Research ArticleClinical Studies
Open Access

Autologous and Allogeneic Stem Cell Transplantation as Salvage Treatment Options for Relapsed/Refractory Multiple Myeloma: A Single-center Experience over 20 Years

NORMANN STEINER, PAULA SCHOBER, WOLFGANG WILLENBACHER, BRIGITTE KIRCHER, EBERHARD GUNSILIUS, DOMINIK WOLF and DAVID NACHBAUR
Anticancer Research December 2022, 42 (12) 5825-5832; DOI: https://doi.org/10.21873/anticanres.16090

Abstract

Background/Aim: Despite multiple treatment options, multiple myeloma (MM) remains an incurable disease with poor outcome. Patients and Methods: We retrospectively analyzed the outcome of MM patients undergoing an allogeneic (allo-SCT; n=34) or autologous stem cell transplantation (auto-SCT; n=41) as salvage treatment for relapsed/refractory (r/r) disease. Results: After a median observation period of 79.9 months in the auto group and 15.7 months in the allo group, the 5- and 10-year OS rates were 54% and 44% in the auto group and 17% and 4% in the allo group (p=0.0002), respectively. The 5- and 10-year disease-free survival in the auto group was 21% and 8%, and 14% and 5% in the allo group (p=0.0142), respectively. The 5- and 10-year cumulative incidence of relapse/progression in the auto group was 69% and 82%, and 64% and 69% in the allo group (p=0.0759), respectively. The 5- and 10-year non-relapse mortality in the auto group was significantly lower than that in the allo group [5% versus 45% (p=0.0001)]. Conclusion: A second autotransplant in selected r/r patients offers an acceptable long-term outcome partly because of the significantly lower treatment-related morbidity and mortality.

Key Words:

Multiple myeloma (MM) is the second most common hematological malignancy characterized by an uncontrolled proliferation of monoclonal plasma cells in the bone marrow resulting in an overproduction of nonfunctional immunoglobulins or their light chains. Despite the dramatic increase in the therapeutic armamentarium [e.g., immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies (mAbs)] multiple myeloma is still considered an incurable disease with a current 5-year survival rate of approximately 47% (1-3).

Plasma cell disorders are the leading indications for autologous stem cell transplantation (auto-SCT) and high-dose melphalan still remains the gold standard for transplant-eligible myeloma patients after induction therapy with new drugs (4, 5), thereby significantly improving progression-free and overall survival (6). However, virtually all patients experience disease relapse/progression without achieving a survival plateau even after frontline tandem auto-SCT (7).

In contrast, allogeneic (allo)-SCT is still considered the only potentially curative treatment option because of its tumor cell-free graft and the possible graft-versus-myeloma effect (7-10). However, survival is limited by an inevitable high treatment-related mortality of 30 to 50%, particularly in the myeloablative setting. Thus, allo-SCT in the past was mainly limited to young patients with early (<12 months) disease relapse/progression after auto-SCT or those with treatment (mainly lenalidomide and PI)-refractory disease. The introduction of reduced intensity conditioning regimen (RIC) has lowered treatment-related mortality to 10-20% with promising results especially when applied as a tandem approach sequentially combining auto- with subsequent RIC allo-SCT in patients with poor-risk cytogenetics (7). Even though these data are encouraging, it remains unclear whether allogeneic SCT still has a place in the treatment algorithm of multiple myeloma in an era of upcoming BiTEs and alternative cellular therapies such as CAR T-cells (11).

In this retrospective single-center observational study, we analyzed the outcome after autologous or allogeneic salvage transplantation in patients with relapsed and/or refractory multiple myeloma who have received ≥2 lines of previous therapy including frontline auto-SCT.

Patients and Methods

Patients. From May 2000 to February 2021, 34 patients underwent a 1st allogeneic and 41 a 2nd auto-SCT because of progressive or relapsed/refractory multiple myeloma after giving written informed consent. Baseline characteristics are listed in Table I.

View this table:
Table I.

Baseline characteristics of patients receiving a 1st allogeneic (n=34) or 2nd autologous (n=41) stem cell transplantation as salvage treatment.

Patients undergoing a 1st allogeneic SCT were significantly younger at time of diagnosis (median age 49 vs. 56 years, p=0.0024) and at time of SCT (median age 55 vs. 61 years, p<0.0001), and the time from diagnosis to SCT was significantly shorter (24.6 vs. 51.7 months, p=0.0421). The groups were balanced regarding myeloma-specific parameters at time of diagnosis [high-risk cytogenetics defined as t(4;14), t(14;16), t(14;20), del 17p, gain of 1q; serum β2 microglobulin >3.5 mg/l; LDH >250 IU/l; serum albumin <3.5 d/dl; ≥3 CRAB criteria], except that there were significantly more patients with Durie & Salmon Stage III in the allogeneic group (34/34 vs. 27/41, p=0.0002) (Table II).

View this table:
Table II.

Myeloma-specific prognostic parameters in patients receiving a 1st allogeneic (n=34) or 2nd autologous stem cell transplantation (n=41) as salvage treatment at the time of diagnosis.

With the exception of three patients undergoing an upfront allogeneic SCT from an HLA-identical sibling donor because of high-risk features and/or primary refractory disease, virtually all patients underwent an up-front 1st auto-SCT after induction treatment with either a vincristine, doxorubicin and dexamethasone (VAD)-based regimen or novel anti-myeloma drugs (proteasome inhibitors, PI, and immunomodulatory drugs, IMiDS). Standard conditioning for auto-SCT was high-dose melphalan (100-200 mg/m2 according to age and co-morbidities). All patients received peripheral blood stem cells (PBSC) with a CD34 count ≥2.0×106/kg body weight mobilized either with chemotherapy (cyclophosphamide 2 g/m2) plus granulocyte colony-stimulating factor (G-CSF) or G-CSF +/− plerixafor alone. Nine patients in the autologous stem cell transplantation (auto-SCT) group had an up-front tandem auto-SCT after a median time interval of 3.6 months (range=1.2-3.2 months) either within an investigational trial or because of not achieving a complete response (CR) or stringent complete response (sCR) or progressive disease (PD) according to the European Society for Blood and Marrow Transplantation (EBMT) response criteria [criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and hematopoietic stem cell transplantation; Myeloma Subcommittee of the EBMT (12)] or the updated International Myeloma Working Group criteria (13). All other patients underwent the 2nd “salvage” auto-SCT at the time of relapse/progression following at least one re-induction cycle or maintenance therapy after the 1st auto-SCT. Usually, cryopreserved PBSCs from the initial stem cell mobilization procedure were used.

Characteristics of patients undergoing a 1st allogeneic SCT are listed in Table III.

View this table:
Table III.

Transplant characteristics of patients receiving a 1st allogeneic SCT (n=34) as salvage treatment.

The majority (88%) of the patients received PBSCs from a matched related or unrelated donor. The conditioning was myeloablative in only 12% of the patients; all other patients underwent a fludarabine-based reduced intensity-conditioning regimen because of one or two auto-SCTs in their history and/or age and/or comorbidities. Immunosuppression consisted of cyclosporine A combined with methotrexate in the myeloablative setting or mycophenolate mofetil +/− anti-thymocyte globulin (ATG F, 30-60 mg/kg) in reduced-intensity transplants. All patients received PBSCs with a median CD34 cell number of 6.19 (range=2.22-13.03)×106/kg body weight and all patients were engrafted after a median of 11 days (range=9-17 days), defined as leukocytes >1.0 g/l for two consecutive days.

Study endpoints. The primary study endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS), cumulative incidence of non-relapse mortality (NRM), and cumulative relapse incidence.

Statistical methods. Data were retrospectively reviewed and analyzed as of October 2021. All statistics were computed using NCSS Statistical Software Version 19.0.5. OS and DFS probabilities were calculated using the Kaplan-Meier method from the date of the 1st allogeneic or 2nd autologous transplant until death. The log-rank test was used to analyze the differences between individual curves. For three patients undergoing a second allogeneic SCT because of relapse/progression, the unit studied was the patient according to the EBMT Statistical Guidelines [suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation (14)].

DFS was defined as the probability of being alive and free of disease at any time point with disease progression/relapse or death treated as events. The cumulative RI was calculated from the date of the 1st allogeneic or 2nd autologous transplant until relapse with death without relapse/progression as competing risk. The cumulative incidence of NRM was calculated from the date of the 1st allogeneic or 2nd autologous transplant to the date of death with death from relapse/progression as competing risk. Pairwise comparisons between patient characteristics were performed using the χ2 test for categorical variables and the Kolmogorov–Smirnov test for different distributions for continuous variables.

Results

Overall and disease-free survival. After a median observation period of 79.9 months (range=0.6-218.6 months) in the auto and 15.7 months (range=0.8-143.7 months) in the allo group, the 5- and 10-year OS was 54% (95%CI=38%-71%) and 44% (95%CI=26%-63%) versus 17% (95%CI=2%-31%) and 4% (95%CI=0%-12%), respectively (log rank, p=0.0002). At the end of the observation period (Oct 2021) only 6/34 (18%) of allo-transplanted patients were still alive, comprising 5/6 (83%) patients without evidence of disease relapse/progression, whereas in the auto group 20/41 (49%) were still alive, including 7/20 (35%) patients without disease relapse/progression (p=0.0373, χ2 test). The 5- and 10-year DFS rates in the auto group were 21% (95%CI=8%-35%) and 8% (95%CI=0%-17%), and 14% (95CI=2%-27%) and 5% (95%CI=0%-14%) in the allo group, respectively (log rank, p=0.0142) (Figure 1A and B). None of the myeloma-specific risk factors at the time of diagnosis were linked to OS or DFS in either the auto or the allo group (data not shown).

Figure 1.
Figure 1.

Overall survival (A) and disease-free survival (B) of multiple myeloma patients undergoing a 2nd autologous or a 1st allogeneic stem cell transplantation as salvage treatment.

Relapse incidence and non-relapse mortality. The 5- and 10-year cumulative incidence of relapse/progression in the auto group was 69% (95%CI=55%-86%) and 82% (95%CI=70%-96%) versus 64% (95%CI=49%-84%) and 69% (95%CI=54%-88%) in the allo group, respectively (p=0.0759). The 5- and 10-year non-relapse mortality in the auto group was 5% (95%CI=1%-19%) and 45% (95%CI=31%-67%) in the allo group, respectively (p=0.0001). The main causes of deaths in the allo group were steroid-refractory acute or chronic graft-versus-host disease (n=8), toxic/septic multi-organ failure (n=8), and disease relapse/progression (n=12). Only two patients in the auto group died because of transplant-related complications, whereas all other patients died because of disease relapse/progression (n=18) (Figure 2A and B). None of the myeloma-specific parameters at the time of diagnosis (see Patient and Methods section) had a significant impact on the CI of relapse/progression or non-relapse mortality in either the auto or the allo group (data not shown).

Figure 2.
Figure 2.

Cumulative incidence of relapse/progression (A) and non-relapse mortality (B) in multiple myeloma patients undergoing a 2nd autologous or a 1st allogeneic stem cell transplantation as salvage treatment.

Discussion

In this retrospective single-center study, we analyzed the outcome of relapsed/refractory multiple myeloma patients either receiving an autologous or allogeneic salvage transplantation. All patients were heavily pretreated with at least two lines of previous therapy including frontline autologous transplantation. Some of our patients in the allo group had even received two autologous transplantations in their history. Usually, allogeneic stem-cell transplantation is mainly offered to young patients with relapsed/refractory disease as a salvage option with a valuable chance for cure at least in a subgroup of patients, but its role remains controversial due to the high non-relapse mortality even with the use of the RIC setting (11, 15).

Prospective comparisons between allo- and auto-SCT as salvage therapy in relapsed/refractory myeloma patients are limited with small patient numbers in most of the studies. Although it was not the primary goal of our analysis to compare both treatment options, our findings with a 5-year OS of 17% in the allogeneic cohort are in accordance with the study by Shouval et al., who reported a 5-year OS rate of 18% (16). Similar results were published by Ikeda et al., with a 5-year OS rate of 24% in the myeloablative and 34% in the RIC allogeneic cohort (17). Other allogeneic SCT studies as salvage treatment for relapsed/refractory myeloma patients reported similar 5-year OS rates between 24% and 40% (17-22).

Although our patient cohorts were not comparable with respect to disease dynamics and aggressiveness, demonstrated impressively by the significantly shorter time interval form diagnosis to salvage transplant, survival was definitely better after a second auto-SCT than after a salvage allo-SCT. Similar results have been published by Ikeda et al., who observed also a better OS after a second auto-SCT than after allo-SCT, at least in relapsing intermediate-risk patients. Moreover, they did not find any benefit of salvage allo-SCT in relapsed/refractory low- or high-risk patients (17). Also, several other groups favor a second auto-SCT as a safe and effective salvage therapy in relapsed/refractory patients with an acceptable low treatment-related mortality (23-25).

Our 5-year PFS rate in the allogeneic cohort of 14% is identical to that reported by Sobh et al. in a matched unrelated donor allo cohort (14%) and to the results reported by Shouval et al. showing a 5-year PFS rate of 17% (16, 20). The high relapse rates of more than 60% in both the allo- and the auto- group in our retrospective analysis as well as in numerous other reports after allo-SCT in relapsed/refectory patients make a generally appliable graft-versus-myeloma effect highly questionable (17, 18, 20, 21, 26-29); however, some anecdotical reports of this phenomenon exist especially after donor lymphocyte infusion (10, 30, 31).

In summary, in light of the pipeline full of highly active new treatment options upcoming soon (BiTEs, ADCs, CAR-Ts) for relapsed/refractory myeloma patients, at this time, a second auto-SCT still remains a valuable treatment option for patients with a long PFS after frontline auto-SCT and those with treatment-sensitive disease. Recommendations for lenalidomide-refractory and -not refractory situations or for relapsed/refractory patients after more than two lines of previous therapy have been recently defined by the International Myeloma Working Group (32). In contrast, according to the agreement of an international consensus conference, allo-SCT remains experimental but should be offered on an individual basis as an appropriate treatment option to young and fit patients with early relapse after frontline treatment including auto-SCT and/or high-risk features and, whenever possible, within clinical trials (33).

Acknowledgements

The Authors would like to acknowledge all patients as well as the nursing team for the excellent clinical care given to the patients.

Footnotes

  • Authors’ Contributions

    N.S. and D.N. conceptualized the project; N.S. and D.N. designed the methodology; N.S., P.S. and D.N. were involved in the data curation, formal analysis, and investigation; N.S., P.S. and D.N. wrote the manuscript. All the co-authors critically revised and approved the paper. All Authors agreed to be held accountable for all aspects of the work. All Authors have read and agreed to the published version of the paper.

  • Conflicts of Interest

    The Authors have no conflicts of interests to declare in relation to this study.

  • Received September 26, 2022.
  • Revision received October 4, 2022.
  • Accepted October 5, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Autologous and Allogeneic Stem Cell Transplantation as Salvage Treatment Options for Relapsed/Refractory Multiple Myeloma: A Single-center Experience over 20 Years
NORMANN STEINER, PAULA SCHOBER, WOLFGANG WILLENBACHER, BRIGITTE KIRCHER, EBERHARD GUNSILIUS, DOMINIK WOLF, DAVID NACHBAUR
Anticancer Research Dec 2022, 42 (12) 5825-5832; DOI: 10.21873/anticanres.16090
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