Study Supports Use of AHCT Over VMP as Intensification in Newly Diagnosed Myeloma

In patients with newly diagnosed myeloma, following induction chemotherapy, early autologous hematopoietic cell transplantation (AHCT) as intensification therapy prolonged progression-free survival (PFS), compared with the three-drug regimen of bortezomib, melphalan, and prednisone (VMP), according to findings published in The Lancet Haematology. Double AHCT was better than single AHCT, and subsequent consolidation therapy with bortezomib, lenalidomide, and dexamethasone (VRD) also led to longer PFS, compared with no consolidation.

“[This study] was designed to prospectively add-ress two widely debated issues in the field of multiple myeloma: the role of upfront AHCT as intensification therapy in the era of highly active novel agents, and the role of consolidation therapy following the intensification phase,” explained lead study author Michele Cavo, MD, of the Bologna University School of Medicine in Italy, and colleagues. Dr. Cavo told ASH Clinical News that these findings may be relevant to clinical care, as post-AHCT consolidation therapy is not widely used in daily clinical practice and is not uniformly recommended in E.U. national and international guidelines. In the U.S., VMP is rarely used, bortezomib, cyclophosphamide, and dexamethasone (VCD) is uncommonly used as induction, and lenalidomide or bortezomib maintenance are commonly administered after AHCT.

The phase III study included 1,503 patients with untreated myeloma from 172 academic and community practice centers in Europe. Patients were between 18 and 65 years of age and presented with symptomatic myeloma at stages 1 to 3. All participants had measurable disease and a World Health Organization performance status grade of 0 to 2.

“Upfront AHCT continues to have an important role … even in the era of active novel agents.”

—Michele Cavo, MD

A total of 1,197 participants received either 3 (n=635) or 4 (n=562) cycles of VCD induction therapy. Following induction, these patients were randomized to:

  • VMP intensification (n=495)
  • AHCT after high-dose melphalan 200 mg/m2 (n=702)

In the VMP group, patients received four 42-day cycles of intravenous or subcutaneous bortezomib 1.3 mg/m2 (days 1, 4, 8, 11, 22, 25, 29, and 32) plus oral melphalan 9 mg/m2 (days 1-4) and oral prednisone 60 mg/m2 (days 1-4). In centers with a double AHCT policy, the first randomization (1:1:1) was to VMP or single or double AHCT, the researchers noted.

Patients then underwent a second randomization to receive either:

  • two 28-day cycles of VRD consolidation (n=449)
  • no consolidation (n=428)

The VRD group received intravenous or subcutaneous bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), oral lenalidomide 25 mg (days 1-21), and oral dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12). All patients in both groups received maintenance therapy consisting of oral lenalidomide 10 mg on days 1 through 21 of a 28-day cycle.

Patient characteristics were similar between the study arms. The median ages were 58 years in the AHCT, VMP, and no-consolidation groups and 57 years in the VRD consolidation group. The median time from the initiation of induction therapy to first randomization was 3.7 months. At time of data cutoff, the median follow-up durations for the AHCT group and VMP group were 60.5 months and 59.4 months, respectively.

The study’s primary endpoint was PFS, defined as the time from randomization to either progression or death from any cause. Secondary outcomes included the proportion of patients who achieved a partial response or higher, overall survival (OS), toxicity, and quality of life.

In the first randomization, after a median follow-up of 60.3 months, the investigators reported that AHCT was associated with significantly longer median PFS, compared with VMP intensification: 56.7 months vs. 41.9 months (hazard ratio [HR] = 0.73; 95% CI 0.62-0.85; p=0.0001).

At the time of the first randomization, 485 of 1,197 patients (41%) had achieved a very good partial response (VGPR) or higher, at similar proportions in the AHCT and VMP groups (41% and 40%, respectively). However, following intensification therapy, the proportion of patients achieving at least a VGPR was higher in the AHCT group: 64% versus 56% (p=0.020). In addition, more AHCT recipients achieved at least a VGPR as their best response (84% vs. 77%; p=0.002).

Some participating centers had a double AHCT policy. The authors found that treatment with double AHCT improved survival outcomes compared with single AHCT. The 5-year PFS and OS rates were 53.5% and 80.3% with double AHCT, compared with 44.9% and 72.6% for single AHCT.

For the second randomization, consolidation with VRD was associated with a significantly improved median PFS versus no consolidation: 58.9 months versus 45.5 months (p=0.014). However, there was no significant difference regarding 5-year OS rates (77.2% vs. 72.2%; HR=0.99 [95% CI 0.71-1.39]; p=0.96).

The investigators noted that grade ≥3 adverse events (AEs) were more common in patients randomized to AHCT compared with VMP, which included:

  • neutropenia (79% vs. 29%)
  • thrombocytopenia (83% vs. 16%)
  • gastrointestinal disorders (12% vs. 5%)
  • mucositis (16% vs. 0%)
  • infections (30% vs. 4%)

At least 1 serious AE was reported in 34% of patients randomized to AHCT and 27% of patients randomized to VMP. The most common serious AEs were infection and infestation in the AHCT (56%) and VMP (37%) groups.

Approximately 12% of the deaths from the time of first randomization were considered likely related to treatment. Of these deaths, 68% (n=26) occurred with AHCT and 32% (n=12) occurred with VMP. The most frequent causes of death included infections (21%), cardiac events (16%), and second primary malignancies (53%).

“AHCT seems to be more effective than VMP intensification, and consolidation therapy following the intensification phase seems to be more effective than observation in terms of PFS,” the authors concluded, noting that study follow-up was short. “[These findings] further support and extend the existing body of evidence suggesting that upfront AHCT continues to have an important role in the management of patients with newly diagnosed multiple myeloma who are fit for high-dose chemotherapy, even in the era of active novel agents.”

The lack of information on patients’ quality of life represents a limitation of the study, and, according to the investigators, these analyses are ongoing and will be reported at a later date. Another limitation, explained Dr. Cavo, was the use of VCD as induction, which is now known to be a less optimal induction strategy than VRD or VTD (bortezomib, thalidomide, and dexamethasone).

Dr. Cavo also noted that these findings will need to be considered against recent data about four-drug regimens in this setting. “The benefits seen with upfront AHCT and subsequent consolidation therapy may be less clear in light of recent data showing unprecedented rates and depth of response with quadruplet therapies incorporating a monoclonal antibody,” he concluded. “[This] remains an open question that should be prospectively addressed in future trials.”

Study authors report relationships with Janssen and Celgene, which funded the study.

Reference

Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020;7:e456-e468.