Chapter 3 – Treatment of transplant-eligible patients

Contributors: Mohamad Mohty, Florent Malard, Jean-Luc Harousseau

2 – Autologous transplantation

The concept of HDT plus auto-SCT was developed in the 1980s. The objective of auto-SCT was to support HDT in order to reduce the duration and toxicity of severe myelosuppression. The IFM group was the first to conduct a randomized trial showing the superiority of HDT/auto-SCT over conventional chemotherapy in patients younger than 65 years regarding response rate, event-free survival (EFS) and overall survival (OS) [17]. These findings were confirmed 7 years later in a larger study conducted by the UK Medical Research Council (MRC Myeloma VII Trial) [18]. Following these results, HDT/auto-SCT became the standard of care in patients without severe comorbidities and aged less than 65 years of age.

Overall, seven randomized studies have compared HDT/auto-SCT to conventional chemotherapy [1]. While EFS was superior with HDT/auto- SCT in five out of seven trials, OS was prolonged significantly in only three trials. These results were confirmed by a meta-analysis that showed a significant benefit for HDT/auto-SCT in terms of EFS, but no benefit in terms of OS [19]. This was partly explained by the impact of auto-SCT at relapse in patients initially treated with conventional chemotherapy. Therefore, although the majority of myeloma experts recommend HDT/auto-SCT as part of initial therapy (early auto-SCT), some experts consider that delaying auto-SCT until relapse (late auto-SCT) is a valuable approach. All of these studies have been performed before the development of the new agents. The place of early auto-SCT in comparison with non-intensive therapies including new agents has been questioned. Palumbo et al reported a higher PFS and OS in patients who received a double auto-SCT compared with six 28-day cycles of lenalidomide, melphalan, and prednisone after a lenalidomide-based induction [20]. Similarly, Gay et al reported a higher PFS and OS in patients who received a double auto-SCT compared with six cycles of lenalidomide, cyclophosphamide, and dexamethasone [21]. Overall, these two studies showed a significant benefit for auto-SCT not only in terms of PFS but also in terms of OS, highlighting the continuing importance of auto-SCT in the new agents’ era. However, it is important to note that in these studies the non-intensive arm is considered suboptimal since it does not use bortezomib.

In the IFM 2009 randomized trial [16], the non-intensive arm was RVD which at that time was considered the best triple combination and is significantly superior to RD [22]. This study showed a significant superiority of the intensive arm in terms of response rate (including CR) and PFS, with a 14-month increase in median PFS (50 months vs. 36 months; adjusted hazard ratio [HR] for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to ISS stage and cytogenetic risk. However, OS at 4 years did not differ significantly between the transplantation group and the RVD-alone group, at more than 80% in both arms. This can be explained by good results of the RVD-alone arm and by improvements of salvage therapy at relapse, but also by the fact that two thirds of the patients in the non-intensive arm received an auto-SCT at relapse. Therefore some investigators still consider that late auto-SCT remains a valuable approach. This opinion is supported by the SWOG S0777 trial which evaluated the addition of bortezomib to lenalidomide/dexamethasone (RVD) induction in patients with previously untreated myeloma without a planned immediate transplantation after induction [22]. Despite the limitations of this trial, RVD induction with continuous RD maintenance significantly improved outcomes versus RD alone, supporting the use of VRD as a standard induction regimen.

The most important result of the IFM 2009 trial is probably the evaluation of MRD by multiparameter flow cytometry [16]. Patients achieving negative MRD have an 80% probability of 4 years’ PFS versus <30% for patients with positive MRD. This confirms the prognostic impact of negative MRD [23] which is becoming a new primary endpoint of myeloma therapy [24]. The prognostic impact of negative MRD was the same in both arms of the IFM 2009 trial but the intensive arm yielded significantly more negative MRD (80% versus 65%). These results indicate that more patients treated with upfront auto-SCT might achieve negative MRD as defined by sensitive methods (next generation flow or next-generation sequencing) and might enjoy prolonged remissions and possibly cures.

Regarding HDT regimens, the best efficacy/toxicity ratio remains intravenous (IV) high-dose melphalan (HDM) 200mg/m2 followed by infusion of peripheral hematopoietic stem cells. Stem cell collection is performed after cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) or G-CSF alone. In poor mobilizers, plerixafor can be used. Attempts for increasing efficacy by increasing doses or adding other agents have induced more toxicity. The dose of melphalan can be reduced (140mg/m2) in cases of renal insufficiency and HDM is usually not prescribed in patients with end-stage renal failure (creatinine clearance <30ml/min) [25].