Highly active novel agents for multiple myeloma aren’t going to bump autologous haematopoietic stem-cell transplantation (aHSCT) from its position as gold standard intensification treatment – yet.

An open-label, phase 3 clinical trial of 1,197 adults with newly diagnosed multiple myeloma and fit for high dose, myeloablative chemotherapy randomised patients to single or double aHSCT or four, 42-day cycles of bortezomib-melphalan-prednisone (VMP) after induction therapy.

The European study then further randomised patients to either two 28-day cycles of bortezomib-lenalidomide-dexamethasone (VRD) consolidation or no consolidation therapy. All patients moved on to lenalidomide maintenance therapy until disease progression.

The study, published in The Lancet Haematology, found that median PFS was significantly longer with aHSCT than VMP (56.7 v 41.9 mths; p=0.0001) across all prognostic subgroups of patients.

However the 5-year overall survival (OS) from the first randomisation was similar in both groups (75·1% v 71·6%; p=0·35).

The study found median PFS was also significantly longer with consolidation therapy than without (58.9 v 45.5 mths; p=0.014) but OS was again similar (77.2% v 72.2%; p=0.96).

In a secondary end-point, the study also found that double aHSCT compared to single aHSCT significantly improved 5-year PFS (53.5% v 44.9%; p=0.036) and 5-yr OS (80.3% v 72.6%; p=0.022).

“Comparisons between del(17p)- positive patients and those with standard-risk cytogenetics showed that double HSCT was likely to overcome the adverse effect of del(17p) on progression-free survival (0·70, 0·28–1·74; p=0·44; appendix p 13) and overall survival (1·48, 0·43–5·04; p=0·53; appendix p 14),” the study said.

The median progression-free survival from start of lenalidomide maintenance was 50·4 months in the overall patient population, 58·0 months in the autologous HSCT group and 43·2 months in the VMP group (HR 0·76, 0·64–0·91; p=0·0030).

Autologous HSCT was associated with more grade 3 adverse events (56% v 48%) and grade 4 or 5 adverse events (81% v 10%) than VMP.

These included grade 3 or worse neutropenia (79% v 29%), thrombocytopenia (83% v 16%), gastrointestinal disorders (12% v 5%), mucositis (16% v 0%), and infections (30% v 4%).

Rates of second primary malignancies were similar in both treatment groups (1.4 v 1.5 per 100 person-years).

The authors, including Australian Professor Andrew Spencer, said their findings supported the use of upfront autologous HSCT as intensification therapy – even in the era of novel agents – plus consolidation therapy.

They suggested a relatively short follow-up or effective therapies given at the time of relapse might explain the lack of benefit in overall survival.

A Comment article in the journal said the study had some limitations such as the fact that some patients were not exposed to an immunomodulatory agent until maintenance therapy.

“This differs substantially to current practice and might have contributed to the favourable results of HSCT in this study.”

And there were many more questions to be answered regarding the role of aHSCT as more potent, daratumumab-based, four-drug combination therapies became established, the US authors said.

“In conclusion, this important study highlights the continued benefit of HSCT, particularly in patients with high-risk disease. Future studies using monoclonal antibody-based induction therapy, with or without HSCT, will be necessary to determine the absolute benefit of HSCT in the current era.”