Key points

Introduction

Induction therapy followed by consolidation with high-dose melphalan and autologous stem cell transplant (ASCT) has been considered the standard of care for transplant-eligible myeloma patients for several decades. The role of allogeneic stem cell transplant (AlloSCT) has been less clear, as both myeloablative and reduced-intensity approaches have been fraught with transplant-related mortality, graft versus host disease (GvHD), and disease relapse. In today’s era of novel agents, which include the immunomodulatory agents (thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), several unanswered questions remain regarding the role of transplant. These unresolved issues include the timing of initial transplant (upfront after induction therapy vs delayed until time of first relapse or later), the incorporation of novel agents into the high-dose regimen, the optimal maintenance regimen after transplant, the role of novel agents versus salvage (second) transplant after relapse from the first transplant, and the role of AlloSCT. In this article we provide an overview of transplantation for myeloma and discuss the areas that remain under active investigation.

Introduction

Induction therapy followed by consolidation with high-dose melphalan and autologous stem cell transplant (ASCT) has been considered the standard of care for transplant-eligible myeloma patients for several decades. The role of allogeneic stem cell transplant (AlloSCT) has been less clear, as both myeloablative and reduced-intensity approaches have been fraught with transplant-related mortality, graft versus host disease (GvHD), and disease relapse. In today’s era of novel agents, which include the immunomodulatory agents (thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), several unanswered questions remain regarding the role of transplant. These unresolved issues include the timing of initial transplant (upfront after induction therapy vs delayed until time of first relapse or later), the incorporation of novel agents into the high-dose regimen, the optimal maintenance regimen after transplant, the role of novel agents versus salvage (second) transplant after relapse from the first transplant, and the role of AlloSCT. In this article we provide an overview of transplantation for myeloma and discuss the areas that remain under active investigation.

Patient evaluation overview

As denoted in Table 1 , the standard pretransplant evaluation includes assessment of organ function, infectious disease status, psychosocial status, and myeloma restaging. Human leukocyte antigen (HLA) typing is performed for patients being considered for AlloSCT and possibly for younger patients being considered for autologous stem cell transplant who could potentially be offered AlloSCT in the future.

Indications for transplant

Traditionally, all patients younger than 65 years with adequate organ function and performance status and who have achieved disease control have been considered candidates for ASCT. Most transplant centers in the United States, however, will perform transplants on patients up to the age 75, and some centers have no age limit but instead rely on performance status and adequate organ function. Multiple studies have shown the feasibility and efficacy of performing ASCT in elderly patients. The role of AlloSCT in myeloma continues to be debated. Outside of a clinical trial, it is most often considered for younger patients with high-risk disease in either the upfront setting or after an early relapse after ASCT ( Box 1 , Fig. 1 ).

Timing of transplants and subsequent therapies in myeloma.

Autologous stem cell transplant

The most widely used high-dose regimen is single-agent melphalan at a dose of 200 mg/m ² (MEL200). As shown in the text box below, MEL200 has been compared with lower doses of melphalan, melphalan in combination with total body irradiation (TBI), melphalan in combination with other agents, and non–melphalan-containing regimens. In aggregate, the toxicity profiles and disease-related outcomes have favored MEL200. It should be noted that there is variation among the studies with respect to timing of melphalan and stem cell infusion and whether melphalan is given over 1 day or 2 days. In general, melphalan is dose reduced to 140 mg/m ² (MEL140) for patients with renal insufficiency (generally creatinine clearance <40) although there are limited data to support this practice. MEL140 is also considered for patients older than 70 years.

More recently, there has been interest in adding bortezomib to high-dose melphalan. While only small, nonrandomized studies have been conducted, these studies do demonstrate tolerability of this approach. The number of doses and timing of bortezomib administration with respect to melphalan administration and stem cell infusion has not yet been fully established ( Box 2 ).

Allogeneic stem cell transplantation

The initial studies that were performed using AlloSCT with myeloablative regimens were associated with unacceptably high early mortality rates ranging from 16% to 50%. Thus, the field has moved away from myeloablative regimens and is instead focusing on reduced-intensity conditioning or nonmyeloablative approaches. Several phase II studies with reduced-intensity conditioning allografts have been performed. The conditioning regimens have primarily consisted of fludarabine plus melphalan with or without antithymocyte globulin (ATG) or TBI. Rates of chronic graft-versus-host disease (GVHD) and transplant-related mortality have ranged from 27% to 58% and 15% to 40%, respectively. There are data to support graft versus myeloma effect, as there is improved progression-free survival (PFS) and overall survival (OS) for patients with chronic GVHD as opposed to those without, and donor lymphocyte infusions are associated with antimyeloma activity.

Timing for transplantation

The possible scenarios for sequencing and timing of transplants are shown in Fig. 1 . Historically, ASCT has been performed in the upfront setting after induction therapy. In today’s era of active novel agents, which can induce deep responses, it is unknown whether ASCT can be delayed until the time of first relapse. A summary of recent and ongoing trials addressing this question is shown in Box 3 . In all of these trials, stem cells are collected after induction therapy.

Tandem autologous versus single autologous transplantation

Once the benefit of ASCT was established in myeloma, several groups explored the approach of performing back-to-back, or tandem, ASCTs. The first randomized trial performed by Attal and colleagues found improved event-free survival (EFS) and OS with tandem transplant. However, subsequent studies did not uniformly show benefit of tandem transplant over a single transplant. A meta-analysis of 6 randomized clinical trials concluded that tandem transplant was associated with a statistically significant better response rate but at the cost of an increased transplant-related mortality rate. There was no difference in EFS or OS. Currently, most transplant centers in the United States do not routinely perform tandem autologous transplants outside of a clinical trial. Both the BMT CTN 0702 and EMN 02 trials are addressing the question of whether single or tandem ASCT is superior along with the role of consolidation.

Tandem autologous versus autologous-allogeneic transplantation

Several studies comparing upfront tandem ASCT with ASCT followed by AlloSCT have been performed and are summarized in Box 4 . Several of these studies used a biologic assignment approach in which patients who had an HLA-identical sibling donor received the autologous-allogeneic transplantation, whereas patients who did not have a sibling match underwent double ASCT. In aggregate, these studies do not show a significant benefit for tandem autologous-allogeneic transplant, and this approach is not routinely recommended outside of a clinical trial.

Posttransplantation monitoring

The standard day-100 evaluations include restaging studies assessing for monoclonal protein as well as a bone marrow aspirate and biopsy ( Table 2 ). There is increasing interest in the detection of minimal residual disease (MRD) as patients who achieve MRD-negative status seem to have improved outcomes compared with those who are MRD positive. Two major techniques under investigation are multiparameter flow cytometry and allele-specific oligonucleotide polymerase chain reaction (ASO PCR), which have sensitivities in the 10 ⁻⁴ to 10 ⁻⁵ range. Consensus guidelines regarding the use of multi-parameter flow cytometry will be forthcoming. The routine use of ASO-PCR has been limited by the requirement to make patient-specific primers.

Table 2

Posttransplant evaluation at day 100

Test	Notes
Myeloma restaging	Quantitative immunoglobulins, serum and urine IFE, serum and urine protein electrophoresis, serum free light chains, skeletal survey, bone marrow aspirate/biopsy with standard karyotyping and FISH panel of CD138-selected cells, flow cytometry
PET/CT scan	Considered for patients with plasmacytoma
Osteoporosis evaluation	DEXA, vitamin D

Abbreviations: DEXA, dual-energy x-ray absorptiometry; FISH, fluorescence in situ hybridization; IFE, immunofixation electrophoresis; PET, positron emission tomography.

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