Melphalan, Total Marrow Irradiation, and Autologous Stem Cell Transplantation in Treating Patients With High-Risk Multiple Myeloma

PRIMARY OBJECTIVES:

I. To assess the safety and determine the maximum tolerated dose (MTD) of melphalan and
fractionated total marrow irradiation (TMI) as conditioning regimen for autologous stem cell
transplantation (ASCT) in patients with high-risk or treatment-insensitive multiple myeloma
(MM). (Phase I) II. Evaluate the safety of the regimen at each dose level by assessing
adverse events: type, frequency, severity, attribution, time course, duration.

III. Evaluate the safety of the regimen at each dose level by assessing complication
including: infection, delayed engraftment and secondary malignancy.

IV. To assess complete response (CR) and minimal residual disease (MRD) rates at 100 days
post ASCT in a phase II expanded cohort of patients treated at the MTD. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the predictive value of high risk features inclusive of fluorescent in situ
hybridization (FISH), lactate dehydrogenase (LDH), International Staging System (ISS) stage,
gene expression profiling (GEP) for CR and minimal residual disease (MRD) for relapse free
survival/progression free survival/overall survival (RFS/PFS/OS) after melphalan TMI
(mel/TMI).

II. To assess MRD by positron emission tomography (PET), next generation sequencing (NGS),
and flow cytometry after mel/TMI, prior to maintenance and correlation with PFS and OS.

III. To assess in a descriptive fashion PFS and OS following mel/TMI and ASCT. IV. Evaluate
changes in fludeoxyglucose F-18 (FDG) PET pre and post TMI/melphalan.

TERTIARY OBJECTIVES:

I. Assessment of bone marrow residual damage. II. Assessment of immune recovery dynamics.
III. To conduct genetic profiling of myeloma cells. IV. Multimodal imaging for non-invasive
assessment of treatment effect on bone and marrow.

OUTLINE: This is a phase I, dose-escalation study of melphalan and TMI followed by a phase II
study.

MOBILIZATION AND APHERESIS: Patients receive cyclophosphamide intravenously (IV) over 2
hours. Beginning 24 hours after cyclophosphamide administration, patients receive filgrastim
subcutaneously (SC) or IV. Patients also undergo apheresis over 4 hours on day 10.

CONDITIONING REGIMEN: Patients receive palifermin IV on days -8, to -6, undergo TMI on days
-5 to -2, and receive melphalan IV over 30 minutes on day -1. Patients then undergo ASCT IV
on day 0, receive palifermin IV on days 1-3, and receive filgrastim SC or IV on day 5.

MAINTENANCE THERAPY: Beginning 30 days after ASCT, patients receive lenalidomide orally (PO)
daily.

Inclusion Criteria:

- Patients with will be eligible if they are either in partial response, or have stable
disease after no more than two attempts of induction therapy

- Patients with high-risk cytogenetics, t(4:14); t(14;16), t(14:20), deletion p17, gain
in 1q, are eligible

- Patients with plasma cell leukemia in >= partial remission are eligible

- Patients with non-quantifiable monoclonal proteins are eligible provided they meet
other criteria for multiple myeloma and they have evaluable or measurable disease by
other (radiographic, magnetic resonance imaging [MRI], computed tomography [CT], lytic
measurable lesion on x-ray,) means

- Karnofsky performance status (KPS) >= 70%

- Less than 12 months since diagnosis

- No contraindication to the collection of a minimum of 4 x 10^6 CD34+ cells/kg by
apheresis

- Bilirubin =< 1.5 mg/dl

- Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) < 2.5 x upper limits of normal

- Creatinine of measured or calculated creatinine clearance of >= 50 cc/min

- Absolute neutrophil count of > 1000/ul

- Platelet count of > 100,000/ul

- Cardiac ejection fraction >= 50% by multi-gated acquisition (MUGA) scan and/or by
echocardiogram

- Forced expiratory volume in 1 second (FEV1) > 60% and diffusion capacity of the lung
for carbon monoxide (DLCO) > 50% of predicted lower limit

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for six months following duration of study participation; should a woman become
pregnant or suspect that she is pregnant while participating on the trial, she should
inform her treating physician immediately; patients must be fully aware of the
teratogenic potential of immunomodulatory drugs (ImIDs) and agree to fully comply with
the mandated guidelines regarding contraception as stated in the informed consent and
the patient warning document attached to the consent form; women of childbearing
potential must have a negative pregnancy test performed within 24 hours prior to
beginning thalidomide, except for woman who have been postmenopausal for at least 2
years, or underwent hysterectomy; use of effective means of contraceptive should be
started at least 2 weeks prior to initiating lenalidomide

- All subjects must have the ability to understand and the willingness to sign a written
informed consent; they are to give voluntary written 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

- Patients should have finished their prior systemic therapy or radiation therapy, at
least 3 weeks before cyclophosphamide or granulocyte colony-stimulating factor
(G-CSF)/plerixafor mobilization, and should have finished dexamethasone at least 7
days prior to Plerixafor priming; administration of bisphosphonates needs to be
completed at least 2 weeks before cyclophosphamide priming; bisphosphonates can be
resumed or started after day 30

Exclusion Criteria:

- Diagnosed or treated for another malignancy within 3 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

- Known hypersensitivity to filgrastim or to Escherichia coli (E. coli) derived proteins

- Inability to lie supine in a full body cast for approximately 30 minutes, the
anticipated duration of each treatment session

- Previous radiation therapy to more than 20% of bone marrow containing areas, or to any
area exceeding 2000 cGy, is an exclusion

- Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
(HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core
antibody or hepatitis B surface antigen must have a negative polymerase chain reaction
(PCR) result before enrollment; those who are PCR positive will be excluded

- No other medical, or psychosocial problems, which in the opinion of the primary
physician or principal investigator would place the patient at unacceptably high risk
from this treatment regimen