Three years (yrs) maintenance with bortezomib, lenalidomide, and dexamethasone (RVD) in multiple myeloma (MM): Results of Total Therapy (TT) IIIB.
Authors: Al Hadidi Samer , Ababneh Obada Ehab , Schinke Carolina D. , Thanendrarajan Sharmilan , Bailey Clyde , Zangari Maurizio , Tricot Guido , Shaughnessy John D. , Zhan Fenghuang , Sawyer Jeffrey , Barlogie Bart , van Rhee Frits 
Published: June 2023

e20053

Background: Maintenance therapy with lenalidomide in MM is associated with improved overall survival (OS). Addition of proteasome inhibitory (PI) is usually suggested for patients (pts) with high-risk disease to overcome worse outcomes. We report long-term follow up data of TT IIIB in which initial results were reported after a median follow up of 2 years (yrs) ( Nair et.al. Blood 2010). Methods: TT IIIB (NCT00572169) used, for newly diagnosed MM, 2 cycles of VTD-PACE (bortezomib, thalidomide, and dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, and etoposide) as induction before and consolidation therapy after melphalan-based tandem autologous transplantation (ASCT), which was followed by 3 yrs of RVD with monthly cycles of bortezomib 1.0 mg/m2 (D 1 4 8 11) in yr 1 followed by weekly administration in yrs 2 and 3; lenalidomide was administered at 15 mg on D 1-20 followed by 5 mg on D 21-28 for all 3 yrs; dexamethasone was given at 20 mg on D 1-4 and D8-11 in year 1 and was given weekly with bortezomib in yrs 2 and 3. Data cut-off was October 10th, 2022. Results: 177 pts enrolled between Nov 2006 and Sep 2008. Median age was 57 yrs with 26% of pts > 65yrs. 39% females and 8% black pts. Gene expression profile (GEP) defined high-risk disease in 22% of pts. After median follow up of 14.2 yrs, median progression free survival (PFS) was 6.37 yrs (95%CI:5.36-10 yrs), 10-yr PFS was 42.4% (95%CI: 35.5%-50.5%) and 15-yr PFS was 34.6% (95%CI: 27.8%-43.2%). Median PFS was better in GEP low risk at 8.69 yrs (95%CI: 6.28-NR) and in ISS stage I at 11.04 yrs (95%CI: 6.37-NR). Median OS was 10.01 yrs (95%CI: 7.75-12.41 yrs) with 15-yr OS of 36.7% (95%CI: 29.6 %-45.6 %). Median OS was 11.14 yrs (95%CI:9.19-NR) and 2.79 yrs (95%CI:2.25-6.62 yrs) in GEP low-risk and high-risk, respectively.10-yr OS for GEP high risk was 21.6% (95% CI: 11.7- 39.9 %). Multivariable analysis showed worse OS outcomes with GEP high risk disease (hazard ratio (HR): 3.12 (95% CI: 2.01-4.82, p < 0.001). When compared with TT IIIA that used 1 yr of bortezomib maintenance, no difference in OS was noted. Achieving minimal residual disease (MRD) negativity at any time during treatment and follow up even for pts who subsequently relapsed was associated with improved OS (HR 0.21 (95% CI 0.12-0.38, P < 0.001). Average MRD assessment per pt was 9.36 times (range: 1-29). Secondary hematological malignancies occurred in 11 pts (6%). Conclusions: T IIIB resulted in further improvement of outcomes with more than one third of patients with OS > 15 yrs. Use of 3 yrs of RVD as maintenance therapy in TT IIIB did not result in improvement of outcomes of high-risk MM patients (defined by GEP) when compared to 1 yr use of maintenance bortezomib and 3 yrs use of maintenance immunomodulatory drug (TT IIIA). High-risk MM remains unmet need despite the use of extended triplet-based maintenance therapy. Clinical trial information: NCT00572169 .