A Phase I Study of Bortezomib During Maintenance Phase After High-Dose Melphalan and Autologous Stem Cell Transplantation In Patients with Multiple Myeloma

Most Autologous stem cell transplant (ASCT) eligible Multiple Myeloma (MM) patients (pts) will have persistent disease after ASCT. Achieving a Complete Response (CR) after ASCT correlates with significantly longer progression free survival (PFS) and overall survival (OS). Since only 30–40% of the pts achieve a CR post ASCT there is a strong rationale for investigating post ASCT maintenance therapy with novel agents to improve PFS and OS. Maintenance therapy can have a potential role in achieving CR as well as maintaining CR post ASCT. The maintenance dose of novel agents including Bortezomib (B) was arbitrarily selected and has not been evaluated in Phase 1 trials. We designed this Phase 1 study to determine the most tolerated Maintenance dose (MtMD) of B after ASCT. To our knowledge, there are no phase 1 trials conducted to determine the maintenance dose of B post ASCT.

We enrolled 15 pts from 11/28/2005 to 10/27/2009. Fourteen patients are evaluable. The primary objective was to determine the MtMD of B in 3x 3 dose de-escalation design. The secondary objectives were to evaluate CR, Overall Response (OR) and response duration. Two pts were enrolled in level (L) 1 utilizing therapeutic dose of B, 1.3 mg/m²on days (D) 1, 4,8 and 11 in a 21 day cycle. Both pts experienced dose limiting toxicities (DLT). Six pts were then enrolled in dose L 2 utilizing B, 1.3 mg² on D 1, 4, 8 and 11 in a 28 day cycle. Seven pts were thereafter enrolled in dose L 3 utilizing B 1mg/m² on D 1, 8 and 15 in a 28 day cycle. All pts who underwent ASCT (Day 0) were eligible and registered between D+30 to D+120 after ASCT. Conditioning regimen included melphalan at a median dose 200 mg/m² (140-260). A maximum of 8 cycles of B were planned. B was administered at a median duration of 107 days (52-123) post ASCT. In order to properly assess dose dependent DLT, pts who received < 4 cycles for reasons other than B -related toxicity were replaced. Enrollment was moved to the next lower dose level if ≥2 DLTs were observed. The pts characteristics included a median age of 58 years old (38-68), median KPS of 90% (70-100) and 2 pts with baseline grade 1 neuropathy. The baseline disease status at the time of ASCT included 4 pts in CRu, 3 pts in VGPR, 4 pts in SD, 3 pts in PR and 1 pt with relapsed disease. Five pts had high risk features on bone marrow FISH analysis. Nine pts had received induction with immunomodulatory agents and 6 pts were treated with B based induction regimens.

Two pts developed DLT on L 1. One patient experienced Grade 2 neuropathy that did not resolve in two weeks and required B dose reduction. The other patient experience Grade 3 neutropenia requiring filgrastim support. In addition, 2 pts on L2 developed DLT. First pt had multiple hospital admissions due to high grade fever and dehydration. Second patient experienced Grade 2 neuropathy that did not resolve with treatment interruption and therefore B was discontinued after two cycles. No DLTs were observed in L3. Eight cycles of B were administered in L1. In L 2, 3pts received 8 cycles (1 off study), 1 pt received 3 cycles and 2 pts received 2 cycles of B. In L3, 6 of 7 pts received 8 cycles. After 1 year of post ASCT, 1 pt was in CRu, 1 pt in PR,3 pts were in SD, 2 pts had PD, 3 pts with relapsed disease and 5 pts were off-study (2 experienced DLTs, 2 withdrew consent and 1 failed to receive at least 4 cycles). All pts except 1 are alive as of 8/2/2010. The median duration of follow up for the entire cohort is 24 months (11-53).The median duration of response in L3 was 12 months (11-24). One pt enrolled on L3 died of sepsis during the course of follow up. He did not complete at least 4 cycles of B and therefore was not evaluable.

To our knowledge, this is the first study that determines MtMD of B post ASCT. We conclude that B at a dose of 1 mg/m² on D 1,8 and 15 in a 28 day cycle can be safely given beginning 52 d post ASCT for maintenance. A maximum of 8 cycles were administered. Phase 2 studies will determine efficacy of this regimen utilizing dose L3.

IMID= Immunomodulatory drugs, VAD=Vincristine, Adriamycin, Dexamethasone, RE=Relapse, CY= Cycles.

Abidi: Millennium: Speakers Bureau. Off Label Use: Bortezomib is currently not approved for maintenance therapy after Autologous stem cells transplant. Lum: Transtarget Inc: Equity Ownership.