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PRIORITY PRESS - 13th International Myeloma Workshop

Paris, France / May 3-6, 2011

The positive impact of proteasome inhibitor-based therapy for the treatment of multiple myeloma (MM) has become apparent in early disease and newly diagnosed patients, both in transplant-eligible and -ineligible patients, as well as for maintenance therapy and in patients with relapsed/refractory disease. Superior response rates, including unprecedented complete response (CR) rates, are being obtained with bortezomib-containing regimens across disease stages.

Improved Response and Duration

The superior response quality with bortezomib produces a longer duration of response, noted Dr. Robert Orlowski, Departments of Lymphoma/Myeloma and Experimental Therapeutics, Division of Cancer Medicine, M.D. Anderson Cancer Center, Houston, Texas. A CR correlates with survival (progression-free survival [PFS] and overall survival [OS]), he noted, and therefore, this agent has become “a crucial part of our armamentarium as we strive to achieve the best quality disease responses.”

In patients not eligible for autologous stem cell transplantation (ASCT), the VISTA (Velcade as Initial Standard Therapy in multiple myeloma) trial demonstrated that “you can use your best drugs early and then revisit them,” Dr. Paul Richardson, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts, told delegates. “Efficacy is not compromised with the early use of bortezomib.” In VISTA, when added to melphalan and prednisone as upfront therapy (in newly diagnosed patients), it improved response rates and the duration of the response, extending the treatment-free interval. Maintenance therapy is emerging as a key strategy in this group, added Dr. Richardson.

In the transplant setting, “bortezomib is the backbone of induction regimens,” stated Dr. Pieter Sonneveld, Department of Hematology, Erasmus Medical Center and University of Rotterdam, The Netherlands. With its use in the induction regimen, very good partial response (=VGPR) and near CR (nCR) rates have improved as demonstrated in several clinical trials.

Single-agent Consolidation Therapy

New findings announced here support its use as a single agent when used as consolidation therapy following high-dose melphalan with ASCT, as induction therapy in elderly patients not eligible for high-dose therapy, and as induction and maintenance therapy in patients with relapsed MM.

In a phase III trial conducted by the Nordic Myeloma Study Group, 370 patients were randomized to either bortezomib consolidation therapy or no consolidation therapy 3 months following high-dose melphalan with ASCT. Consolidation was given as a standard dose of 1.3 mg/m² twice weekly in a 3-week schedule for the first 2 cycles. In the following 4 cycles, the proteasome inhibitor was administered once weekly in a 4-week schedule, for a total of 20 injections over 21 weeks.

“We had a 90% median of the relation of planned to total dose, so most patients got most of their treatment,” reported Dr. Ulf-Henrik Mellqvist, Sahlgrenska University Hospital, Gothenburg, Sweden. The median PFS measured from the time of randomization, the main outcome measure, was 27 months for patients in the proteasome-inhibitor arm compared to 20 months for patients in the control group (P=0.037).

The best reported CR/nCR rates were in the bortezomib group (45%) vs. controls (35%, P<0.05); the proportion of patients achieving =VGPR was 71% and 58%, respectively. Additionally, 68 patients had an improvement in their response after consolidation: 51 improved from a partial response to =VGPR and 17 improved from =VGPR to nCR. In the control group, 42 patients had an improvement in response.

The estimated OS was approximately 87% in both groups after a median follow-up of 27 months. Neuropathic pain and peripheral sensory neuropathy of grade =3 were experienced by 6% and 5% of patients in the bortezomib arm compared with 0.5% and 2% of patients in the control arm, respectively.

Single-agent Maintenance Therapy: UPFRONT Data

In the community-based, open-label, multicentre phase IIIb UPFRONT study, all 3 bortezomib-based induction regimens proved effective in the treatment of elderly MM patients and the proteasome inhibitor modestly improved =VGPR rates as a single agent for maintenance therapy, reported Dr. Ruben Niesvizky, Center of Excellence for Lymphoma, Weill Medical College of Cornell University, New York City, in a poster presentation.

UPFRONT examined the safety and efficacy of 3 induction regimens with bortezomib added to dexamethasone (VD), thalidomide/dexamethasone (VTD) and melphalan/prednisone (VMP), all followed by single-agent bortezomib maintenance (1.6 mg/m² on days 1, 8, 15 and 22, with a rest period on days 23 to 35). One hundred patients were randomized to each induction regimen.

After a median follow-up of 18.8 months, the median PFS was not significantly different between the 3 arms: VD, 14.7 months; VTD, 14.9 months; and VMP, 17.2 months.

Maintenance was associated with an improvement in =VGPR from 36% to 39% in the VD arm, from 44% to 47% in the VTD arm and from 40% to 44% in the VMP arm. VTD was associated with the highest rate of all-grade adverse events, grade 3 or higher adverse events, serious adverse events and study discontinuations. The incidences of at least 1 serious adverse event were 49% with VD, 56% with VTD and 47% with VMP. Single-agent bortezomib maintenance was well tolerated. “Compared with post-induction rates, the rates of grade =3 adverse events and all-grade and grade =3 peripheral neuropathy did not increase substantially during maintenance in all 3 treatment arms,” observed Dr. Niesvizky.

Extending Time to Progression with Combination Maintenance Therapy

In patients with relapsed MM, VD therapy is usually stopped after 11 cycles, even though maintenance therapy with these 2 agents may further extend time to progression. A new study suggests that VD used from cycle 1 as treatment and maintenance therapy improves the response rate and PFS in relapsed MM patients. The study data were presented by Dr. Simon J. Harrison, Peter MacCallum Cancer Centre, East Melbourne, Australia, during a poster session.

In the open-label single-arm study, the response to immediate VD followed by maintenance therapy until disease progression was measured in 90 patients who had relapsed MM. The response rate was compared to a matched group of 90 patients who received eight 3-week cycles of bortezomib as part of the APEX study conducted in patients with relapsed or refractory MM.

The overall response rates by EBMT criteria were 62% with VD treatment and maintenance and 42% with bortezomib in the matched APEX participants. There was no increase in toxicity with VD treatment and maintenance. The median time to progression was 9.9 months with VD treatment and maintenance compared to 5.1 months with bortezomib treatment in APEX, which suggests that maintenance therapy may delay relapse and should be considered a standard of care, stated Dr. Harrison.

Modified Dosing Reduces High-grade Peripheral Neuropathy

Various dosing schedules of the proteasome inhibitor as part of a VMP regimen have been used in untreated MM patients who are ineligible for high-dose therapy. A comparison of cumulative doses in the induction regimens used in 3 clinical trials of MM patients revealed high efficacy with each dosing schedule but a lower rate of toxicity with a reduced cumulative dose in the GIMEMA trial, in which bortezomib was given weekly for nine 5-week cycles, as presented by Dr. Maria-Victoria Mateos, University Hospital, Salamanca, Spain, in a poster session.

The 3 bortezomib induction schedules used in phase III studies were: twice-weekly for four 6-week cycles, then weekly for five 6-week cycles (VISTA and 1 group of GIMEMA); twice-weekly for one 6-week cycle, then weekly for five 5-week cycles, plus 3 years of bortezomib maintenance (GEM05 study); and weekly for nine 5-week cycles (GIMEMA study).

The median cumulative dose was lowest with the GIMEMA weekly bortezomib protocol (20.8 mg/m²) compared to 29.4 to 32.9 mg/m2 in the other 3 groups. Response rates were 71% to 87% with all 4 regimens, with CR rates of 20% to 30%. There were no differences in PFS between the GEM05 and the GIMEMA biweekly/weekly schedules. However, grade =3 peripheral neuropathy occurred at a rate of 13% and 14% in VISTA and GIMEMA twice-weekly then to weekly schedules, respectively, but was reduced to 7% with the GEM05 schedule and 2% with the GIMEMA weekly schedule.