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Dr. Francesca Gay - Maintenance therapy with lenalidomide significantly improved survival of young newly diagnosed MM patients

Francesca Gay,
Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy



Program: Oral and Poster Abstracts
Session: 731. Clinical Allogeneic and Autologous Transplantation - Results: Poster I

Saturday, December 7, 2013, 5:30 PM-7:30 PM, Hall G (Ernest N. Morial Convention Center)

Francesca Gay, MD1*, Federica Cavallo1*, Tommaso Caravita, MD2*, Maide Cavalli2*, Arnon Nagler, MD, MSc3, Vittorio Montefusco, MD2*, Enrico Maria Pogliani, MD2*, Silvia Buttignol, MD2*, Elena Zamagni, MD2*, Carmela Palladino1*, Magda Marcatti, MD2*, Pellegrino Musto, MD2*, Lucio Catalano2*, Anna Baraldi, MD2*, Angelo Michele Carella, MD2*, Anna Maria Cafro, MD2*, Agostina Siniscalchi, MD2*, Claudia Crippa, MD2*, Letizia Maria Vallone2*, Giovannino Ciccone4*, Dina Ben Yehuda5*, Francesco Di Raimondo, MD2*, Izhar Hardan, MD6*, Mario Boccadoro, MD1* and Antonio Palumbo, MD1

1Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
2Italian Multiple Myeloma Network, GIMEMA, Italy
3Director Division of Hematology Chaim Sheba Medical Center, Tel Hashomer, Israel
4Unit of Cancer Epidemiology, University of Torino and CPO Piemonte, A.O. Città della Salute e della Scienza di Torino, Torino, Italy
5Department Hadassah Medical Center, Jerusalem, Israel
6Meir Medical Center, Kfar-Saba, Israel

Background: High-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients  in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the  treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and  this analysis provides a longer follow-up.

Aims: To compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients.

Methods: A 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd).  As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population.

Results: From November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS)  and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group.  In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance. 

After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001).

A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics.

The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects.

During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200.

During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm.

Conclusion: The administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment.

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