Reports

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PRIORITY PRESS - 52nd Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 4-7, 2010

Findings on Subcutaneous Administration

Results of a phase III randomized, multinational trial have demonstrated that subcutaneous (s.c.) administration of the proteasome inhibitor bortezomib is as effective but better tolerated than the intravenous (i.v.) formulation in patients with relapsed or refractory multiple myeloma (MM). The results will facilitate use of this agent, which has been found to extend progression-free survival (PFS) when used alone or in combination with other novel therapies in controlled trials, including one recently published trial in transplant-ineligible MM patients (J Clin Oncol 2010;28:5101-9). The data mark a continuing evolution in optimal therapeutic strategies for this disease.

“The efficacy and safety of s.c. bortezomib is especially good news for patients with difficult venous access or those who have been most vulnerable to the adverse events, such as peripheral neuropathy, which are associated with this agent, but s.c. administration is easier and may also improve compliance in a general sense,” reported Prof. Philippe Moreau, Department of Hematology, University Hospital, Nantes, France. Senior author of this multinational trial, Prof. Moreau suggested that the s.c. approach is an incremental step forward in providing a standard of care in patients not eligible for a potentially curative stem-cell transplant.

In this open-label, phase III study, 222 MM patients from 53 centres in 10 countries were randomized in a 2:1 ratio to s.c. or i.v. bortezomib. The main eligibility criterion was relapse or progression after a previous systemic therapy. The dose and schedule in both arms was 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days for a total of 8 cycles. The i.v. injection was administered in a concentration of 1 mg/mL as a 3- to 5-second i.v. push. The s.c. injection was administered in a concentration of 2.5 mg/mL. In both arms, bortezomib was administered as a monotherapy, but if a patient did not do better than a partial response (PR) after 4 cycles (but had not progressed), oral dexamethasone 20 mg was added in the next 4 cycles.

The primary end point was the objective response (OR) rate after 4 cycles of therapy. At 42%, this was exactly the same in the 2 arms. After an additional 4 cycles, when patients without a complete response (CR) received dexamethasone in addition to bortezomib, the OR rates climbed to 52% in both arms. When CR and near CR (nCR) were tabulated, the rate was slightly but not significantly higher in the s.c. arm (22% vs. 20%). Median PFS and overall survival (OS) rates at 1 year were 10.2 months vs. 8 months and 72.6% vs. 76.7% in the s.c. and i.v. arms, respectively. Neither difference was statistically significant.

However, there were significant safety advantages for s.c. relative to i.v. administration. While a trend for a lower rate of grade =3 side effects in the s.c. arm (57% vs. 70%) fell short of significance, the rates of any peripheral neuropathy (38% vs. 53%; P=0.04) and grade =3 peripheral neuropathy (6% vs. 16%; P=0.03) were both lower on s.c. therapy. There was also a trend for a reduced risk of any-grade gastrointestinal adverse events on the s.c. arm (37% vs. 58%).

“These results support those of a previous phase I study that showed s.c. and i.v. provide comparable drug exposure and response rates. The greater tolerability of s.c. administration is a bonus, because s.c. administration, which eliminates the need for repeated i.v. access or insertion of a central venous access device, already has advantages over the i.v. route,” Prof. Moreau maintained. He suggested that this approach should be tested in other populations, particularly in elderly patients liable to have limited venous access, or in the maintenance setting where indefinite treatment with bortezomib may have benefit.

UPFRONT New Results

The evidence for its role as a maintenance regimen was expanded with new results from the phase IIIb UPFRONT study that randomized elderly MM patients to 1 of 3 bortezomib-containing induction regimens followed by bortezomib maintenance therapy. The goal was to determine which regimen was superior on the basis of the primary end point of PFS. The 3 regimens were bortezomib/dexamethasone (VD), bortezomib/thalidomide/dexamethasone (VTD) or bortezomib/melphalan/prednisone (VMP). The induction regimens were administered for 8 cycles and bortezomib maintenance administered for an additional 5 cycles.

While response rates were modestly but consistently higher on VTD relative to either of the 2 other regimens, the median PFS of 13.8 months, 18.4 and 17.3 months for VD, VTD and VMP, respectively, were not statistically different. However, the senior author of the study, Dr. Ruben Niesvizky, Center of Excellence for Lymphoma and Myeloma, Weill Medical College, New York City, placed emphasis on the ability of bortezomib maintenance to boost response.

“Maintenance with bortezomib monotherapy was well tolerated after all 3 induction regimens and improved the proportion of patients achieving a very good PR (VGPR) or better,” Dr. Niesvizky reported. Notably, bortezomib maintenance administered in a dose of 1.6 mg/m2 on days 1, 8, 15 and 22 for the five 35-day cycles did not increase the rates of peripheral neuropathy, the most common grade =3 toxicity of the induction regimens. While VTD provided the highest response rates, it also produced the highest rate of any-grade peripheral neuropathy (61% vs. 49% for VD and 45% for VMP).

Strategies for Specific Mutations

The role of maintenance bortezomib in improving response in MM was further highlighted in new data from a subgroup analysis of the HOVON-65/GMMG-HD4 trial, which compared strategies for efficacy in specific mutations that affect outcome in this malignancy. In this study, transplant-eligible MM patients were randomized to 3 cycles of vincristine/doxorubicin/dexamethasone (VnAD) or bortezomib/doxorubicin/dexamethasone (VAD). Hematopoietic stem cells were then mobilized prior to autologous stem cell transplantation. This was followed by maintenance therapy with thalidomide 50 mg q.d. in the VnAD group and bortezomib 1.3 mg/m² once q2 weeks in the VAD group. The focus of this sub-analysis was fluorescent in situ hybridization (FISH) analyses of genetic translocations and their effect on prognosis.

“The most pronounced impact on prognosis was seen for t(4;14), del17p13 and gain1q21, each significantly associated with poor prognosis with respect to PFS and OS,” reported Dr. Hartmut Goldschmidt, University Hospital, Heidelberg, Germany. However, this was found to be treatment-dependent. In particular, the median PFS was half as long in patients with the t(4;14) translocation receiving VnAD, but not in those receiving VAD. At 3 years, the OS in t(4;14) patients was 39% on VnAD but 76% on VAD. In patients without t(4;14), the OS on VAD was 87%.

“Although patients with t(4;14) treated with VAD still had an inferior prognosis than those without t(4;14), the negative impact of t(4;14) on PFS could almost completely be overcome by the bortezomib-based treatment,” remarked Dr. Goldschmidt. Although he did not attempt to quantify the independent impact of bortezomib maintenance on efficacy in t(4;14) patients, he indicated that both induction and maintenance were likely to have contributed to the relative advantage.

Summary

Guidelines for MM continue to list several regimens as potential front-line therapies, but the recently presented data support a role for novel therapies in both induction and maintenance regimens. Although many forms of MM are treated without curative intent, the ability to prolong PFS with reasonably well tolerated and effective therapies has been an important advance. A variety of evidence at the ASH meeting, including a 432-patient study by Dimopoulos et al. (Poster 3027) associating the addition of dexamethasone to bortezomib monotherapy with higher CR rates in relapsed MM, makes further evolution in defining optimal MM therapy almost certain. However, the relative hierarchy of first-line, salvage and maintenance regimens is being recognized with increasing clarity.