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Hematopoietic Cell Transplantation in Multiple Myeloma
Introduction
The goal of treatment for multiple myeloma, an incurable hematologic malignancy, is to achieve the deepest possible response with the longest duration of remission upfront to achieve a durable disease-free state. The pivotal multicenter trial IFM 90 established the superiority of consolidation with autologous hematopoietic cell transplant (auto-HCT) in chemosensitive disease as standard of care for upfront treatment of myeloma, with improved response rate, event-free survival (EFS), and overall survival (OS) compared to standard chemotherapy, with less than 5% mortality. The role and optimal use of auto-HCT, however, continues to be questioned, especially with the availability of novel agents, including immunomodulatory drugs (IMiD: lenalidomide, thalidomide, pomalidomide), proteasome inhibitors (PI: bortezomib, carfilzomib, ixazomib), and monoclonal antibodies (elotuzumab, daratumumab, isatuximab), which have led to deeper responses. Ongoing studies are evaluating the optimal combination and sequencing of these new agents, with or without auto-HCT, in the induction, consolidation, and maintenance settings. Furthermore, the emergence of immunotherapeutic approaches including chimeric antigen receptor T (CAR-T-cell) cells will also be challenging the traditional role of auto-HCT. Although auto-HCT remains the standard of care, the role of allogeneic hematopoietic cell transplant (allo-HCT) in relapsed/refractory myeloma patients is still being evaluated. In this chapter, we plan to discuss the current evidence for the use of auto-HCT in myeloma focusing on auto-HCT versus nontransplant approaches, single versus tandem auto-HCT, the ideal timing and appropriate patient selection for auto-HCT, as well as the role of allo-HCT.
Eligibility for Autologous Hematopoietic Cell Transplant
With increased utilization and the cumulative experience with auto-HCT, improvement in supportive care, and favorable long-term outcomes, more and more patients are considered to be transplant-eligible. Although the earlier studies used an upper age limit of 65 years, several subsequent studies reported on the safety and efficacy of auto-HCT in older patients, highlighting the importance of physiologic age over chronologic age. In a large retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) study comparing auto-HCT outcomes across age groups, auto-HCT was shown to be a safe procedure in appropriately selected patients, with a transplant-related mortality (TRM) of less than 1% up to age 70 years, and reached 1% in patients age 70 years or above. There has been an increase in the use of auto-HCT in the ≥70-year age group with time, with 28% undergoing an auto-HCT in 2017 compared to 15% in 2013. Results from that study showed comparable relapse rates, progression-free survival (PFS), and OS in patients ≥70 years compared to patients age 60 to 69 years, when deemed eligible and treated with melphalan 200 mg/m 2 as conditioning regimen. Patients with an Eastern Cooperative Oncology Group performance status of 3 or 4, New York Heart Association functional status of class III or IV, frank liver cirrhosis, or diffusing capacity for carbon monoxide less than 50% are considered transplant-ineligible. Furthermore, melphalan dose may be reduced to 140 mg/m 2 in patients with organ dysfunction and comorbidities. All patients therefore deserve an evaluation for eligibility for auto-HCT and the main factors include physiologic age rather than chronologic age, as well as organ function and comorbidities.
Autologous Hematopoietic Cell Transplant Versus Nontransplant Approaches
The first two large randomized trials to establish the superiority of high-dose chemotherapy followed by autologous transplant as compared to standard dose chemotherapy were conducted by the Intergroupe Français du Myélome (IFM) and the Medical Research Council Adult Leukaemia Working Party. Both these studies showed an improvement in OS, PFS, and response rates, making auto-HCT a standard treatment option for newly diagnosed, transplant-eligible patients. With incorporation of IMiDs and PI in frontline induction regimens of myeloma, the benefit of auto-HCT was re-evaluated with these novel regimens. Two large randomized trials, both performed in Italy, showed an improvement in both OS and PFS with auto-HCT after a doublet regimen consisting of four cycles of lenalidomide and dexamethasone (RD), compared to standard chemotherapy. In the IFM 2009 trial, bortezomib, lenalidomide, and dexamethasone (VRD) regimen was used for induction in both upfront and delayed transplant arms. This trial also showed the benefit of upfront auto-HCT with an improvement in PFS in the upfront auto-HCT arm. The OS was comparable between the transplant and no transplant arms in three recent studies that included a PI or IMiD-based triplet, which reflects the efficacy of these novel drugs as salvage therapy in relapsed or refractory myeloma. Auto-HCT therefore remains the standard of care in frontline treatment of newly diagnosed multiple myeloma in transplant-eligible patients. Table 21.1 lists large randomized trials that compared standard versus high-dose chemotherapy with an auto-HCT for the frontline treatment of newly diagnosed multiple myeloma.
Table 21.1
Standard Versus High-Dose Chemotherapy With Autologous Hematopoietic Cell Transplant in Frontline Treatment of Newly Diagnosed Multiple Myeloma
| Trial | N | Treatment Arms | Response Rate | EFS/PFS | OS | Comment |
|---|---|---|---|---|---|---|
| Attal et al . 1996 | 200 |
|
|
|
Median NR vs. 37.4 mo ( P = .03) | Auto-HCT improved OS, EFS and responses |
| Child et al . 2003 | 401 |
|
|
|
Median 54.1 vs. 42.3 mo ( P = .04) | Auto-HCT improved OS, PFS and responses |
| Bladé et al . 2005 | 216 |
|
|
|
Median 61 vs. 66 mo ( P = NS) | Auto-HCT only showed improved response rate |
| Fermand et al . 2005 | 190 |
|
|
|
Median 47.8 vs. 47.6 mo ( P = .91) | TwiSST was different only ( P = .03) |
| Barlogie et al . 2006 | 899 |
|
|
|
7 y 37% vs. 42% ( P = NS) | Comparable response rate, PFS and OS |
| Palumbo et al . 2014 | 402 |
|
|
|
4 y 81.6% vs. 65.3% ( P = .02) | Comparable CR, improved OS and PFS |
| Gay et al . 2015 | 389 |
|
|
|
4 y 86% vs. 73% ( P = .004) | Improved OS and PFS, comparable response rate |
| Attal et al . 2017 | 700 |
|
|
|
4 y 81% vs. 82% ( P = .87) | Improved PFS, CR and MRD- rate. Comparable OS |
| Cavo et al . 2020 | 1197 |
|
|
|
5 y 75.1% vs. 71.6% ( P = .35) | Improved PFS, ORR Comparable OS |
| Gay et al . 2021 | 474 |
|
|
|
N/A | Comparable response rates Improved PFS for high-risk patients |
ABCM , Doxorubicin, carmustine, cyclophosphamide, melphalan; ACVP , doxorubicin, cyclophosphamide, vincristine, prednisone; BVAP , carmustine, vincristine, doxorubicin, prednisone; CR , complete remission; EFS , event-free survival; KCD , carfilzomib, cyclophosphamide, and dexamethasone; Mel , melphalan; MPR , melphalan, prednisone, and lenalidomide; MRD , minimal residual disease; NR , not reached;
ORR , overall response rate; OS , overall survival; PFS , progression-free survival; R-maint , lenalidomide maintenance; RVD , lenalidomide, bortezomib, and dexamethasone; sCR , stringent complete remission; TwiSTT , time without symptoms, treatment, and treatment toxicity; VAD , vincristine, doxorubicin, doxorubicin; VCD , bortezomib, cyclophosphamide, and dexamethasone; VGPR , very good partial response; VMCP , vincristine, melphalan, cyclophosphamide, prednisone; VMP , bortezomib, melphalan, and prednisone.
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