Personalized Vaccine in Treating Participants With Smoldering Multiple Myeloma

PRIMARY OBJECTIVES:

I. To demonstrate that developing a custom vaccine for smoldering multiple myeloma (SMM) is
feasible.

II. To show that a custom peptide-based vaccine in smoldering multiple myeloma is safe.

SECONDARY OBJECTIVES:

I. To determine the intensity and longevity of antigen specific T-cell mediated immune
responses to the neoantigen vaccine.

II. Time to progression to multiple myeloma (TTM) at the end of the follow up period (18
months).

III. Duration of response. IV. Clinical benefit rate (minor response [MR] or better) after 6
cycles of vaccine treatment per modified International Myeloma Working Group (IMWG) criteria
for multiple myeloma (MM).

V. Overall survival.

EXPLORATORY OBJECTIVES:

I. Rate of minimal residual disease (MRD) negativity at complete remission (CR), if achieved.
MRD assessment will be based on bone marrow aspirates.

II. Molecular profiling (including whole exome sequencing, gene expression profiling and
ribonucleic acid (RNA) sequencing of tumor/bone marrow samples) and cellular (including flow
cytometry) profiling at baseline using bone marrow aspirate samples and peripheral blood.

III. Immunophenotypic characterization of dendritic, T-, B-, natural killer (NK)- and
NKT-cells, and inhibitory/activation markers on tumor cells at baseline (bone marrow and
peripheral blood), day 1 of each cycle (peripheral blood only) and at completion of 6 cycles
of therapy (bone marrow and peripheral blood) in bone marrow aspirate samples and/or
peripheral blood.

IV. To identify shared human leukocyte antigen (HLA) class I-restricted antigens that can be
targeted with immunotherapy.

OUTLINE:

Participants undergo collection of blood and bone marrow for making the vaccine. Participants
then receive personalized vaccine subcutaneously (SC) on days 1 and 15 of courses 1-2 and on
day 1 of courses 3-6. Treatment repeats every 28 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 3 and 12 months.

Inclusion Criteria:

- Adult patients with intermediate or high-risk SMM are eligible

- Patients must have histologically confirmed SMM based on the following criteria. Both
criteria must be met: (a) Serum monoclonal protein (IgG or IgA) >= 3 g/dL or urinary
monoclonal protein >=500 mg per 24 hours and/or clonal bone marrow plasma cells more
or equal to 10% (b) Absence of myeloma defining events or amyloidosis

- Additionally, patients must meet criteria for intermediate or high risk of progression
to multiple myeloma by Programa para el Estudio de la Terapeutica en Hemopatía Maligna
(PETHEMA) criteria (patients must have at least 1 risk factors present): (1) >= 95%
abnormal plasma cells/total plasma cells in bone marrow compartment. (This is measured
as a percentage of the total abnormal versus normal plasma cells in the bone marrow
compartment using standard flow cytometry of the bone marrow aspirate. Having >= 95%
abnormal plasma cells/total plasma cells constitutes a risk factor for progression to
multiple myeloma by PETHEMA criteria) (2) Immunoparesis (The patient having low
uninvolved immunoglobulins in peripheral blood, for example if a patient has IgA
smoldering multiple myeloma, then either having a low IgM and/or low IgG will qualify
as a risk factor for progression to multiple myeloma) *1 of 2 risk factors:
intermediate risk for progression at a rate of ~50% at 5 years *2 of 2 risk factors:
high risk for progression at a rate of 72% at 5 years

- Creatinine clearance >= 40 ml/min using the modification of diet in renal disease
(MDRD) equation

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

- Hemoglobin >= 10 g/dL

- Platelet count >= 50 x 10^9/L

- Platelet and blood transfusions are allowed on protocol. Growth factors, including
granulocyte colony stimulating factors and erythropoietin are allowed

- Bilirubin < 1.5 x the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN

- Subjects must be able to give informed consent

Exclusion Criteria:

- Evidence of myeloma defining events due to underlying plasma cell proliferative
disorder meeting at least one of the following 1) Hypercalcemia: serum calcium > 0.25
mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
2) Renal Insufficiency: creatinine clearance < 40 ml/min or serum creatinine > 2 mg/dL
3) Anemia: hemoglobin value < 10 g/dL 4) Bone lesions: one or more osteolytic lesions
on skeletal radiography, computerized tomography (CT) or 2-deoxy-2[F-18]
fluoro-D-glucose positron emission tomography CT (PET-CT)

- Prior or concurrent systemic treatment for SMM. a) Bisphosphonates are permitted. b)
Treatment with corticosteroids is not permitted (allowed for physiologic doses). c)
Radiotherapy is not permitted. d) Prior treatment for smoldering multiple myeloma with
chemotherapy agents approved for the treatment of multiple myeloma is not permitted

- Plasma cell leukemia

- Pregnant or lactating females

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

- Has a known history of active TB (Bacillus tuberculosis)

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 60 days after the last dose of trial treatment

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)