Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed Refractory Multiple Myeloma

doi:10.21203/rs.3.rs-3884915/v1

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Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed Refractory Multiple Myeloma

https://doi.org/10.21203/rs.3.rs-3884915/v1

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Objectives

Allo-Hematopoietic Stem Cell Transplantation (HSCT) offers a curative option for relapsed and refractory multiple myeloma in younger aged and fit patients with high-risk cytogenetic properties.

Material and Methods

Results

Prior to allo-SCT, 6 (20.0%) patients were in complete remission; 8 (26.6%) had partial response; 14 (46.6%) had progressive disease, and 2 (6.6%) had stable disease. Overall survival (OS) at 1, 2, 3 and 5 years post-transplant were 45%, 36.3%, 31.7% and 22.7% respectively; transplant-related mortality (TRM) was 25.0% at 100 days. While the 5-year OS was 11.7% in the group with less than PR according to the pre-transplant disease status, it was found to be statistically significant as 45.8% in the group with CR or PR (p = 0.001). TRM was significantly higher in patients with less than PR compared has CR or PR at pre-transplantation (100% vs 43.7% p = 0.01). Like as these findings, PFS was shorter in patients with less than PR compared has CR or PR at pre-transplantation (6.2 vs 77.1 months, p = 0.01).

Conclusions

We found longer OS and PFS in patients with complete response before allo-SCT. This shows that the depth of response before allogeneic stem cell transplantation is effective on 100-day TRM in multiple myeloma patients. Allo-HSCT may be a therapeutic option in MM patients that relapse/ refractory after auto-SCT, particularly after achieving the least partial response.

Allogeneic Hematopoietic Stem Cell Transplantation

Relapsed Refractory Multiple Myeloma

PFS

TRM

Allo-Hematopoietic Stem Cell Transplantation (HSCT) offers a curative option for relapsed and refractory multiple myeloma in younger aged and fit patients with high-risk cytogenetic properties [1, 2]. Nevertheless, despite improvements in supportive care, allo-HSCT performed with myeloablative conditioning regimens carries a risk of non-relapse mortality (NRM) rate of 20–44% secondary to organ toxicities and graft-versus-host disease (GVHD) [3, 4]. Reduced-intensity conditioning (RIC) regimes have begun to be used in order to reduce toxicities of the conditioning regimens and to preserve the immunological effect (i.e. the graft-versus-tumor effect) of donor lymphoid cells [5]. Allo-HSCT is still not the standard treatment approach in MM treatment; its use is limited due to high TRM rates and is still an experimental therapy spared only for resistant and recurrent MM patients with high-risk cytogenetics. The objective of the present study was to assess the effect of allogeneic stem cell transplantation performed at our center for multiple myeloma on disease mortality and morbidity.

This study retrospectively enrolled the medical data of 30 patients who had undergone allogeneic stem cell transplantation at the Gazi University Adult Stem Cell Transplant Unit between 2005 and 2020. The medical records screened to record demographic properties, pre-transplant disease status, chemotherapy administered during and after the transplantation, complications that occurred during and after transplantation, time of engraftment, and relapse and mortality rates. The demographic properties of the patients were presented in Table 1. The patient’s EBMT risk score [6] and Sorror score [7] at the time of transplant entry were calculated. Response to myeloma therapies was assessed according to IMWG criteria. Informed consent was obtained from all patients for being included in the study.

Table 1

Demographic properties of the study population
Variable	n (%)
Sex Female Male	8 (26.6%) 22 (74.4%)
MM Subtype IgG Kappa IgG Lambda IgA Kappa Kappa Light Chain Lambda Light Chain IgD Lambda	12 (40.0%) 5 (16.6%) 4 (13.3%) 6 (20.4%) 1 (3.3%) 2 (6.6%)
Pre-transplant status Complete Remission Partial Remission Progressive Disease Stable Disease	6 (20.0%) 8 (26.6%) 14 (46.6%) 2 (6.6%)
Donor Type Full match sibling 10/10 unrelated 9/10 unrelated Full match relative	23 (76.6%) 1 (3.3%) 5 (16.6%) 1 (3.3%)
Conditioning Regimen Flu-TBI Flu-Mel TBI-Cy Flu-TBI-Cy	9 (30.0%) 18 (60.0%) 2 (6.6%) 1 (3,3%)

Flu-Mel conditioning regimen was used [fludarabine (50mg/day, a total of 5 days between D-6 and D-2) and melphalan 140mg/m2/day at D-2] in 18 patients. Flu-TBI ± Cy conditioning regimen [fludarabine (30mg/m2/day, a total of 5 days between D-5 and D-1), total body irradiation (TBI) (at day D-6 2x200 cGray/day) and/or cyclophosphamide (50 mg/kg/day at days D + 3, D + 4)] was used in 10 patients. TBI-Cy conditioning regimen [total body irradiation (TBI) (2x200 cGray/day at days D-6, D-5, D-4; a total of 1200 cGray), cyclophosphamide 60 mg/kg/day at days D-3, D-2 were used in 2 patients. Cyclosporine and mycophenolate mofetil were used as GVHD prophylaxis in patients received was Flu-TBI-Cy or Flu-Mel conditioning regimens; cyclosporine and methotrexate in those that received TBI-Cyc. Rabbit ATG was added for unrelated donor transplantation.

Neutrophil engraftment was defined as an unsupported absolute neutrophil count (ANC) rising above 500/ mm³ for three consecutive days or reaching 1000/mm3 for the first time; thrombocyte engraftment was defined as an unsupported thrombocyte count rising above 20.000/ mm³ for three consecutive days or reaching 50.000/mm3 for the first time; OS was defined as the time to death or for those who were alive, to the final follow-up visit; PFS was defined as the time to recurrence, progression, death, or the final follow-up visit; non-relapse mortality was defined as death due to any cause unrelated to MM.

2.1. Statistical Analysis

Statistical analyses of the study data were performed using IBM SPSS 22.0 statistical software. Data were summarized by descriptive statistics. Survival analyses were performed with Kaplan Meier analysis. Log rank test was used to compare survival results. p < 0.5 was accepted as significant.

2.2. Ethical Approval and Informed Consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Local Ethics Committee and the approval number is 04 and date 07.04.2020.

Among a total of 30 patients who were under follow-up with relapsed refractory multiple myeloma for which allo-HSCT was carried out at Gazi University Adult Stem Cell Transplantation Unit, 22 (74.4%) were male and 8 (26.6%) were female. The patients’ median age at the time of allo-HSCT was 49.64 (28–64) years. The demographic properties, MM subgroups, disease status at the time of transplantation, donor type, and conditioning regimens were shown in Table 1. The median donor age was 46 (23–65) years. The median follow-up after allo-HSCT was 7 (0.3–152) months, and the median time from the diagnosis to allo-HSCT was 27.8 (6.8–181) months. The median EBMT score was 5 (2–6) and the median Sorror score was 5 at the time of allo-SCT (2–6). The patients had received a median of 4 (1–10) lines (21 patients (70%) had received > 3 lines) of therapy before allo-HSCT. Autologous stem cell transplantation was performed in 20 patients (66.6%) prior allo-HSCT.

Prior to allo-HSCT, 6 (20.0%) patients were in complete remission; 8 (26.6%) had partial response; 14 (46.6%) had progressive disease, and 2 (6.6%) had stable disease. Allo-HSCT was performed using peripheral blood as the stem cell source from full match siblings in 23 (76.6%) patients; fullmatch unrelated donor in 1 (3.3%); fullmatch related donor (except sibling) in 1 (3.3%); and un-related donors with 9/10 HLA compatible in 5 (16.6%). The median neutrophil engraftment time was 15 (11–23) days, and the median thrombocyte engraftment time was 13 (10–44) days. Primary or secondary graft rejection and moderate or severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) did not detected in any patients. Any grade of acute GVHD and chronic GVHD were found in 11 (36%) and 9 (30%) patients respectively. Grade 3/4 acute GVHD was observed 13.3%, and extensive chronic GVHD was found 16.6%.

Overall survival (OS) at 1, 2, 3 and 5 years post-transplant were 45%, 36.3%, 31.7% and 22.7% respectively (Fig. 1); TRM was 25.0% at 100 days. While the 5-year OS was 11.7% in the group with less than PR according to the pre-transplant disease status, it was found to be statistically significant as 45.8% in the group with CR or PR (p = 0.001). TRM was significantly higher in patients with less than PR compared has CR or PR at pre-transplantation (100% vs 43.7% p = 0.01). Like as these findings, PFS was shorter in patients with less than PR compared has CR or PR at pre-transplantation (6.2 vs 77.1 months, p = 0.01).

In the era of novel anti-myeloma agents, improved patient survival has been observed with the advent of autologous hematopoietic stem cell transplantation (auto-HSCT) followed by effective salvage therapies [8]. The current treatment of multiple myeloma (MM) involves corticosteroids, immunomodulatory drugs (IMIDs) (thalidomide, lenalidomide, pomalidomide) [9], proteasome inhibitors (bortezomib, carfilzomib) [10], target-specific molecules, and monoclonal antibodies. Apart from these, auto-HSCT in combination with high-dose chemotherapy is considered as the frontline strategy for fit MM patients [11]. Although patient’s response and survival rates have been dramatically increased by these therapies [12], most patients cannot persistently sustain response and the disease eventually relapses. Allo-HSCT may be considered a potential way of curing MM through its Graft Versus Myeloma (GvM) effect [13]. Allo-HSCT is a curative therapeutic option in many hematological disorders [14]. However, allo-HSCT has not been commonly used to treated MM patients owing to unsuitable donors, high risk of TRM, and development of GVHD for a couple of decades [15–17]. As allo-HSCT is associated with higher mortality and morbidity rates compared to auto-HSCT, it is still not considered a standard therapy at MM onset. As the myeloablative regimens used in allo-HSCT cause a very high mortality rate, they have become obsolete over time. A more commonly used system to reduce mortality is to perform allo-HSCT using reduced-intensity conditioning regimens.

Once in the 1990s, a high rate of TRM (± 40%) in allo-HSCT patients [4] non-myeloablative (NMA)/reduced-intensity conditioning (RIC) was developed in the 1990s to decrease the incidence of TRM as seen with myeloablative conditioning regimens. In a large EBMT analysis of 229 myeloma patients who received allo-HSCT with RIC regimens, the TRM at 1 year was 22% [18]. Our patients had 100-day TRM found to be 25%, although there were refractory patients who had previously received multiple lines of chemotherapy and previously had auto-HSCT. A large retrospective study indicated patients in CR at transplantation had lower risk of TRM than those in non-CR on multivariate analysis [19]. In our patients, when we divided the patients with CR or PR into a group and less than PR group according to their pre-transplant disease status, it was observed that all 7 patients with TRM in the first 100 days were less than PR (p = 0.01). This shows that the depth of response before allogeneic stem cell transplantation is effective on 100-day TRM in multiple myeloma patients. Another study found that the depth of response prior to allo-HSTC was a significant independent prognostic factor for both OS and PFS [20]. We likewise found longer OS and PFS in patients with complete response prior to allo-HSCT. According to the International Myeloma Study Group (IMWG), the expected 4-year OS with conventional treatments in newly diagnosed MM patients with high-risk characteristics is 33% [21]. Overall survival (OS) at 1, 2, 3 and 5 years after allo-HSTC in our patients was 45%, 36.3%, 31.7% and 22.7%, respectively.

VOD/ SOS is important complication during post-transplantation period. The review of 135 studies with VOD/ SOS prevalence and outgrowth data for post-HSCT cases set up that the absolute prevalence rates reported in individual studies ranged from 0 to 62 [22]. Still, other clinical factors, the use of reduced intensity conditioning (RIC) regimens, may reduce the threat, and VOD/ SOS treatment with the use of defibrotide has bettered survival [23]. In our series, moderate or severe hepatic VOD/ SOS wasn't detected.

Before the 2000s, allo- HSCT through graft versus- myeloma (GvM) effect was gradationally arising as an implicit way to cure MM [24]. Still, allo- HSCT couldn’t be extensively used to treat MM cases [25] due to unusable donors, high threat of TRM and the circumstance of GVHD during several decades. In a meta- analysis from 2007 to 2017, the frequentness of stage II- IV acute GVHD and chronic GVHD were 34 (95 CI 30–37) and 51 (95 CI 46–56) independently [19]. Analogous to the literature, acute GVHD of any grade was set up in 36 and chronic GVHD of any grade in 30 of our cases. Grade3/4 acute GVHD was observed 13.3, and expansive chronic GVHD was set up 16.6. The circumstance rate of TRM and GVHD has been reduced through advanced conservation strategies, better probative care, further suitable case selection and strategies for GVHD prophylaxis.

Allogeneic stem cell transplantation in Multiple Myeloma is still recommended within the scope of clinical trials as stated in the NCCN guidelines version 4.2022 multiple myeloma. It is thought that more patients and series from more centers should be included in the literature in order to discuss its place in routine recommendations.

The limitations of our study are the retrospective evaluation in a small number of patients and lack of cytogenetic data. However, we were able to reach some conclusion on still controversial issue.

Allo-HSCT may be a therapeutic option in MM patients that relapse/ refractory after auto-SCT, particularly after achieving the least partial response.

Authors have no conflict of interest.

Statement of Ethics

Informed consent was obtained from the patients for the publication.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contribution

H.B.A.O and Z.N.O wrote the main manuscript text and Z.N.O and Z.A.Y. prepared figures 1-2. and table 1. Z.N.O. made statistical analysis. H.B.A.O, L.A.K, A.A.D and F.C. entered data. All authors reviewed the manuscript.

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed Refractory Multiple Myeloma

Status:

Version 1

Abstract

Objectives

Material and Methods

Results

Conclusions

Figures

1. Introduction

2. Material and Methods

2.1. Statistical Analysis

3. Results

4. Discussion

5. Conclusion

Declarations

Statement of Ethics

Declaration of Competing Interest

Author Contribution

References

Additional Declarations

Status:

Version 1