PRIMARY OBJECTIVE:
I. To determine the anti-myeloma activity of single-agent daratumumab post-autologous stem
cell transplantation (ASCT) as assessed by progression-free survival at 1 year post ASCT.
SECONDARY OBJECTIVES:
I. To characterize the extent of minimal residual disease (MRD) pre-/post-consolidation
treatment segment and at one year during the maintenance treatment segment.
II. To characterize and evaluate toxicities, including type, frequency severity, attribution,
and duration (e.g., infections, secondary primary malignancies, peripheral neuropathy).
III. To obtain estimates of overall response rate (stringent complete response [sCR],
complete response [CR], very good partial response [VGPR], and partial response [PR]),
response duration, depth of response, clinical benefit response, and overall survival.
EXPLORATORY OBJECTIVES:
I. Quantify CD38+ cells from the peripheral blood mononuclear cells (PBMC) fraction,
including T, natural killer (NK), and monocytic subsets using pre- and on-daratumumab
treatment samples by flow cytometry.
II. Assess possible changes in CD38+ expression, as well as the co-receptor marker CD31, and
possible correlation with response using pre- and on-daratumumab treatment samples by flow
cytometry.
III. Assess cytokine levels in peripheral blood plasma. IV. Quantify CD38+ cells from the
bone marrow CD-138 negative fractions and acellular fractions, including T, NK, and monocyte
subsets using pre- and on-daratumumab treatment samples by flow cytometry.
V. Assess possible changes in CD38+ expression, as well as the co-receptor marker CD31, and
possible correlation with response using pre- and on-daratumumab treatment samples by flow
cytometry.
VI. Assess cytokine levels in the bone marrow acellular fraction. VII. Investigate CD38
cellular localization in multiple myeloma cells and extracellular vesicles from blood plasma.
VIII. Assess messenger ribonucleic acid (mRNA) expression in the PBMC, the bone marrow
CD130-negative fraction, the T cell fraction, and multiple myeloma cells.
IX. If differences in CD38 expression are found, investigate epigenetic changes in CD38 mRNA
expression.
OUTLINE:
Patients undergo standard of care ASCT with a conditioning regimen of melphalan. Beginning
60-120 days after ASCT, patients receive daratumumab intravenously (IV) every week for 8
weeks, every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 18 months.
Inclusion Criteria:
- All subjects must have the ability to understand and the willingness to sign a written
informed consent
- Histologically confirmed diagnosis of multiple myeloma; (patients with multiple
myeloma with secondary amyloidosis are eligible)
- Received at least two cycles of any regimen as initial systemic therapy for multiple
myeloma and are within 2-13 months of the first dose of initial therapy
- Eastern Cooperative Oncology Group (ECOG) =< 2
- Patients with planned standard of care ASCT using melphalan 200 mg/m^2; dose
modifications in accordance with creatinine clearance levels are allowed per physician
judgment
- Adequate organ function for high dose chemotherapy and autologous stem cell transplant
(as per institution standard operating procedure [SOP])
- Adequate cell dose > 2.5 x 10^6 CD34+ cells/kg
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Platelet count >= 75,000/mm^3; platelet transfusions to help patients meet eligibility
criteria are not allowed within 7 days before study enrollment
- Total bilirubin =< 1.5 x the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) =< 3 x ULN
- Alanine aminotransferase (ALT) =< 3 x ULN
- Calculated creatinine clearance >= 30 mL/min
- Woman of childbearing potential must be practicing a highly effective method of birth
control consistent with local regulations regarding the use of birth control methods
for subjects participating in clinical studies: e.g., established use of oral,
injected, or implanted hormonal methods of contraception; placement of an intrauterine
device or intrauterine system; barrier methods; condom with spermicidal
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps)
with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true
abstinence (when this is in line with the preferred and usual lifestyle of the
subject) during and after the study (6 months after the last dose of daratumumab for
women)
- A man who is sexually active with a woman of childbearing potential and has not
had a vasectomy must agree to use a barrier method of birth control, e.g., either
condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive
cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository, and all men must also not donate sperm during
the study and for 6 months after receiving the last dose of study drug
Exclusion Criteria:
- Prior disease progression with daratumumab or other anti-CD38 antibody
- History of organ or previous autologous/allogeneic stem cell transplantation
- Any condition medical or psychosocial that in the opinion of the investigator would
hinder compliance
- Female patients who are lactating or have a positive pregnancy test during the
screening period
- Evidence of multiple myeloma (MM) disease progression any time prior to enrollment;
progression from smoldering to active myeloma is not exclusionary
- History of plasma cell leukemia or central nervous system (CNS) involvement
- Major surgery within 14 days prior to start of study treatment
- Infection requiring systemic antibiotic therapy within 14 days prior to the start of
study treatment
- Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for
cancer treatment; Note: Concurrent use of hormones for noncancer-related conditions
(e.g., insulin for diabetes) is acceptable
- Vaccination with live attenuated vaccines within 4 weeks of first study agent
administration
- Subject is currently using or has used immunosuppressive medication within 14 days
prior to the first dose of study treatment; the following are exceptions:
- Intranasal, topical, inhaled, or local steroid injections (e.g., intra-articular
injection)
- Chronic systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent
- Steroids as premedication for hypersensitivity reaction (e.g., infusion-related
reactions, computed tomography [CT] scan premedication)
- Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes),
or primary amyloidosis
- Subjects with uncontrolled, systematic infection should be excluded
- Subject has known chronic obstructive pulmonary disease (COPD) with a forced
expiratory volume in 1 second (FEV1) < 50% predicted normal; Note that FEV1 testing is
required for patients suspected of having COPD and subjects must be excluded if FEV1 <
50%
- Subject has known moderate or severe persistent asthma within 2 years, or currently
has uncontrolled asthma of any classification; (Note that subjects who currently have
controlled intermittent asthma or controlled mild persistent asthma are allowed in the
study)
- Subject has active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., Crohn's disease], diverticulitis, celiac disease,
irritable bowel disease, or other serious gastrointestinal chronic conditions
associated with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia
gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis, etc) within the
past 3 years prior to the start of treatment; the following are exceptions:
- Subjects with vitiligo or alopecia
- Subjects with hypothyroidism (e.g., following Hashimoto's disease) stable on
hormone replacement
- Psoriasis not requiring systemic treatment
- Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies
or human proteins, or their excipients
- Subject has history of primary immunodeficiency
- Subject is seropositive for human immunodeficiency virus (HIV-1)
- Active hepatitis A
- 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 finding 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)
- Subject has any one of the following:
- Clinically significant abnormal electrocardiogram (ECG) finding at screening
- Congestive heart failure (New York Heart Association class III or IV)
- Myocardial infarction within 12 months prior to starting study treatment
- Unstable or poorly controlled angina pectoris, including Prinzmetal variant
angina pectoris
- Subject has prior history of malignancies, other than MM, unless the subject has been
free of the disease for >= 5 years with the exception of the following malignancies:
- Basal cell carcinoma of the skin
- Squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
node, metastasis [TNM] clinical staging system) or prostate cancer that is
curative
- Any other condition that would, in the opinion of the investigator's judgement,
contraindicate the patient's participation in the clinical study due to safety
concerns with clinical study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
