Allogeneic Stem Cell Transplantation in Multiple Myeloma

Abstract

The development of new inhibitory and immunological agents and combination therapies significantly improved response rates and survival of patients diagnosed with multiple myeloma (MM) in the last decade, but the disease is still considered to be incurable by current standards and the prognosis is dismal especially in high-risk groups and in relapsed and/or refractory patients. Allogeneic hematopoietic stem cell transplantation (allo-SCT) may enable long-term survival and even cure for individual patients via an immune-mediated graft-versus-myeloma (GvM) effect, but remains controversial due to relevant transplant-related risks, particularly immunosuppression and graft-versus-host disease, and a substantial non-relapse mortality. The decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Here, allo-SCT should be considered within clinical trials in first-line as part of a tandem approach to separate myeloablation achieved by high-dose chemotherapy with autologous SCT, and following allo-SCT with a reduced-intensity conditioning to minimize treatment-related organ toxicities but allow GvM effect. Our review aims to better define the role of allo-SCT in myeloma treatment particularly in the context of new immunomodulatory approaches.

Immunotherapy for the treatment of multiple myeloma

“…The potential role of immunotherapy for MM was initially established with the graft-versus-myeloma effect of allogeneic hematopoietic cell transplantation (allo-SCT). Allo-SCT has been shown to induce long-term remission and potential cure in a subset of MM patients, which is thought to be due to anti-myeloma activity of graft alloreactive lymphocytes ( 2 , 21 – 23 ). The efficacy of this approach was further underscored by success of donor lymphocyte infusion (DLI) for patients who relapsed after allo-SCT ( 24 ).…”

“…To reduce treatment-related morbidity and mortality and increase the pool of allo-SCT eligible patients, non-myeloablative or reduced-intensity conditioning (RIC) allo-SCT has similarly been used ( 25 – 27 ); however, this strategy has been associated with increased risk of relapse, highlighting the importance of initial high-dose cytotoxic conditioning for durable response and remission ( 2 , 25 ). High-dose chemotherapy with autologous transplant followed by RIC allo-SCT has been evaluated to potentially balance these two approaches, but studies have demonstrated some late relapses as well as unclear efficacy or reduced survival when compared with tandem autologous transplantation ( 2 , 23 , 25 ). While allo-SCT may still have a potentially curative role in a curated subset of patient ( 28 ), risks related to infection and GVHD remain significant.…”

Telomeres and Telomerase in the Control of Stem Cells

“…It has already provided the basis for a number of advanced technologies, such as the breeding of transgenic animals, including those tolerant to diseases [ 1 ] or producing biologically active substances [ 2 ], somatic cell nuclear transfer (SCNT)-based animal cloning [ 3 ], and in vitro production of bioartificial tissues and organs [ 4 ]. Stem cell transplantation (stem cell therapy) and stem cell-based tissue engineering are the keystones of regenerative medicine, an innovative trend in medicine with the potential to become a new healthcare industry [ 5 , 6 , 7 , 8 , 9 ]. New stem cell therapy applications, such as hematopoietic and mesenchymal stem cell transplantation in patients with hematological malignancies or autoimmune diseases, are emerging [ 10 , 11 ].…”

Improving outcome of haematopoietic stem cell transplantation

“…NK cells recover within 3-4 weeks after HSCT, but until 6 months posttransplant there is an imbalance between mature and immature NK cells in the peripheral blood. However, as the first reconstituted lymphocyte subset after transplantation, early NK cell reconstitution plays a critical role in controlling potential relapse in allogeneic HSCT 48,49 . Recovery of the adaptive immunity takes much longer.…”

“…Nevertheless, it was clearly an effect of the HSCT. Furthermore, the fact that the patients already received several treatment lines (average 3, range 2 to 7) could also be of influence to the lack of response, since the best responses of allogeneic HSCT in MM in general are seen when it is used in an earlier course of the disease 49 .…”