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PRIORITY PRESS - 51st Annual Meeting of the American Society of Hematology

New Orleans, Louisiana / December 5-8, 2009

Recently, the large multicentre VISTA trial established bortezomib, melphalan and prednisone (VMP) as the new induction standard in the treatment of multiple myeloma (MM) in elderly patients, replacing MP alone (San Miguel et al. N Engl J Med 2008;359:906-17).

New survival analyses reinforce the combination’s potency. After a median three years of follow-up in a preplanned survival analysis, VMP continues to be associated with a 35% reduction in the risk of death (HR 0.65, P=0.0008) relative to MP even as patients who participated in this study continue to receive subsequent therapies. These new data reinforce the efficacy of VMP induction and led Dr. Maria-Victoria Mateos, Hospital Universitario Salamanca, Spain, to conclude, “VMP treatment upfront appears more beneficial than saving bortezomib or other novel agents for relapse.”

However, for induction therapy, the optimal agent for combination with the proteasome inhibitor bortezomib remains to be elucidated. Following induction, can the response rate be increased with acceptable toxicity with a bortezomib-based maintenance therapy?

Reduced Toxicity and Increased Response

A new multicentre study, also characterized as practice-changing, has reinforced the efficacy of this induction regimen and demonstrated that a bortezomib-containing maintenance doublet can provide relatively long periods of progression-free survival (PFS) with good tolerability. “Adding the maintenance therapy increased the complete response (CR) rate but was associated with a low toxicity profile over an extended treatment period,” reported senior author Dr. Mateos.

The two-phase design and randomization scheme of the study generated a variety of new data, not least that bortezomib-based regimens “appear to overcome the poor prognosis of high-risk cytogenetic abnormalities,” according to Dr. Mateos.

In the study, 260 patients were randomized to one of two induction regimens (six cycles) and then randomized again to one of two maintenance therapies for up to three years. In the induction phase, the current standard of VMP (bortezomib 1.3 mg/m² on days 1,4, 8, 11, 22, 25, 29 and 32 of the first six-week cycle reduced to a weekly schedule for the subsequent five cycles; melphalan 9 mg/m² and prednisone 60 mg/m² administered on days 1 to 4 of all six cycles) was compared to the same regimen with thalidomide (VTP) substituted for melphalan. Thalidomide was administered at 50 mg/day for the first 15 days and 100 mg/day for the remaining part of the first six-week cycle and for the remaining five five-week cycles. In the maintenance phase, bortezomib 1.3 mg/m² on days 1, 4, 8, 11 q3 months plus prednisone (VP) 50 mg every 48 hours was compared to the same bortezomib dose plus thalidomide (VT) 50 mg/day.

Induction Responses

Responses to both induction regimens were rapid and similar. The median time to response was 1.6 months and the overall response rate was 80% for VMP and 81% for VTP. CRs were achieved in 32% on VMP and 37% on VTP and partial responses (PR) in 48% and 46%, respectively. None of these differences were statistically significant. However, there were differences in the types of toxicity. VMP was associated with greater hematologic toxicity, particularly more neutropenia (39% vs. 22%; P=0.008) and thrombocytopenia (27% vs. 12%; P=0.001), while VTP was associated with more cardiac events (8% vs. 0%; P=0.001). Peripheral neuropathy was low and non-significantly different between VMP and VTP (5% and 9%, respectively), but infections were more common on VMP (7% vs. <1%; P=0.01). Discontinuations for serious side effects were significantly more common on VTP (17% vs. 11%; P=0.03). Deaths occurred in 5% of both groups, with cardiac causes accounting for most deaths in those taking VTP and infection accounting for most deaths in those on VMP.

Maintenance Response

In the 178 evaluable patients who went on to the maintenance randomization phase of the study, both regimens were found to be highly effective for increasing CR rates including in patients with poor-prognosis cytogenetic abnormalities. Overall, a CR or near CR was achieved in 59% of those on VT maintenance and 55% of those on VP maintenance. This was a near doubling of CR rates from the end of induction. The rate of immunofixation negative complete response (CRIF-) was also slightly greater on VT than VP (44% vs. 39%) but not significantly different.

An increased depth of response was associated with major advantages for outcome independent of therapy in this study with stepwise improvements for time to progression (TTP) and overall survival (OS) for near CR plus PR relative to PR alone, CRIF- relative to near CR plus PR, and immunophenotypic remission relative to CRIF-. As in other studies, there were also substantial improvements in TTP and OS for minimal residual disease (MRD)-negative relative to MRD-positive.

Both maintenance regimens were well tolerated with only 5% of VP and 7% of VT patients discontinuing therapy due to side effects. Cardiac events (1% vs. 2%) and infections (1% vs. 2%) did not differ significantly between VP and VT, respectively. Of note, the incidence of peripheral neuropathy on these regimens was very low (2% for VP and 5% for VT).

After a median follow-up of 24 months, PFS was not yet reached on VT and 23 months on VP (P=0.05). The OS at two years was similar (86% and 81%; P=0.7). However, when a Cox regression analysis was performed on outcomes over the induction and maintenance periods, there was a 60% improvement for VMP/VT relative to VTP/VP (RR 1.6; P=0.008) for PFS. This led the authors to consider VMP induction followed by VT maintenance as the preferred regimen.

Additional Findings of Clinical Relevance

Two additional findings from this study that are important for clinical practice is the high rate of response in patients with cytogenetic abnormalities (t[4;14], t[4;16], del17p) as defined by FISH. Regardless of induction strategy, response rates in those with abnormal and standard cytogenetics were similar (29% vs. 23%). Similarly, regardless of maintenance therapy, CRIF- rates among those with abnormal and standard cytogenetics were similar (38% vs. 42%). In addition, Dr. Mateos also emphasized the low rate of peripheral neuropathy relative to previous bortezomib studies. She attributed this to weekly rather than twice-weekly treatments.

The Weekly Advantage

Two other newly completed studies reinforced the advantages of weekly bortezomib. One was a study comparing VMP to VMP with thalidomide (VMPT). After enrolment was initiated, the protocol was changed from twice-weekly to weekly bortezomib in both arms. When the 370 patients who entered the study after the switch were compared to the 141 patients who received the original twice-weekly infusion, the overall incidence of peripheral neuropathy fell from 45% to 27% (P=0.0002) and the incidence of grade <u>></u>3 peripheral neuropathy fell from 16% to 3% (P<0.0001), according to senior author Dr. Francesca Gay, Department of Hematology, Mayo Clinic, Rochester, Minnesota. Although the slight fall in the CR rate on weekly administration did approach statistical significance (25% vs. 33%; P=0.07), there was no significant difference in PFS (68% vs. 60%; P=0.31) or OS (91% vs. 89%; P=0.44) at two years.

In a second, much smaller study, 63 untreated symptomatic MM patients were studied in two cohorts with a standard CyBorD (cyclophosphamide, bortezomib [twice-weekly] and dexamethasone) regimen or a modified CyBorD regimen (once-weekly bortezomib). When the two cohorts were compared, the increased tolerability of the modified regimen led to higher overall doses of the proteasome inhibitor (6.0 vs. 5.2 mg/m2 per cycle) and it eliminated grade 3 peripheral neuropathy (0% vs. 6%).

Summary

Less than two years after VMP was established as the most effective therapy for untreated elderly MM patients deemed ineligible for high-dose therapy, a new study has suggested that benefits can be extended with a maintenance regimen that combined bortezomib with thalidomide. The two-drug regimen is relatively well tolerated, providing patients with improved survival and an acceptable quality of life. The induction/maintenance sequence of VMP/VT has created a benchmark against which other strategies will be compared.