Clinical Trials

Trial Description:
PRIMARY OBJECTIVE:
I. To determine the proportion of patients who are in very good partial response (VGPR) or better after twenty cycles of therapy with daratumumab.

SECONDARY OBJECTIVES:
I. To determine the number of patients, with VGPR or better, who are minimal residual disease (MRD) negative disease at the completion of therapy and every 6 months after therapy for up to 5 years.
II. To assess duration of response.
III. To assess safety of the agent in this patient population.
IV. To evaluate clonal heterogeneity in these patients using deep sequencing at the deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) level and determine association of genomic aberrations with response/progression to daratumumab and progression to smoldering multiple myeloma (SMM)/multiple myeloma (MM).
V. To evaluate T cell response (flow cytometry, T cell receptor [TCR] sequencing, functional T cell status) in this patient population.
VI. To assess changes in the immune microenvironment in high-risk MGUS and low-risk SMM patients over the course of the study; to assess these immune changes and association with progression to SMM or MM.
VII. To examine the immunoglobulin sequence in MGUS and SMM patients to determine if common clonal sequences are noted among high-risk MGUS and low-risk SMM, and to evaluate whether common Ig sequences are associated with progression.
VIII. To assess the rate of secondary hematologic malignancies.

OUTLINE:
Patients receive daratumumab intravenously (IV) over up to 15 hours on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6, and on day 1 of cycles 7-20. Treatment repeats every 28 days for up to 20 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 or 6 months for up to 5 years.

Eligibility Requirements:
Age >= 18 years

Must meet criteria for high-risk MGUS or low-risk smoldering myeloma as described below:

High-risk MGUS: must have < 10% plasma cells and < 3.0 g/dL M-spike and at least 2 of the following 3 criteria: * Abnormal free light-chain (FLC) ratio (< 0.26 or > 1.65) * M-protein concentration (>= 1.5 g/dL) * Non-immunoglobulin (Ig)G M protein (including IgA)

Low-risk smoldering multiple myeloma: must only present with 1 of the following criterion: * Monoclonal protein >= 3 g/dL * >= 10% bone marrow plasma cells * FLC ratio < 0.125 or > 8

No evidence of hypercalcemia, renal-failure, anemia and bone-lesions (CRAB) criteria or new criteria of active MM which including the following: * Increased calcium levels (corrected serum calcium > 0.25 mmol/dL above the upper limit of normal or > 0.275 mmol/dL) * Renal insufficiency (attributable to myeloma) * Anemia (hemoglobin [Hb] 2 g/dL below the lower limit of normal or < 10 g/dL) * Bone lesions (lytic lesions or generalized osteoporosis with compression fractures) * No evidence of the following new criteria for active MM including the following: bone marrow plasma cells > 60%, serum involved/uninvolved FLC ratio >= 100, and magnetic resonance imaging (MRI) with more than one focal lesion ** Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible

Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

Absolute neutrophil count (ANC) >= 1000/uL (obtained =< 42 days prior to registration)

Platelets (PLT) >= 50,000/uL (obtained =< 42 days prior to registration)

Total bilirubin =< 2.0 mg/dL (if total is elevated check direct and if normal patient is eligible) (obtained =< 42 days prior to registration)

Aspartate aminotransferase (AST) =< 3 x institutional upper limit of normal (ULN) (obtained =< 42 days prior to registration)

Alanine aminotransferase (ALT) =< 3 x institutional upper limit of normal (ULN) (obtained =< 42 days prior to registration)

Creatinine =< 2 mg/dL or creatinine clearance >= 40 mL/min (obtained =< 42 days prior to registration)

Ability to understand and the willingness to sign an informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

Female patients who are postmenopausal for at least 1 year before the screening visit or are surgically sterile are eligible; females of childbearing potential (as defined below) may also be eligible but must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 42 days of registration * A female of childbearing potential is a sexually mature female who: ** Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) OR ** Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)

Any prior therapy for symptomatic multiple myeloma or smoldering multiple myeloma should also be excluded, including prior use of immunomodulatory imide drugs (IMIDs), proteasome inhibitors, or CD138 inhibitors; prior therapy for smoldering multiple myeloma with agents that are not therapeutically active against MM is not an exclusion criterion; other prior treatment may be allowed after discussion and approval by the overall principal investigator (PI)

Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational; prior therapy with bisphosphonates is allowed; prior radiation therapy to a solitary plasmacytoma is allowed

Concurrent exposure to any commercially available agents known to be active against SMM and MM

Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

Subject has known chronic obstructive pulmonary disease (COPD) or severe, persistent asthma with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal * Note that FEV1 testing is required at screening for patients suspected of having COPD or severe, persistent asthma and subjects must be excluded if FEV1 < 50% of predicted normal

Subject has known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification * Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrollable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Pregnant or nursing women will be excluded from the study

History of allergic reactions attributed to compounds of similar chemical or biologic composition to daratumumab

Seropositive for or has active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) as defined by a positive test for hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV). * 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. * Those who are 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).

Major surgery within 4 weeks before enrollment

Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder); subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

Vaccination with live attenuated vaccines within 4 weeks of first study agent administration

Subject has clinically significant cardiac disease, including significant ischemic coronary disease, congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 6 months before randomization, a history of additional risk factors for torsades de pointes (eg, electrolyte abnormalities, family history of long QT syndrome), or a family history of sudden cardiac death before age 40

Participation in other therapeutic clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial