Abstract
The proteasome-inhibitor bortezomib is active in Waldenstrom's macroglobulinemia (WM) though is associated with considerable peripheral neuropathy (PN) that results in frequent dose reduction and treatment discontinuation. We therefore examined the efficacy and safety of carfilzomib, a neuropathy-sparing proteasome-inhibitor, along with rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor-naive and rituximab-naive symptomatic WM patients. The preliminary findings of this study were previously published (Treon et al, Blood 2014), and herein we provide a long-term update of this study. The median baseline characteristics for patients enrolled on this prospective clinical trial were as follows: Age 61 (range 47-75 years), prior therapies 0 (range 0-1), hematocrit 32.3%, serum IgM 3,375 mg/dL, serum B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV carfilzomib 20mg/m2 (cycle 1) and 36mg/m2 (cycles 2 and beyond) along with IV dexamethasone 20 mg on days 1, 2, 8, 9. Rituximab 375 mg/m2 was administered on days 2, 9 of each 21-day cycle. Treatment consisted of six 21-day induction cycles, followed by maintenance therapy that was given every 8 weeks for eight cycles and consisted of carfilzomib 36 mg/m2 and IV dexamethasone 20 mg on days 1, 2. Rituximab was given at 375 mg/m2 on day 2 of each maintenance cycle. Following protocol therapy, the median serum IgM levels declined to 561 mg/dL at best response (p<0.00001). Median hematocrit rose to 41.9% (p<0.00001). Thirty patients completed induction therapy, with reduction in bone marrow tumor burden from a median of 60% to 7.5% at end of induction (p<0.0001). Twenty patients completed maintenance therapy and had a bone marrow tumor burden reduction to 2.5% at end of maintenance treatment (p<0.0001 versus pre-treatment baseline; p=0.0088 versus end of induction). The best overall response was 80.64% (1 CR, 11 VGPR, 10 PR, 3 MR), and major response rate was 71%. Median time to response (MR or better) was 2.1 months. As shown in Figure 1A, the median progression-free survival (PFS) for all patients was reached at 46 months (range 2-63 months). PFS was associated with depth of response. Patients who achieved at least a VGPR have not reached median PFS, whereas the median PFS was 52 months for those who attained a PR, and 4 months for those with less than a PR (Figure 1B; Chi-square 35.5, p<0.0001). All patients are alive, and 14 patients remain in follow-up without a progression event.
Grade >2 treatment-related toxicities included elevated lipase (12.9%), steroid-related hyperglycemia (6.45%), neutropenia (9.67%), and reversible cardiomyopathy in a patient with multiple risk factors (3.22%). Only one grade 2 PN (3.2%), and no grade 3/4 PN events occurred. At baseline, the median serum IgA level was 47 mg/dL, versus 46 mg/dL at last follow-up (p=0.11). Conversely, median serum IgG levels declined from 715 mg/dL at baseline to 372 mg/dL at last follow-up (p=0.0004). Treatment related IgG hypogammaglobulinemia was associated with recurring sino-bronchial infections, and necessitated IVIG treatment in 6 (19.4%) patients. Discontinuation of protocol therapy occurred for non-response (n=8), hypogammaglobulinemia associated with infections (n=2), grade 2 PN (n=1), cardiomyopathy (n=1), progressive disease (n=1), and prolonged hold of protocol therapy for an unrelated procedure (n=1). The long-term results of this study show that CaRD is an active, PN-sparing regimen that is associated with durable responses in symptomatic patients with WM. PFS is impacted by depth of response, and IgG hypogammaglobulinemia is commonly encountered with this regimen.
Castillo: Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon: Pharmacyclics: Consultancy, Research Funding.
