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Elderly patients with newly diagnosed multiple myeloma: comparison of sequential vs alternating administration of Bortezomib, Melphalan and Prednisone ( VMP ) and Lenalidomide Plus Dexamethasone ( Rd )


VMP and Rd are two of the most efficient and widely accepted regimens in the treatment of elderly newly diagnosed multiple myeloma patients. In order to further improve the outcome of elderly patients, one possibility would be to use regimens including all these drugs simultaneously, but this may result into high toxicity. Alternatively, the use of these regimens ( VMP and Rd ) in a sequential or alternating scheme could improve the treatment of elderly patients.

Researchers have hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis they decided to compare VMP and Rd in a sequential vs an alternating scheme.

241 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach ( one cycle of VMP alternating with one Rd [ half of the patients started by VMP and half by Rd ] up to 18 cycles ).

VMP included the iv administration of Bortezomib ( Velcade ) 1.3 mg/m2 twice weekly for 1 six-weeks cycle, followed by once weekly for 8 four-weeks cycles in combination with oral Melphalan ( Alkeran ) 9 mg/m2 and Prednisone 60 mg/m2 once daily on days 1–4 of each cycle.
Rd treatment consisted on Lenalidomide ( Revlimid ) 25 mg daily on days 1-21 plus Dexamethasone 40 mg weekly.

121 patients were allocated to receive the sequential scheme and 120 the alternating regimen. Both arms were well balanced according to the baseline characteristics. 52% patients in the sequential arm and 55% in the alternating and had high risk cytogenetic abnormalities [ t(4;14), t(14;16), del17p or 1q gains ].

After 9 cycles of treatment, in the sequential arm, 35 out of 66 ( 54% ) achieved at least VGPR vs 51 out of 65 patients ( 78% ) in the alternating arm ( p=0.002 ), including stringent complete responses / complete response ( sCR/CR ) rate of 28% vs 38% in the sequential and alternating arms, respectively ( p=NS ).
Seven patients in each arm achieved immunophenotypic complete response. Moreover, while four patients progressed in the sequential arm under treatment with VMP, no patients in the alternating scheme developed disease progression during the first 9 cycles.

After a median follow up of 12 months, there was a trend for shorter time to progression ( TTP ) in the sequential as compared with the alternating scheme ( 18 m-TTP of 83% vs 89% [ p=NS ] ).

In terms of overall survival, 83% of patients in the sequential arm were alive at 18 m versus 93% in the alternating ( p=NS ). Patients who achieved sCR/CR had a significantly longer 18 m-TTP as compared with patients who didn’t achieve it in both sequential ( 100% vs 71%; p=0.006 ) and alternating arms ( 100% vs 79%; p=0.006 ) and this translated into a significant benefit in overall survival.

No differences were observed in overall response rates and CR rates in standard and high risk patients. The 18 m-TTP was similar in standard and high risk groups in both sequential ( 86% vs 81% ) and alternating arms ( 84% vs 94% ), noting that 94% of patients receiving the alternating scheme were progression-free at 18 months.

Regarding hematologic toxicity, the frequency of G3-4 neutropenia was slightly lower in the sequential than in the alternating arm ( 16% and 23% ) and the same trend was observed for G3-4 thrombocytopenia ( 16% vs 20% ).
Concerning non-hematologic toxicity, 5% and 4% of the patients in the sequential and alternating arms developed G3-4 infections, respectively; the rate of G3-4 skin rash was 4% in the sequential and 3% in the alternating arm; 4% of patients in the sequential arm developed G3-4 peripheral neuropathy and 3% in the sequential arm.
The rate of grade 3-4 thrombotic events was 2% in both arms.

In conclusion, the administration of Melphalan, Bortezomib, Lenalidomide and steroids in elderly multiple myeloma patients in a sequential or alternating scheme is feasible. Although longer follow-up is necessary, the alternating scheme may be superior in terms of response rate and outcome, as result of the early exposure of the plasma cell to different agents.
Toxicity profile is acceptable. Aparently both schemes of therapy seems to overcome the poor prognosis of high risk cytogenetic. ( Xagena )

Source: American Society of Heamtology ( ASH ) Meeting, 2013

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