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

Pilot Study of recMAGE-A3 + AS15 ASCI as Consolidation for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

This was an open-label, single-arm, pilot study of the recombinant MAGE-A3 protein plus the immunological adjuvant AS15 (recMAGE-A3 + AS15) in subjects with symptomatic multiple myeloma who had completed induction therapy with at least a Very Good Partial Response (VGPR) by the International Myeloma Working Group (IMWG) criteria and who were eligible for high-dose chemotherapy with autologous stem cell transplant (auto-SCT). The primary objective was to determine the safety and tolerability of immunizations when administered prior to stem cell mobilization and multiple times after stem cell reinfusion. Secondary objectives were to assess the humoral and cellular immunogenicity and clinical outcomes of immunization.

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:

1. Symptomatic multiple myeloma, ISS stage 1, 2 or 3 within 12 months of starting therapy.

2. 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.

3. 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.

4. MAGE-A3 expression determined by immunohistochemistry (IHC) present in a bone marrow specimen or plasmacytoma specimen.

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

6. 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)

7. Age ≥ 18 years.

8. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Prior treatment with melphalan (Alkeran®), other than 1 cycle (4 days) of oral melphalan.
2. Prior autologous or allogeneic SCT.
3. Prior immunization against MAGE-A3 or other cancer-testis antigens.
4. Concurrent malignancies, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
5. Known immunodeficiency, human immunodeficiency virus (HIV) positivity, or active hepatitis B or C.
6. Known allergy or history of life-threatening reaction to G-CSF or GM-CSF.
7. History of autoimmune disease (eg., rheumatoid arthritis, lupus), other than vitiligo, diabetes, or treated thyroiditis.
8. History of severe allergic reactions to vaccines or unknown allergens.
9. History of myocardial infarction, angina, congestive heart failure, ventricular tachyarrhythmia, stroke or transient ischemic attack within the previous 6 months.
10. 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.
11. Pregnancy and breastfeeding.
12. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first immunization.
13. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
14. Lack of availability for immunological and clinical follow-up assessments.