Single Vs. Tandem Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Real-World Multi-Center Study from the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy (DRST)

Introduction

Autologous stem cell transplantation (ASCT) after high dose chemotherapy achieves high response rates and is a standard of care for eligible newly diagnosed multiple myeloma (NDMM) patients (pts). Tandem transplantation regimes are guideline-recommended for pts who do not achieve at least very good partial response (VGPR) after the first ASCT or for those with high-risk features. However, multiple studies with conflicting results have been published. In addition, most studies comparing transplantation regimen were conducted before the advent of modern induction therapies. To study which patient cohorts benefit from a tandem ASCT, we analyzed a large dataset of the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy (DRST) including 12763 NDMM pts from 94 centers between 1998 and 2021.

Methods

Event free survival (EFS) was defined as the time from first ASCT to either progressive disease, relapse or death. Overall survival (OS) was calculated as the time between first ASCT and death. The chi-squared test was performed for categorical and the Kruskall-Wallis test for continuous variables when comparing patient characteristics. The Kaplan-Meier method was used to calculate survival probabilities and the log-rank test was applied for subgroup comparison. We accounted for immortal time bias when comparing transplantation strategies with a landmark analysis that excluded pts who did not have an EFS or OS of at least six months after initial diagnosis. Multivariable Cox regression analysis was performed on EFS and OS for single and tandem transplantation regimes. P-values <0.05 were considered statistically significant.

Results

We included n=6581 pts who underwent single ASCT and n=4027 with tandem ASCT. Additionally, pts who received a following ASCT or an allogeneic transplantation after the first 6 months of the first ASCT were also considered as single ASCT (n = 1744 and n = 411, respectively). When stratifying for treatment eras, there was a shift in transplantation practices, with tandem ASCT becoming less common in recent years (47.4% before 2008 to 25.7% in 2017-2021, p<0.001). In terms of responses, the proportion of pts in complete remission (CR) after induction therapy was notably higher in recent years, with 7.4% between 1998 and 2007 compared to 13% after 2017 (p<0.001), as was the fraction of pts achieving CR after the first ASCT, with 20.5% before 2008 compared to 32.3% after 2017 (p<0.001).

The multivariable analyses identified several factors associated with reduced OS and EFS across both transplantation strategies, including higher age at transplantation, presence of t(4;14) aberration, ISS III, IgA heavy chain, and initial diagnosis in earlier time periods. NonCR status following the initial ASCT was associated with poorer OS and EFS among pts undergoing single ASCT (HR 1.5, 95% CI 1.2-1.86, p < 0.001 and HR 1.31, 95% CI 1.14-1.51, p < 0.001, respectively). Next, we compared single with tandem ASCT independently from other characteristics and found no significant differences in pts who achieved CR after the first transplantation compared to others (p=0.66 for OS, p=0.21 for EFS). However, a significant benefit in OS was noted in pts receiving tandem ASCT who did not achieve CR after the initial ASCT (p<0.001). The significant benefit of tandem over single ASCT was also seen in pts who did not achieve CR after induction therapy (p<0.001). Notably, there was no significant benefit in OS or EFS for tandem transplantation in pts who transitioned from nonCR to CR through the first ASCT (p=0.44 and p=0.1, respectively).

We further analyzed the impact based on ISS and renal impairment, which were significantly associated (p<0.001). Only 3.3% of pts with ISS stage I had high serum creatinine levels, whereas 42.1% of those with ISS stage III had a renal impairment. When comparing transplantation regimes in OS we found a significant benefit for those pts with ISS I and no renal impairment (p = 0.026). In contrast, results show significantly better OS for pts with ISS III and renal impairment who underwent single ASCT (p=0.011).

Conclusion

We demonstrate that patients who did not achieve CR after induction therapy or initial ASCT benefited from a second ASCT. In contrast, patients with ISS III and renal impairment experienced poorer outcomes compared to those who underwent a single ASCT regime.

Oeser:Janssen-Cilag: Research Funding. Sauer:Janssen: Honoraria, Other: travel expenses; Bristol Myers Squibb: Honoraria; Amgen: Honoraria, Other: travel expenses, Research Funding; Sanofi: Honoraria, Other: travel expenses. Goldschmidt:Molecular Partners: Research Funding; MorphoSys AG: Research Funding; Pfizer: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Karyopharm: Research Funding; Incyte Corporation: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Hoffmann-La Roche: Research Funding; Heidelberg Pharma: Research Funding; GlycoMimetics Inc.: Research Funding; GlaxoSmithKline (GSK): Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Novartis: Honoraria, Other: Support for attending meetings and/or travel, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; Celgene: Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product; support for attending meetings and/or travel, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; grants and/or provision of Investigational Medicinal Product, Research Funding; Takeda: Research Funding; Array Biopharma/Pfizer: Other: Grants and/or provision of Investigational Medicinal Product; Bristol Myers Squibb/Celgene: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar Hopp Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Mundipharma GmbH: Other: Grants and/or provision of Investigational Medicinal Product. Salwender:Pfizer: Honoraria; Oncopeptides: Honoraria; Sanofi: Honoraria, Other: Travel grant; Janssen: Honoraria, Other: Travel grant; Stemline: Honoraria; Roche: Honoraria; Takeda: Honoraria; Chugai: Honoraria; GlaxoSmithKline: Honoraria; Bristol Myers Squibb/Celgene: Honoraria, Other: Travel grant; Amgen: Honoraria, Other: Travel grant; AbbVie: Honoraria; Sebia: Honoraria. Fenk:GlaxoSmithKline (GSK): Other: travel expenses; Janssen: Honoraria, Other: travel expenses; BMS/Celgene: Honoraria, Other: travel accommodation and expenses; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Engelhardt:Janssen, BMS, Sanofi, Takeda, Pfizer: Consultancy; Janssen, BMS, Sanofi, Pfizer: Honoraria; Janssen: Research Funding. Zeiser:Sanofi: Honoraria; Mallinkrodt: Consultancy, Honoraria; Medac: Honoraria; Incyte: Consultancy, Honoraria; Neovii: Consultancy; Ironwood Pharmaceuticals, Inc.: Consultancy; Novartis: Consultancy, Honoraria. Vucinic:Gilead/Kite, Janssen, BMS Celgene, Novartis: Consultancy, Honoraria; Amgen: Honoraria, Other: Travel grant. Einsele:Sanofi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kull:Pfizer: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Besemer:GlaxoSmithKline: Honoraria; Pfizer: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AMGEN: Honoraria. Kröger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Neovii: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Therakos: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; DKMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Provirex: Consultancy. Platzbecker:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding. Merz:Amgen, BMS, Celgene, Gilead, Jannsen, Stemline, SpringWorks and Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.