MAGE-A3 Protein + AS15 as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Subjects were enrolled sequentially following confirmation of eligibility criteria, including International Staging System (ISS) stage 1, 2, or 3 multiple myeloma with MAGE-A3 tumor antigen expression. Subjects received a total of 8 immunizations with 300 µg of recMAGE-A3 + AS15. The first immunization was administered approximately 6 to 15 weeks prior to auto-SCT (Day 0), with subsequent immunizations administered every 3 weeks (± 3 days) starting 10 days after auto-SCT (ie, Days 10, 31, 52, 73, and 94). Two additional immunizations were administered at 3-month intervals (± 7 days, ie, Days 180 and 270). No dose adjustments were allowed. Platelet counts must have been ≥ 50 x 10E9/L prior to immunization, with blood product transfusions permitted as necessary.

The process for auto-SCT comprised the following: (1) up to 3 steady-state leukopheresis procedures to collect and freeze a sufficient quantity of peripheral blood mononuclear cells (PBMCs), with the first leukopheresis performed 3 weeks (± 6 days) after the first immunization; (2) stem cell mobilization with cyclophosphamide, granulocyte-colony stimulating factor (G-CSF) and/or plerixafor; (3) high-dose melphalan (total dose 200 mg/m2) on Days -3 through -1; (4) auto-SCT on Day 0; and (5) re-infusion with thawed PBMCs on Day 3.

Inclusion criteria

• Symptomatic multiple myeloma, ISS stage 1, 2 or 3 within 12 months of starting therapy.
• Completion of induction therapy with VGPR, or better, by IMWG criteria. All induction myeloma therapy (oral or intravenous, including steroids) must have been discontinued for 3 weeks prior to the first immunization. Subjects did not need to have measurable disease at the time of the screening visit.
• Signed separate informed consent for stem cell mobilization and high-dose chemotherapy/auto-SCT, and was found to be eligible for SCT by standard institutional criteria.
• MAGE-A3 expression determined by immunohistochemistry (IHC) present in a bone marrow specimen or plasmacytoma specimen.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
• The following laboratory parameters within the ranges specified:

• Neutrophil count: ≥ 1.5 x 109/L
• Lymphocyte count: ≥ 0.5 x 109/L
• Platelet count: ≥ 50 x 109/L
• Serum creatinine: ≤ 2 mg/dL
• Serum bilirubin: < 1.5 x the upper limit of normal (ULN)
• Aspartate and alanine aminotransferase (AST and ALT): < 2 x ULN
• Hemoglobin: ≥ 8.0 g/dL
• International normalized ratio (INR): ≤ 1.5
• Partial thromboplastin time: ≤ 1.5 x ULN (unless known history of anti-phospholipid antibody or lupus anticoagulant)
• Age ≥ 18 years.
• Able and willing to give valid written informed consent.

Exclusion criteria

• Prior treatment with melphalan (Alkeran®), other than 1 cycle (4 days) of oral melphalan.
• Prior autologous or allogeneic SCT.
• Prior immunization against MAGE-A3 or other cancer-testis antigens.
• Concurrent malignancies, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
• Known immunodeficiency, human immunodeficiency virus (HIV) positivity, or active hepatitis B or C.
• Known allergy or history of life-threatening reaction to G-CSF or GM-CSF.
• History of autoimmune disease (eg., rheumatoid arthritis, lupus), other than vitiligo, diabetes, or treated thyroiditis.
• History of severe allergic reactions to vaccines or unknown allergens.
• History of myocardial infarction, angina, congestive heart failure, ventricular tachyarrhythmia, stroke or transient ischemic attack within the previous 6 months.
• Other serious illnesses or co-morbid conditions (e.g., serious infections requiring antibiotics, bleeding disorders, other heart or lung conditions) that, in the opinion of the investigator, made the subject inappropriate for high-dose melphalan and auto-SCT.
• Pregnancy and breastfeeding.
• Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first immunization.
• Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
• Lack of availability for immunological and clinical follow-up assessments.