Comparison of Sequential Vs Alternating Administration of Bortezomib, Melphalan, Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) in Elderly Pts with Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial
Authors: Mateos Maria-Victoria , Martinez-Lopez Joaquin , Hernandez Miguel-T , Martinez Rafael , Rosiñol Laura , Ocio Enrique M. , Echeveste Maria Asuncion , Pérez de Oteyza Jaime , Oriol Albert , Bargay Joan , Gironella Mercedes , Martín Jesús , Cabrera Carmen , De La Rubia Javier , Gutiérrez Norma C , Martin Maria-Luisa , Paiva Bruno , Montalbán Maria Angeles , Bladé Joan , Lahuerta Juan José , San Miguel Jesus F. 
Published: October 2019

Abstract
Background: VMP and Rd are two of the most effective regimens in the treatment of elderly newly diagnosed MM pts. In order to further improve its outcome, one possibility would be to use regimens including all these drugs simultaneously, but this may result toxic. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of these pts. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and Rd in a sequential vs an alternating scheme.
Pts and methods: 242 pts 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, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly.
Results: 233 pts were evaluable for safety and efficacy (118 in the sequential and 115 in the alternating arm). Both arms were well balanced according to the baseline characteristics. Of note, 55% of pts in the sequential and 44% in the alternating arm were older than 75 yrs. Fifty-one percent in the sequential arm and 52% in the alternating had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles, the sCR/CR rate was lower in the sequential (20%) than in the alternating arm (32%)(p=0.02). However, among the 179 pts that were evaluable for efficacy after the 18 planned cycles of treatment, the pattern reversed: 51% achieved sCR/CR in the sequential vs 38% in the alternating arm (p=0,05). The flow-CR rate among patients in sCR/CR was 66% and 48% in the sequential vs alternating arms, respectively (P=0.16). To achieve flow-CR was associated with a significantly longer TTP (median not reached vs 15 months since the end of treatment; P=.01).
After a median f/u of 27 months, median PFS was of 30 months in both sequential and alternating arms (p=NS). Median OS has not been reached, and 68% and 67% of pts are alive at 3 yrs (p=NS).
Pts who achieved sCR/CR had significantly longer PFS and OS as compared with pts who did not (3-yrs PFS for sCR/CR of 76% vs 18% for <CR (p<0.0001), and 3-yrs OS of 94% vs 53% for sCR/CR vs <CR (p<0.0001)) in both arms. The achievement of flow-CR has been also associated with 3-yrs PFS of 84% vs 38% months for pts who did not achieve flow-CR. This benefit has been observed in both arms.
Pts younger than 75 yrs showed a significantly longer survival as compared to pts ≥75y (3-yrs PFS of 55% vs 27m, p=0.04) and 3-yrs OS of 89% vs 35m, p<0.0001 ) , with no significant differences between sequential and alternating arms.
No differences were observed in overall response rates and sCR/CR rates in standard and high risk pts, but there was a trend toward shorter PFS and OS in the subgroup of high-risk CA (median PFS of 28 months and 3-yrs OS of 64%, pNS) vs standard-risk (3-yrs PFS of 54% and 3-yrs OS of 80%, pNS).
Regarding hematologic toxicity, no significant differences were observed between the sequential and alternating arms in the frequency of G3-4 neutropenia (19% and 22%) or thrombocytopenia (21% and 20%). Concerning non-hematologic toxicity, 3% and 6% of the pts in the sequential and alternating arms had G3-4 infections. No differences were observed neither in the the incidence of peripheral neuropathy in the sequential and alternating arms (4% and 3%, respectively) nor in the rate of grade 3-4 thrombotic events (1% and 2%). The rate of early discontinuations (15%) and deaths (4%) before the cycle 9 were identical in both arms; of note 71% of early discontinuations occurred in pts aged over 75 yrs and all early deaths but one were also in pts older than 75 yrs.
Conclusions: The alternating regimen has demonstrated to be not superior to the sequential approach. Toxicity profile is acceptable. This Total Therapy approach, including the four active anti-myeloma agents (melphalan, bortezomib, lenalidomide and steroids) is particularly active in pts between 65-75 years old, with similar survival to that of transplant candidate pts with outstanding outcome when sCR/CR is achieved.

Disclosures
Mateos: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide as first-line combination therapy for AL amyloidosis.. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Ocio:Celgene Corporation: Honoraria, Research Funding. Pérez de Oteyza:Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Oriol:Celgene Corporation: Consultancy. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.