Noa Biran, MD
High dose chemotherapy with autologous stem cell transplant (ASCT) following induction therapy has been the mainstay of treatment of multiple myeloma since the mid-90s given the improvement in progression-free survival (PFS) and potentially overall survival (OS). However, with the development of novel therapies, the role and optimal timing of ASCT have come into question. The role of consolidation therapy posttransplant as well as maintenance therapy have also been investigated. Given the long-established correlation between depth of response and prolonged survival, there has been an increasing interest in striving for minimal residual disease (MRD) as a surrogate end point for risk-adapted treatment, particularly in the consolidation and maintenance setting. Here, we review the current progress in the treatment of transplant-eligible multiple myeloma (MM) as it pertains to the role of ASCT, consolidation, and maintenance therapy.
The Role of High Dose Chemotherapy With Autologous Stem Cell Rescue in Multiple Myeloma in the Era of Conventional Cytotoxic Chemotherapy
Before the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), high dose melphalan with ASCT following induction therapy was considered the standard approach for transplant-eligible patients with newly diagnosed MM. The first randomized controlled trial from the Intergroupe Francais du Myelome (IFM90), published in 1996, randomized newly diagnosed MM patients to an older chemotherapy regimen (vincristine/carmustine, cyclophosphamide, prednisone alternating with carmustine, vincristine, adriamycin, prednisone; VMCP/BVAP) for 12 cycles versus 4 to 6 cycles of VMCP/BVAP followed by high dose therapy with autologous bone marrow transplant.1
Those patients randomized to the transplant arm compared with the high dose chemotherapy arm had a superior 5-year event-free survival (EFS) (28% versus 10%, respectively, P
= .01) and OS (52% versus 12%, respectively P
= .03). Seven years later, the United Kingdom’s Medical Research Council (MRC VII) published their trial randomizing newly diagnosed MM patients to adriamycin, carmustine, cyclophosphamide, and melphalan for 4 to 12 cycles or to adriamycin, vincristine, cyclophosphamide, and methylprednisolone for a minimum of 3 cycles followed by high-dose melphalan with autologous ASCT.2
The patients randomized to ASCT versus non-ASCT demonstrated an improvement in PFS (32 vs 20 months, respectively, (P
<.001), and a trend toward improved OS (55 vs 42 months, respectively, P
= .04). Both of these trials restricted eligibility to patients under the age of 65 years and utilized interferon maintenance posttransplant.
Subsequent randomized trials comparing single ASCT versus conventional chemotherapy demonstrated a benefit in PFS in the ASCT versus delayed or non-ASCT arm, although no benefit in OS was demonstrated.3-5
These studies, however, with the exception of the 2005 Fermand trial, did not truly compare transplant versus no transplant. Patients who progressed were eligible for salvage transplant. Thus, they compared early versus delayed transplant. A systematic review and meta-analysis of 9 randomized controlled trials published between 1990-2000 evaluating upfront single ASCT versus standard-dose therapy (with conventional cytotoxic chemotherapy) concluded that upfront ASCT provided a PFS but not an OS benefit,6
although this analysis may be compromised due to the mixture of studies comparing early versus late transplant and transplant versus no transplant.The preponderence of evidence suggests a survival benefit of ASCT. A preplanned or unplanned introduction of delayed ASCT does not call into question the role of ASCT.
Novel Therapies Have Changed Survival Outcomes in Multiple Myeloma and the Role of ASCT
Therapy for MM has markedly changed in the past decade with the introduction of PIs (bortezomib was approved in 2003) and IMiDs (lenalidomide and thalidomide were FDA approved in 2006). As such, survival has improved significantly for patients with MM over the past decade, with 5-year OS improving from 31% to 56% in patients diagnosed between 2001-2005 and 2006-2010, respectively.7
Thus, with the achievement of high response rates with PIs and IMiDs, including an overall response rate of 100% with the combination of bortezomib, lenalidomide, and dexamethasone in newly diagnosed MM,8
the role of ASCT as part of frontline therapy has become a matter of debate.