Older multiple myeloma patients show active response to novel agents

ABSTRACT: Incorporating bortezomib into induction, and lenalidomide into consolidation and maintenance, leads to high rates of response. Italian group also saw a trend toward better PFS.

Fully 88% of older adults with newly diagnosed multiple myeloma have at least a very good partial response when treated with low-dose autologous stem cell transplantation that is preceded by bortezomib-containing induction therapy and followed by lenalidomide-containing consolidation and maintenance therapy, according to trial results from the University of Turin in Italy.

Antonio P. Palumbo, MD, and his colleagues enrolled patients, ages 65 to 75 years, with newly diagnosed multiple myeloma or younger patients in whom full-intensity transplantation was contraindicated.

The patients were treated with a sequential strategy entailing four cycles of bortezomib, pegylated doxorubicin, and dexamethasone (PAD) for induction; one to two cycles of peripheral blood stem cell mobilization; two cycles of low-dose melphalan with autologous stem cell transplantation (MEL100); four cycles of lenalidomide and prednisone (LP) for consolidation; and, finally, ongoing lenalidomide for maintenance.

The analyses presented were based on the first 86 patients. Some 62% had the 13q deletion and 21% had the 4;14 translocation (ASCO 2008 abstract 8518).

The rate of at least very good partial response increased from 59% after PAD to 88% after PAD-MEL100 and remained at 88% after PAD-MEL100-LP; however, the respective rates of complete response and near-complete response combined were 21%, 59%, and 70%. Dr. Palumbo noted that the increase in the latter rates appeared to be mainly driven by gains among patients who initially had at least a partial response. Projected 2-year event-free survival was 83% and 2-year overall survival was 92%.

The 34 trial patients who completed the regimen (PAD-MEL100-LP) had a significantly higher rate of at least very good partial response when compared with 124 historical control patients who received dexamethasone, doxorubicin, and vincristine induction followed by full-dose melphalan with autologous transplantation (DAV-MEL200) (88% vs 36%)-despite the fact that the latter group had a median age that was 10 years younger (Figure 1). Moreover, the rate of complete and near-complete response was more than twice as high with the former (70% vs 29%).

Values were also higher than those achieved historically with another regimen (Haematologica 91:1498-1505, 2006), bortezomib and dexamethasone induction with full-dose transplantation (VD-MEL200).

In preliminary subgroup analyses among patients treated with PAD-MEL100-LP, there was a trend toward better progression-free survival in patients younger than 70 years relative to older patients.

“This we have to look at carefully because 70 years to some extent could be the age limit for these procedures,” Dr. Palumbo noted. In contrast, this outcome did not differ by baseline b2-microglobulin level or del(13q) or t(4;14) status.

A comparison of grade 3/4 adverse events between the PAD and historical DAV induction alone showed PAD led to higher rates of thrombocytopenia, infection, peripheral neuropathy, deep vein thrombosis, and death, Dr. Palumbo noted. “In the first 2 cycles, a gentle approach may be better because the majority of toxicity, the majority of early deaths is usually confined to the first 2 cycles of treatment, where we achieve with this drug the majority of cytoreduction.” In contrast, the rate of grade 3/4 adverse events was similar for PAD-MEL100 and DAV-MEL200 transplantation (Figure 2).

Taken together, the findings suggest that addition of pegylated doxorubicin increases the efficacy of prednisone and bortezomib induction, that PAD-MEL100 transplantation is feasible in older adults, and that LP consolidation improves response rate, Dr. Palumbo asserted.

“The final conclusion is that the sequential approach using bortezomib as induction, the transplant after induction, and consolidation and maintenance with lenalidomide may to some extent become a sort of new strategy to treat myeloma patients and to treat myeloma patients who may be unfit for the full-dose transplant but maybe can benefit from reduced-intensity autologous transplant,” he said.