 mg of
prednisone per day, or equivalent, as indicated for other medical conditions, or up to
100 mg of hydrocortisone as pre-medication for administration of certain medications
or blood products prior to enrolment in this study.
6. Subjects who have received any investigational agents within 28 days or 5 half-lives
(whichever is shorter, however the minimum allowed timeframe is 14 days) of the first
dose (Cycle 1 Day 1).
7. Prior history of malignancies, other than MM, unless the subject has been free of the
disease for 3 years or longer. Exceptions include the following:
1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix or breast
3. Adenocarcinoma of the prostate (TNM stage of T1a or T1b)
8. Other concurrent severe and/or uncontrolled medical conditions (i.e. uncontrolled
diabetes, active or uncontrolled infection, acute diffuse pulmonary disease,
pericardial disease, uncontrolled thyroid dysfunction) including abnormal laboratory
values, that could cause unacceptable safety risks or compromise compliance with the
protocol.
9. Known chronic obstructive pulmonary disease (COPD), defined as a FEV1 < 50% predicted
value.
10. Known moderate or severe persistent asthma within the last 2 years, or currently has
uncontrolled asthma of any classification.
11. History of or current uncontrolled cardiovascular disease including:
1. Unstable angina, myocardial infarction, or known congestive heart failure Class
III/IV (Appendix 4) within the preceding 12 months
2. Transient ischemic attack within the preceding 3 months, pulmonary embolism
within the preceding 2 months.
3. Any of the following: sustained ventricular tachycardia, ventricular
fibrillation, Torsades de Pointes, cardiac arrest, Mobitz II second degree heart
block or third-degree heart block; known presence of dilated, hypertrophic, or
restrictive cardiomyopathy.
4. QTc prolongation as confirmed by ECG assessment at screening (QTc >470
milliseconds).
12. Women who are pregnant, breastfeeding or planning to become pregnant while enrolled in
this study, or within 6 months after the last dose of study medications. Male subject
who plans to father a child while enrolled in this study, within 90 days after the
last dose of study medications.
13. Subjects who are:
1. Known seropositive for human immunodeficiency virus (HIV).
2. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (ie, 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) 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.
3. 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).
14. Known allergies, hypersensitivity to mannitol, corticosteroids, monoclonal antibodies
or human proteins, or their excipients (refer to the Daratumumab PM), or known
sensitivity to mammalian-derived products.
15. Known CNS involvement, amyloidosis, or currently active plasma cell leukemia.
16. Subjects who are receiving any other investigational agent.
17. Autologous, peripheral stem cell transplant within 12 weeks of the first dose of study
drug.
18. Any other condition that, in the Investigator's opinion, would contraindicate the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures.
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