María-Victoria Mateos1*, Norma C. Gutierrez2*, Bruno Paiva3*, Albert Oriol4*, Joaquín Martínez-López5*, Ana Isabel Teruel6*, Raquel de Paz7*, Jose Garcia-Laraña8*, Enrique Bengoechea9*, Alejandro Martín10*, Joaquín Díaz-Mediavilla11*, Luis Palomera12*, Yolanda Gonzalez13*, Jose Mariano Hernández14*, Ana Sureda15*, Jose Luis Bello16*, Joan Bargay17*, Francisco-Javier Penalver18*, Josep-Maria Ribera, MD, PhD19, María-Luisa Martín-Mateos20*, Ramón García-Sanz2*, María Teresa Cibeira, MD, PhD21*, María-Luisa Martín-Ramos5*, María-Belén Vidriales2*, María-Angeles Montalbán5*, Juan-Jose Lahuerta5*, Joan Blade22 and Jesús F. San Miguel Sr., MD, PhD23
1University Hospital of Salamanca, Salamanca, Spain
2Hospital Universitario de Salamanca, Salamanca, Spain
3Service of Hematology, Hospital Universitario de Salamanca, Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain
4Hematology, Hospital Germans Trials i Pujol, Badalona, Spain
5Hematology, Hospital 12 de Octubre, Madrid, Spain
6Hospital Clínico, Valencia
7Hospital La Paz, Madrid, Spain
8Hospital Ramón y Cajal, Madrid, Spain
9Hospital de Donostia, San Sebastian, Spain
10Hospital Virgen de la Concha, Zamora, Spain
11Hospital Clinico San Carlos, Madrid, Spain
12Hospital Lozano Blesa, Zaragoza, Spain
13Institut d'Oncologia Dr. Josep Trueta, Girona, Spain
14Hospital General de Segovia, Segovia, Spain
15Hospital Santa Creu i Sant Pau, Barcelona, Spain
16Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
17On behalf of CETLAM Cooperative Group, Palma de Mallorca, Spain
18Fundación Hospital de Alcorcón, Madrid, Spain
19Clinical Hematology, ICO-Hospital Germans Trias i Pujol and PETHEMA Group, Badalona, Spain
20Hospital San Pedro de Alcántara, Cáceres, Spain
21Hematology Department, Hospital Clinic of Barcelona, Barcelona, Spain
22Hematology, Hospital Clinic, Barcelona, Spain
23Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. DNA ploidy is another important prognostic factor with non-hyperdiploid cases being associated with a poor outcome. There are some controversies about whether or not bortezomib-based combinations are able to overcome the poor prognosis of CA. In the VISTA trial, bortezomib plus melphalan and prednisone (VMP) appeared to overcome the poor prognosis of CA in terms of response rate (RR) and survival; however, the number of patients with CA was rather small. Here we report a subanalysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM05MAS65 trial, in order to evaluate the influence of CA by FISH as well as DNA ploidy status on RR and survival.
Patients and methods: Patients included in this study were randomized to receive 6 cycles of VMP vs bortezomib, thalidomide and prednisone (VTP) as induction therapy consisting on one 6-week cycle of bortezomib using a bi-weekly schedule (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32) plus either melphalan 9 mg/ m2 on days 1 to 4 or oral daily thalidomide 100 mg, and prednisone 60 mg/ m2 on days 1 to 4; this first cycle was followed by five 5-week cycles of once-weekly bortezomib (1·3 mg/ m2 on days 1, 8, 15 and 22) plus the same doses of MP and TP. After induction therapy, patients were subsequently randomised to maintenance therapy with VP or VT, consisting of one convencional 3-week cycle of bortezomib (1·3 mg/ m2 on days 1, 4, 8 and 11) every 3 months, plus either prednisone 50 mg every other day or thalidomide 50 mg/day, for up to 3 years. FISH analysis for del(13q), t(11;14), t(4;14), t(14;16) and del(17p) was performed at diagnosis according to standard procedures using purified plasma cells, and DNA ploidy status was analysed following induction therapy by multiparametric FCM using propidium Iodide and specific markers for discrimination between myelomatous and normal cells.
Results: In 231 out of the 260 patients included in the trial, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 44 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=187 patients without CA, and/or del(13q) and/or t(11;14)). There weren’t differences in the rates of CA according to the treatment arm. RR was the same in the high-risk vs standard-risk groups, both after induction (21% vs 27% CR) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter PFS as compared to standard risk both from first (24 versus 33 months, p=0·04, HR 0·6, 95% IC 0·4-0·9) and second randomization (17 versus 27 months, p=0·01, HR 0·5, 95% IC 0·2-0·8). This also translated into shorter OS for high risk patients (3-year OS rate: 55% versus 77% from first randomization, p=0·001, HR 0·4, 95% IC 0·2-0·7) and 60% versus 85% from second randomization, p<0·001, HR 0·2, 95% IC 0·1-0·5). This adverse prognosis applied to either t(4;14) or del(17p), without differences in terms of PFS from the first (24 months for del(17p) patients and 20 months for t(4;14)) and second randomization (16 months for both CA); in addition, the outcome was not modified by the treatment scheme used.
When we analyzed the influence on survival of the DNA ploidy status (224 patients) by comparing patients with hyperdiploid (132 patients) versus non-hyperdiploid DNA content (92 patients) assessed by FCM, it was found that the former group showed longer OS (77% versus 63% at 3 years, p=0·04), and this difference was more evident in patients treated with VTP (77% versus 53% at 3 years, p=0·02), while no significant differences were observed in the VMP arm.
Conclusions: The present schema, particularly after month sixth (using maintenance with bortezomib every 3 months) doesn’t overcome the negative prognosis of high-risk cytogenetics in terms of PFS and OS in elderly myeloma patients, and this applied to either patients with t(4;14) or del(17p), and it was independent of the induction treatment arm. Our data also show that non-hyperdiploid cases displayed worse outcome than hyperdiploid patients, particularly under VTP induction treatment. These results suggest that continuous efforts are still required in order to overcome the dismal prognosis of high-risk patients.