This is a single arm, two-stage, phase II study to evaluate the rate of ≥ Complete Response
(CR) post-Autologous Stem Cell Transplant (ASCT) in Multiple Myeloma (MM) subjects who failed
to achieve at least a Very Good Partial Response (VGPR) post initial induction therapy for
newly diagnosed disease, and for whom an ASCT is planned. Subjects will be treated with four
weekly doses of daratumumab before mobilization for Hematopoietic Progenitor Cells (HPC)
collection, followed by high dose chemotherapy and ASCT and four weekly doses of daratumumab
after ASCT. A two-stage design will be implemented. Twenty three (23) subjects will be
enrolled in the first stage, and if at least 12 of the 23 subjects have at least a CR after
ASCT, an additional 16 subjects will be enrolled in the second stage (a total of 39
subjects).
Inclusion Criteria
Subject must meet all of the following applicable inclusion criteria to participate in this
study:
1. Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.
2. ≥ 18 years of age
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 within 28 days
prior to day 1 of daratumumab.
4. Failure to achieve a VGPR or better per IMWG 2016 criteria following a three-drug
induction regimen for newly diagnosed MM. Subjects must have achieved at least minimal
response to induction therapy.
5. Measurable disease at time of diagnosis (collected within 42 days prior to initiation
of initial induction therapy) defined as:
1. Serum M-protein ≥ 0.5. g/dL OR
2. Urine M-protein ≥ 200 mg/24 h OR
3. Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is
abnormal
6. ASCT is planned for post-induction therapy.
7. Prior radiotherapy must be completed at least 14 days prior to day 1 of daratumumab
and subject must have recovered from any radiation-induced toxicities.
8. Recovered from all reversible acute toxic effects of induction therapy (other than
alopecia) to ≤Grade 1 or baseline.
9. Demonstrate adequate organ function within 28 days of day 1 of daratumumab as defined
in the table below:
- White Blood Cell (WBC) ≥ 2,000/mm3
- Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 without growth factors for 1 week
prior
- Hemoglobin (Hgb) ≥ 8 g/dL
- Platelet count ≥ 70,000/mm3 if bone marrow plasmacytosis of <50%; otherwise ≥
50,000/mm3(*)
- Serum creatinine OR Creatinine clearance ≤ 1.5 × upper limit of normal (ULN) OR ≥
30 mL/min as measured by a 24-hour urine collection or estimated by the Cockcroft
- Gault formula
- Bilirubin ≤ 2 × ULN; < 3.0 for subjects with Gilbert's Syndrome
- Aspartate aminotransferase (AST) ≤ 2.5× ULN
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN
10. Females of childbearing potential (FCBP) must have a negative serum pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to day
1 of daratumumab. NOTE: Females are considered of child bearing potential unless they
are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no
menses without an alternative medical cause).
11. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a
failure rate of <1% per year when used consistently and correctly) from the time of
informed consent until 90 days (3 months) after the last dose of daratumumab.
Contraceptive methods with low user dependency are preferable but not required.
12. Male subjects who are sexually active with a FCBP must be willing to use condoms from
the time of informed consent until 3 months after the last dose of daratumumab has
been discontinued. The FCBP partner should also consider contraception recommendations
(see inclusion #11).
13. As determined by the enrolling physician, ability of the subject to understand and
comply with study procedures for the entire length of the study.
Exclusion Criteria
Subjects meeting any of the criteria below may not participate in the study:
1. Active infection requiring systemic therapy (i.e., involving IV antibiotics)
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study, and any female subject must agree not to donate eggs
during the study and for 3 months after the last dose of daratumumab).
3. Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, carcinoma of the prostate with a current PSA value of <0.5
ng/mL or other cancer for which the subject has completed treatment, been disease-free
for at least five years, and is considered by Sponsor-Investigator to be at <30% risk
of relapse, or on hormonal therapy for a history of either prostate cancer or breast
cancer, provided that there has been no evidence of disease progression during the
previous three years.
4. Non-secretory MM.
5. Active involvement of the central nervous system by MM.
6. Prior cerebrovascular accident with persistent neurological deficit.
7. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, and skin changes).
8. Had major surgery within 2 weeks prior to day 1 of daratumumab.
9. Treatment with any investigational drug within 4 weeks prior to day 1 of daratumumab.
10. Uncontrolled clinically significant illness including, but not limited to,
uncontrolled hypertension (as per the most updated Joint National Committee for the
Management of Hypertension definitions), symptomatic congestive heart failure (as per
New York Heart Association [NYHA] class III or IV [see Appendix C], uncontrolled
angina pectoris, myocardial infarction within the past 6 months from consent, known or
suspected amyloidosis, uncontrolled cardiac arrhythmia, psychiatric illness/social
situations that would limit compliance with study requirements as determined by the
investigator, or any other condition (including laboratory abnormalities) that would,
in the opinion of the Sponsor-Investigator, place the subject at unacceptable risk if
he/she were to participate in the study.
11. Known allergies, hypersensitivity or intolerance to monoclonal antibodies or human
proteins, daratumumab or its excipients.
12. 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.
13. Known to be 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. Is known to be seropositive for human immunodeficiency virus.
