Daratumumab, Bortezomib, Dexamethasone, Pegylated Liposomal Doxorubicin Hydrochloride, and Lenalidomide in Treating Participants With Plasma Cell Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose(s) (MTD)/recommended phase 2 dose(s) (RP2D) of,
bortezomib and pegylated liposomal doxorubicin hydrochloride (doxil) when given in
combination with fixed dose daratumumab, lenalidomide, and dexamethasone.

SECONDARY OBJECTIVES:

I. To assess the tolerability and safety of the planned regimen, by evaluation of toxicities
including: type, frequency, severity, attribution, time course and duration.

II. To estimate and assess overall response rate, response duration, and survival
probabilities (overall and progression-free).

EXPLORATORY OBJECTIVES:

I. Quantify CD38+ cells from the peripheral blood mononuclear cells (PBMC) fraction,
including T, natural killer (NK), and monocytic subsets.

II. Assess possible changes in CD38 expression, as well as the co-receptor marker CD31,
overall and by response status (responder/non-responder).

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 monocytic
subsets.

V. Assess possible changes in CD38 expression, as well as the co-receptor marker CD31,
overall and by response status (responder/non-responder).

VI. Assess cytokine levels in the bone marrow acellular fraction. VII. Investigate CD38
cellular localization in plasma cells and extracellular vesicles from blood plasma.

VIII. Assess messenger ribonucleic acid (mRNA) expression in the peripheral blood mononuclear
cell (PBMC), the bone marrow CD138-negative fraction, the T cell fraction, and plasma cells.

IX. Investigate epigenetic changes in CD38 mRNA expression.

OUTLINE:

Participants receive daratumumab intravenously (IV) on days 1, 8, 15, and 22, dexamethasone
IV/orally (PO) on days 1, 2, 8, 9, 15, 16, 22, and 23, pegylated liposomal doxorubicin
hydrochloride IV on day 8, lenalidomide PO daily on days 1-14, and bortezomib subcutaneously
(SC) on days 1, 4, 8, and 11 of courses 1 and 2. Participants then receive daratumumab IV on
days 1, and 15, dexamethasone IV/PO on days 1, 2, 8, 9, 15, 16, 22, and 23, pegylated
liposomal doxorubicin hydrochloride IV on day 8, lenalidomide PO daily on days 1-14, and
bortezomib SC on days 1, 4, 8, and 11 of courses 3 and 4. Courses repeat every 28 days for up
to 4 courses in the absence of disease progression or unacceptable toxicity. Participants may
receive up to 8 courses at the discretion of treating physician.

After completion of study treatment, participants are followed up at 30 days and then every 3
months for 18 months.

Inclusion Criteria:

- Documented informed consent of the participant and/or legally authorized
representative. Assent, when appropriate, will be obtained per institutional
guidelines.

- Willingness to provide bone marrow and peripheral blood samples for research purposes.
If unavailable, exceptions may be granted with study principal investigator (PI)
approval.

- All study participants must be registered into the mandatory Revlimid Risk Evaluation
and Mitigation Strategies (REMS) program and be willing to comply with its
requirements.

- Karnofsky performance status (KPS) > 60.

- Plasma cell leukemia; either newly diagnosed or relapsed: defined as the presence of >
2 x 10^9/L peripheral blood plasma cells or plasmacytosis accounting for > 20% of the
differential white cell count.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Absolute
neutrophil count (ANC) >= 500/mm^3

- NOTE: Growth factor is not permitted within 14 days of ANC assessment unless
cytopenia is secondary ot disease involvement.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Total
bilirubin =< 2.0 x ULN (unless has Gilbert's disease).

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Aspartate
aminotransferase (AST) =< 3.0 x ULN.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Alanine
aminotransferase (ALT) =< 3.0 x ULN.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Creatinine
clearance of >= 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Left
ventricular ejection fraction (LVEF) > 45%

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Hemoglobin
>= 8.0 g/dL

- Note: Transfusion support is allowed.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated:
Seronegative for human immunodeficiency virus (HIV) antigen-antibody (Ag/Ab) combo,
hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative),
and syphilis (RPR).

- If positive, hepatitis C RNA quantitation must be performed.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Meets other
institutional and federal requirements for infectious disease titer requirements.

- Note: Infectious disease testing to be performed within 28 days prior to day 1 of
protocol therapy.

- Within 14 days prior to day 1 of protocol therapy unless otherwise stated: Women of
childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine
test is positive or cannot be confirmed as negative, a serum pregnancy test will be
required.

- Agreement by females and males of childbearing potential* to use an effective method
of birth control or abstain from heterosexual activity for the course of the study
through at least 6 months after the last dose of protocol therapy.

- Childbearing potential defined as not being surgically sterilized (men and women)
or have not been free from menses for > 1 year (women only).

- Women of childbearing potential must follow pregnancy testing requirements as outline
in REMS program material.

Exclusion Criteria:

- Progression or intolerance to daratumumab, bortezomib, or lenalidomide.

- Prior stem cell transplant.

- Participant 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.

- Participant is currently using or has used immunosuppressive medication within 14 days
prior to the first study 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 reactions (e.g., infusion-related
reactions, computed tomography [CT] scan premedication).

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study agent.

- Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1
second (FEV1) < 50% of predicted normal.

- Has known moderate or severe persistent asthma within the past 2 years, or currently
has uncontrolled asthma of any classification.

- Clinically significant uncontrolled illness.

- Active infection requiring intravenous antibiotics or antifungals within 14 days prior
to start of study treatment.

- Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection.

- Grade >= 3 peripheral neuropathy, or grade >= 2 with pain on clinical examination
during the screening period.

- Evidence of current uncontrolled cardiovascular conditions, including cardiac
arrhythmias, congestive heart failure, angina, or myocardial infarction within the
past 6 months. Note: Prior to study entry, any electrocardiogram (ECG) abnormality at
screening must be documented by the investigator as not medically relevant.

- Other active malignancy. Exceptions: Non-melanoma skin cancer, ductal breast carcinoma
in situ (DCIS) or carcinoma-in-situ of the cervix. Note: If there is a history or
prior malignancy, they must not be receiving other specific treatment for their
cancer. Prior malignancy treated with curative intent is not an exclusion.

- Females only: Pregnant or breastfeeding.

- Any other condition that would, in the Investigator's judgment, 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).