Bortezomib, Lenalidomide, and Dexamethasone Maintenance Therapy Does Not Show Improved Outcomes for Patients With High-Risk Multiple Myeloma

15.4-Year Follow-Up of the Total Therapy 3B Study

According to a 15.4-year median follow-up of the Total Therapy (TT) 3B study, 3 years of bortezomib, lenalidomide, and dexamethasone (VRD) maintenance therapy did not improve outcomes for patients with high-risk multiple myeloma (MM) defined by gene expression profiling (GEP). This study includes the longest follow-up of patients treated with maintenance VRD reported to date, according to study authors. 

This phase 2 study incorporated bortezomib into tandem melphalan–based hematopoietic stem cell transplantation (HSCT) with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and VRD for maintenance in patients with newly diagnosed MM. 

 Patients with newly diagnosed MM received 2 cycles of bortezomib, thalidomide, and dexamethasone (VTD)-PACE (VTD and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, and etoposide) as induction prior, and as consolidation therapy after, melphalan–based tandem hematopoietic stem cell transplant. This was followed by 3 years of VRD with monthly cycles of bortezomib 1 mg/m² (days 1, 4, 8, and 11) in year 1 followed by weekly administration in years 2 and 3. For the 3 years, lenalidomide was administered on days 1 to 20 (15 mg), then on days 21 to 28 (5 mg) of each 28-day cycle. It was noted that dexamethasone (20 mg) was administered on days 1 to 4 and 8 to 11 of a 28-day cycle of year 1, and then weekly with bortezomib for years 2 and 3.

Investigators enrolled 177 patients, with a median age of 58 years, with 26% of patients >65 years. Of this patient population, 21% of patients had GEP–defined high-risk MM. The 15-year progression free survival (PFS) was 27.9%. Additionally, the median PFS was better in GEP–defined low-risk patients at 7.8 years and in International Staging System (ISS) stage 1 patients at 8.7 years.

It was noted by study authors that 3-years of bortezomib during maintenance (TT 3B) did not result in improvement of overall survival (OS) compared to 1-year of bortezomib during maintenance (TT 3A) (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.9 to 1.5; P = .166). Furthermore, TT 3B included a higher incidence of certain adverse factors such as albumin levels below 3.5 g/dL (45% vs 26%; P < .001) and B2M levels ≥3.5 mg/L (57% vs 45%, P = .012).

Overall, results demonstrated that the median OS was 9.1 years, and 15-year OS was 35.9%. The GEP–defined low-risk patients' median OS was 11.2 years, and the GEP–defined high-risk patients was measured at 2.8 years. There was no recorded difference in OS between TT 3B and TT 3A. Among patients with GEP-defined low-risk, nearly ½  and ⅓ of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. It was noted that ⅓ of patients survived more than 15 years, but that the 3 years of bortezomib, lenalidomide, and dexamethasone maintenance did not improve outcomes for these patients with GEP-defined high-risk MM.

Samer Al Hadidi, MD, Myeloma Institute, The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, and colleagues concluded, “[3] years of VRD maintenance did not improve outcomes for patients with high-risk MM defined by gene expression profiling.”

“Our study provides valuable long-term follow-up data which is limited in MM clinical trials and highlights the importance of analyzing long-term outcomes in MM clinical trials to fully appreciate the impact of therapy,” they added.

Source:

Hadidi S, Ababneh O, Schinke C, et al. Three years of maintenance with VRD in multiple myeloma: Results of total therapy IIIB with a 15-year follow-up. Blood Adv (2024) 8 (3): 703–707. doi: 10.1182/bloodadvances.2023011601