Study of Personalized Melphalan Dosing in the Setting of Autologous Transplant

PRIMARY OBJECTIVES:

I. Identify whether targeting approximate (approx.) 3- or 5-days of severe neutropenia after
exposure to a personalized melphalan hydrochloride (melphalan) dose results in best clinical
outcome.

II. Measure melphalan-related toxicities in both 3-day and 5-day arms. III. Measure response
per International Myeloma Working Group (IMWG). IV. Record overall survival (OS) and
progression free survival (PFS).

SECONDARY OBJECTIVES:

I. To administer a test dose of melphalan and obtain test dose melphalan pharmacokinetics
(PK) data from the first 33 patients.

II. Measure drug-induced deoxyribonucleic acid (DNA) damage in peripheral blood mononuclear
cells (PBMCs) treated with melphalan ex vivo post exposure.

III. Measure drug-induced DNA damage in patient myeloma cells treated with melphalan ex vivo.

IV. Assess melphalan-induced DNA damage in treated patients. V. Measure allele and genotype
frequencies of variants, as well as gene expression of XRCC1 rs25487 and XRCC3 rs861529.

VI. Additional genetic variants relevant to DNA repair, melphalan transport, and clinical
toxicities may be tested as well.

VII. Test cytotoxicity (half maximal inhibitory concentration [IC50]) of patient PBMCs prior
to autologous transplant after exposure to melphalan ex vivo.

VIII. Measure p53 and phospho(TP53) in patient PBMCs prior to autologous transplant at
baseline and after exposure to melphalan ex vivo.

IX. Incorporate both disease progression and drug-related toxicities into separate models
linked to our calculated melphalan area under the curve (AUC) model.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients receive personalized dose of melphalan hydrochloride intravenously (IV) on
day -2 for predicted 3-day duration of severe neutropenia and undergo standard of care
autologous stem cell transplant on day 0.

ARM II: Patients receive personalized dose of melphalan hydrochloride IV on day -2 for
predicted 5-day duration of severe neutropenia and undergo standard of care autologous stem
cell transplant on day 0.

After completion of study treatment, patients are followed up for 30 days, at 3 months after
transplant, and then every 6-12 months.

Inclusion Criteria:

- Patient must have relapsed or refractory myeloma that fits or did fit IMWG diagnostic
criteria for multiple myeloma; patients with AL amyloidosis and polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) are
excluded; measurable disease is not required

- Patient undergoing autologous transplant as part of first line therapy

- All races and ethnic groups are eligible for this study

- Patients must also have an adequate autologous graft as defined as a cryopreserved
peripheral blood stem cell (PBSC) graft containing > 2 x 10^6 CD34+ cells/kg patient
weight

- Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%) is
required for eligibility; those patients with lower performance status based solely on
bone pain secondary to multiple myeloma are eligible

- Absolute neutrophil count (ANC) > 1000/uL

- Platelet count > 50,000

- Transfusion independent

- Total bilirubin < 1.5 mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x the
institutional upper limit of normal

- Left ventricular ejection fraction >= 40%

- Carbon monoxide diffusing capability (DLCO) > 50% predicted

- Forced expiratory volume in 1 second (FEV1) > 50% predicted

- Forced vital capacity (FVC) > 50% predicted

- Ability to understand and willingness to sign a written informed consent document

- Females of childbearing potential (FCBP) must not be pregnant as per institutional
standard; if no institutional standard exists, then patients must have a negative
serum or urine pregnancy test prior to transplant; a female of childbearing potential
(FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months)

Exclusion Criteria:

- Patients who are receiving any other anti-myeloma investigational agents

- Uncontrolled illness including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,
myocardial infarction in the preceding 6 months, or psychiatric illness/social
situations that would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued

- Patients with a "currently active" second malignancy that, in the opinion of the
principal investigator, will interfere with patient participation, increase patient
risk, shorten survival to < 1 year, or confound data interpretation

- Concurrent use of complementary or alternative medicines that in the opinion of the
principal investigator would confound the interpretation of toxicities and/or
antitumor activity of the study drug