Randomized Phase II Study of BLP25 Liposome Vaccine (L-BLP25) in Patients with Multiple Myeloma

Abstract 2927

The standard of care for patients (pts) with asymptomatic multiple myeloma (MM) stage I/II or a stable response after chemotherapy is “watchful waiting”, with conventional agents failing to demonstrate benefits as early or maintenance therapy. We report data from a randomized, open-label, phase II study of BLP25 liposome vaccine (L-BLP25, Stimuvax^®), a therapeutic cancer vaccine (TCV) targeting the mucin 1 (MUC1) antigen, in pts with previously untreated, slowly progressive, asymptomatic MM I/II or MM II/III in stable response/plateau phase following anti-tumor therapy.

Pts were randomized to L-BLP25 and either a single (Group [Gp] A) or multiple (Gp B) low dose(s) of cyclophosphamide (CP). In both Gps, L-BLP25 (930 μg) was administered weekly for 8 wk, followed by maintenance vaccination every 6 wk until disease progression requiring anti-tumor therapy. A single dose of CP (300 mg/m², maximum total dose 600 mg) was given 3 days before the first L-BLP25 dose and, in Gp B, also prior to the vaccination at wk 5 and each maintenance phase vaccination.

The primary objective was to investigate the immune response to L-BLP25. A specific induced immune response to MUC1 was defined as ≥2-fold increase over baseline and no peptide control in an IFN- γ ELISpot, lymphoproliferation or intracellular IFN- γ FACS assay following short-term in vitro stimulation of PBMCs with MUC1-derived peptides, on ≥2 assessments. Secondary objectives included safety/tolerability, quality of the immune response, linkage of immune response to HLA restriction, clinical effects, time to progression and time to anti-tumor therapy. Median data are presented.

Thirty-four pts (age: 64 years; 15 male) were randomized and received treatment (Safety Analysis [SA] set; A/B = 17/17) of which 32 (17/15) pts met the pre-specified criteria for immunologic analysis (Immunological Diagnostic Analysis [IDA] set). The duration of MM (SA set) was 34 vs 37 months (Gp A vs B) at study entry. The proportion of pts with untreated stage I/II vs previously treated stage II/III MM was 29 vs 71% (Gp A) and 47 vs 53% (Gp B). Of the previously treated pts, 83% (Gp A) and 100% (Gp B) had received high-dose chemotherapy with autologous stem cell transplantation.

In this analysis, all pts had reached ≥50 wk or had discontinued study treatment. Treatment duration was 54 vs 87 wk (Gp A vs B), with 15 vs 21 L-BLP25 vaccinations and 1 vs 11 CP infusions (SA set). Cumulative CP dose (first 50 wk) was 297 vs 1769 mg/m² (Gp A vs B), corresponding to a relative dose intensity of 100 and 97%.

As in previous studies, spontaneously induced specific MUC1 immune responses were seen frequently pre-vaccination (baseline Gp A/B = 59/47%). Specific induction/augmentation of the MUC1 response was seen in 53% of pts following L-BLP25 treatment with no difference between Gps A and B. Rates of induction/augmentation following vaccination were similar for pts with vs without a spontaneous (pre-vaccination) immune response. First immune responses occurred early (≤9 wk) in the course of treatment. Assessments of cytokines will be presented.

Objective clinical responses (Bladé criteria) were not seen, and were not anticipated given the aim of TCVs is to stabilize disease rather than induce a response according to established chemotherapy criteria. In a preliminary analysis, reduction in the slope of on-study M-protein concentration over time compared with pre-study data was seen in 13 of 30 pts (10/13 previously untreated and 3/17 previously treated; updated analysis will be presented). There was no association between presence of a treatment-induced MUC1 response and on-study changes in M-protein (area under the curve at wk 26 [AUC₂₆]; IDA set). However, on-study M-protein AUC₂₆ was significantly lower in pts without vs with a spontaneous pre-vaccination MUC1 response (pooled data for both groups: AUC₂₆ = -5.2 [n=13] vs 16.2 [n=16], p=0.015). However, these data should be interpreted with caution given the small number of pts.

Treatment was generally well tolerated. One possibly treatment-related fatal event of encephalitis occurred in Gp B.

In summary, L-BLP25 led to MUC1-specific immune responses in a large proportion of MM pts and was associated with emerging clinical effects on M-protein concentration over time. Our data suggest that pts with previously untreated, early-stage disease may be the most likely to benefit from L-BLP25 vaccination. Further investigation of L-BLP25 in MM is warranted.