Autologous stem cell transplantation (auto-SCT) has been the standard of care in eligible newly diagnosed multiple myeloma (MM) patients. Outcomes of patients with MM have improved significantly due to the advent of several novel drugs. Upfront use of these drugs in induction therapy has significantly increased the rate and depth of responses that have translated into longer remission and survival. In addition, post-SCT maintenance have even further improved the PFS and OS in patients. Patients with renal insufficiency and older patients are now able to safely undergo auto-SCT. Evolving role of minimal residual disease together with emerging role of bispecific antibodies provide patients with more effective choices and better outcomes.
- Stem Cell Transplantation
- multiple myeloma
- Autologous
1. Introduction
Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies [1]. It is a malignant disorder in which plasma cells accumulate in the bone marrow and secrete either an entire immunoglobulin (usually IgG or IgA) and light chain (kappa or lambda) or only immunoglobulin light chains. It has been shown to arise from a benign condition monoclonal gammopathy of undetermined significance (MGUS). Often it can behave in an aggressive manner and can become resistant to most chemotherapeutic drugs. Multiple myeloma is a heterogeneous disease and hence requires treatment to be more personalized [2].
About 35 years ago, alkylating agents and corticosteroids were the most effective conventional agents for the treatment of this disease but without any major improvement in the outcomes [3]. Intravenous melphalan was then introduced at high doses to overcome drug resistance. This, however, induced severe and prolonged myelosuppression [4][5]. The functional bone marrow was restored by the infusion of autologous hematopoietic stem cells that were collected before the administration of melphalan. The Intergroupe Francophone du Myélome was the first to conduct a randomized trial showing the superiority of this approach, as compared with conventional chemotherapy [6]. Several other studies compared conventional chemotherapy with ASCT, showing a significant impact on progression free survival, but failed to show a significant improvement in overall survival [7].
About 35 years ago, alkylating agents and corticosteroids were the most effective conventional agents for the treatment of this disease but without any major improvement in the outcomes [3]. Intravenous melphalan was then introduced at high doses to overcome drug resistance. This, however, induced severe and prolonged myelosuppression [4,5]. The functional bone marrow was restored by the infusion of autologous hematopoietic stem cells that were collected before the administration of melphalan. The Intergroupe Francophone du Myélome was the first to conduct a randomized trial showing the superiority of this approach, as compared with conventional chemotherapy [6]. Several other studies compared conventional chemotherapy with ASCT, showing a significant impact on progression free survival, but failed to show a significant improvement in overall survival [7].
The efficacy of high-dose chemotherapy is mostly related to damage to tumor-cell DNA. It has, however, been shown that agents such as thalidomide, bortezomib, and lenalidomide act not only on myeloma cells, but also on the tumor microenvironment [8]. Hence, these agents may offer another means of overcoming drug resistance. In addition, some studies have tried to evaluate the role of novel agents as part of maintenance therapy post ASCT [9][10]. An important finding from these studies was a significant increase in complete remission with ASCT, results that translated into significantly prolonged progression-free survival (PFS) and overall survival (OS). Although transplantation improved the response rate and progression-free survival, there was no overall survival benefit in most of the trials [11]. This has been thought to be partly related to the patient selection criteria and different conditioning therapy in the trials. In addition, significant benefit with transplantation at relapse in patients who were initially treated with conventional chemotherapy raised the question of early versus delayed ASCT [12]. In addition, progress has been made on the role of allogeneic stem cell transplantation (allo-SCT) in relapsed/refractory settings in the era of combination of novel agents. Advances in the management of toxicity and improved GVHD prophylaxis have allowed allo-SCT to be used in the treatment of relapsed and refractory multiple myeloma (RRMM), especially in patients who have already undergone prior ASCT.
The efficacy of high-dose chemotherapy is mostly related to damage to tumor-cell DNA. It has, however, been shown that agents such as thalidomide, bortezomib, and lenalidomide act not only on myeloma cells, but also on the tumor microenvironment [8]. Hence, these agents may offer another means of overcoming drug resistance. In addition, some studies have tried to evaluate the role of novel agents as part of maintenance therapy post ASCT [9,10]. An important finding from these studies was a significant increase in complete remission with ASCT, results that translated into significantly prolonged progression-free survival (PFS) and overall survival (OS). Although transplantation improved the response rate and progression-free survival, there was no overall survival benefit in most of the trials [11]. This has been thought to be partly related to the patient selection criteria and different conditioning therapy in the trials. In addition, significant benefit with transplantation at relapse in patients who were initially treated with conventional chemotherapy raised the question of early versus delayed ASCT [12]. In addition, progress has been made on the role of allogeneic stem cell transplantation (allo-SCT) in relapsed/refractory settings in the era of combination of novel agents. Advances in the management of toxicity and improved GVHD prophylaxis have allowed allo-SCT to be used in the treatment of relapsed and refractory multiple myeloma (RRMM), especially in patients who have already undergone prior ASCT.
2. Patient Eligibility for Autologous SCT in MM
2.1. Patient Related Factors
ASCT is offered as consolidation therapy to young patients and eligible elderly (older than 65 years) patients with newly diagnosed MM (NDMM). There is no age cut-off for ASCT eligibility, at least in the United States. In a study by Wildes et al. [13], after adjusting for performance status, disease stage, and comorbidities, patients older than 65 years who underwent ASCT for MM had prolonged survival compared to those who did not. In a single center retrospective analysis of patients older than 70 years who received ASCT, outcomes were comparable to those seen in younger patients [14]. The peak incidence of MM in older age along with increase in life expectancy and longer disease related survival with the use of novel drugs has created an increased number of older adults for whom ASCT is an option. As such, MM is one of the most common indications of ASCT. In the last decade, 44% of the ASCT recipients were at least 60 years of age according to data from CIBMTR, which is an encouraging trend [15]. Even on the European side, ASCT for MM in patients 70 years and older has increased from 1.1% to 3% between 2006 and 2010 [16]. The significance of biological age in the outcomes of ASCT in MM, especially increased non-relapse mortality (NRM) has been well studied. Hayden et al. [16] reported increasing day +100 death with advancing age in ASCT recipients in MM (2.4% in patients ≥70 years compared with 1.2% in patients 40–49 years and 0.7% in those younger than 40 years of age). However, due to the heterogeneity of the effects of ageing, it is difficult to assess eligibility for ASCT solely based on biological age. Functional or physiological age rather than chronological or biological age should be the determining factor for ASCT eligibility in MM. The former is a reflection of patient’s performance status along with their health reserve that correlates better with how well they tolerate the stem cell transplantation. The next important determinant of transplant outcomes that has been well studied and recognized is comorbidity. The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) is one such index that is based on the presence of pre-SCT comorbidities and organ dysfunction, and has been shown to correlate well with survival and non-relapse mortality of patients after transplant. Day+100 mortality post ASCT was 3% for patients with an HCT-CI score of ≥3 [17]. Elderly patients need a thorough evaluation of their overall health status and functional reserve and not just a brief evaluation in the clinic. Geriatric assessment is a comprehensive evaluation of the functional capacity of elderly patients, and it is a summative assessment of several domains of health including comorbidities, physical performance (based on both patient report and objective evaluation), nutritional status, cognitive and psychological capacities that determine disease outcomes [18][19][18,19]. Lack of social support and polypharmacy are other major issues that influence the outcomes of ASCT in elderly patients and need to be addressed during transplant evaluation. Consideration of functional age and comprehensive geriatric evaluation will help in more accurate assessment of transplant eligibility and post-transplant outcomes.
2.2. Renal Insufficiency and ASCT
Renal insufficiency (RI) is prevalent in 20–50% of the MM patients, and a portion of these patients are dialysis dependent [20]. ASCT has been the mainstay of treatment in young multiple myeloma patients with normal renal function but has been of concern for RI patients [21]. In the past, reports have shown high dose melphalan with ASCT to be effective even in myeloma patients with RI [22][23][22,23]. The majority of the previously published data suggests increased toxicity, including infections and mucositis, in patients with RI [22][24][25][22,24,25]. Studies evaluating the effectiveness and toxicity of high dose melphalan conditioning in patients with either normal renal function or RI showed that patients in the RI group experienced more mucositis and infections compared to patients in the normal group [22][24][22,24]. However, the decision to do ASCT or not is usually at the physician’s discretion depending on several other factors as mentioned above. Melphalan to date has been shown to be an effective conditioning regimen; thus, the question arises as to what the effective dose of melphalan in patients with RI is. Studies have reported high-dose melphalan to yield a good hematological response but poor survival outcomes compared to lower doses [24][25][24,25]. There have been conflicting reports on the most effective dose of melphalan in RI, partly due to the heterogeneity of the studies for the outcome measure (clinical response or remission status). In a recent study, Mahindra et al. showed that melphalan 200 mg/m2 was safe in both moderate and severe RI [23]. Moderate RI patents had improved outcomes with high doses, and importantly, a portion of dialysis patients achieved dialysis independence post ASCT. Thus, the escalation of melphalan dose may result in better response rates in patients with mild to moderate RI. Lower doses at 140 mg/m2, however, have been seen to have lower associated mortality and be beneficial for renal recovery [24][25][26][27][24,25,26,27]. Unlike other hematological malignancies, MM patients on dialysis are not excluded from having ASCT. In these patients, lower doses (140 mg/m2) are routinely used.