The impact of daratumumab pretreatment on multiple myeloma patients undergoing autologous transplantation

doi:10.21203/rs.3.rs-3605104/v1

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The impact of daratumumab pretreatment on multiple myeloma patients undergoing autologous transplantation

https://doi.org/10.21203/rs.3.rs-3605104/v1

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The anti-CD38 antibody daratumumab (Dara) has been reported to improve the prognosis of multiple myeloma (MM) patients, but its use before autologous stem cell transplantation (ASCT) remains controversial. To clarify the prognostic impact of Dara before ASCT on MM, we performed a retrospective observational analysis.

We analyzed 2,626 patients who underwent ASCT between 2017 and 2020. In the comparison between patients not administered Dara (Dara- group) and those administered Dara (Dara + group), the 1-year progression-free survival (1-year PFS) rates were 87.4% and 77.3% and the 1-year overall survival (1-year OS) rates were 96.7% and 90.0% in the two groups, respectively. In multivariate analysis, age < 65 years (p = 0.015), low ISS stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.037) and good treatment response before ASCT (p < 0.001) were independently associated with superior PFS. In matched pair analysis, the PFS/OS of the Dara- group were also significantly superior. For MM patients who achieved complete or very good partial response (CR/VGPR) by Dara addition before ASCT, both PFS and OS significantly improved. However, in patients who did not achieve CR/VGPR before ASCT, the PFS/OS of the Dara + group were significantly inferior to those of the Dara- group.

Health sciences/Medical research/Translational research

Biological sciences/Cancer/Haematological cancer/Myeloma

multiple myeloma

autologous stem cell transplantation

daratumumab

prognosis

The development of new drugs for multiple myeloma (MM), such as proteasome inhibitors, immunomodulatory drugs, and particularly monoclonal antibodies, has dramatically improved the overall survival (OS) of patients with MM^1,2. Even in the modern era, however, autologous stem cell transplantation (ASCT) remains the mainstay for transplant-eligible MM patients^3–5. In previous studies, we demonstrated that the overall survival of patients with MM after ASCT has improved over time along with the introduction of new drugs for the treatment of MM^6,7. However, most of the data used in those analyses were derived from the era before monoclonal antibodies, particularly daratumumab (Dara), were available^8–10.

Several clinical studies have recently examined the administration of Dara-containing regimens before ASCT^11–14. Although favorable results of receiving Dara before ASCT have been reported^11–14, still there is a debate regarding the usefulness of Dara before ASCT¹⁵. For example, it has been reported that the neutrophil or platelet recovery after ASCT could be delayed by the prior use of Dara¹⁶, and delayed platelet recovery has a negative impact on the prognosis of MM¹⁷.

To better clarify the impact of pretreatment with Dara before ASCT on the prognosis of MM, we here conducted a retrospective observational analysis using the Transplant Registry Unified Management Program (TRUMP) database of the Japanese Society for Transplantation and Cellular Therapy (JSTCT).

2.1. Data source and patients

We analyzed the TRUMP database, which includes physician-reviewed data and yearly follow-ups^18,19. This study was approved by the Data Management Committee of the JSTCT and the Kyoto University Hospital institutional review board (approval no. R1437).

The database cases included 2,626 patients (1,493 men and 1,133 women) with a median age of 61 (range 27–76) years who were treated with a bortezomib-based regimen with lenalidomide and underwent ASCT after treatment with high-dose melphalan (200 mg/m²) for newly diagnosed symptomatic MM; we included the patients who underwent ASCT in Japan between January 2017 and December 2020. We divided the patients into two groups according to the use of Dara treatment before ASCT. We excluded the patients with a prior history of allogeneic stem cell transplantation or ASCT. No patients received isatuximab (another type of CD38 antibody) treatment before ASCT in this cohort. All the patients were diagnosed with MM based on institutional assessment.

Responses to treatment were assessed based on the European Group for Blood and Marrow Transplantation criteria and the international uniform response criteria for multiple myeloma²⁰. We classified the patients into two categories by referring to the International Myeloma Working Group consensus²¹: unfavorable cytogenetic abnormality and not-unfavorable cytogenetic abnormality. The category of unfavorable cytogenetic abnormality included patients with deletions 17p, t (4;14), and t (14;16).

2.2. Statistical analyses

The primary endpoint of this study was the progression-free survival (PFS) of MM patients with or without Dara treatment (Dara + or Dara- group) before ASCT. The secondary endpoint was the overall survival (OS) of the two groups. The distributions of categorical and continuous variables of the two groups were compared using Pearson's chi-squared test and the Kruskal-Wallis test, respectively. The PFS and OS were calculated from the time of the ASCT until the date of progression, death by any cause, or last contact. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used for comparisons among groups. The Cox proportional hazards model was used to calculate the hazard ratios (HRs) of each variable along with the 95% confidence interval (CI). The clinical outcomes of the Dara + group and the Dara- group were compared by a matched pair analysis (1 to 5 ratio) using the Mantel–Haenszel test to match data from the two groups based on the age at ASCT, international staging system (ISS) stage at diagnosis and cytogenic abnormalities. All statistical analyses were performed using the EZR (ver. 1.54) software package (Saitama Medical Center/Jichi Medical University, Saitama, Japan) along with a graphical user interface for the R software package (ver. 4.0.3; The R Foundation for Statistical Computing).²² P-values < 0.05 were considered significant in all analyses.

3.1. The PFS and OS of the MM patients with or without the use of Dara treatment before ASCT

The characteristics of patients are summarized in Table 1. We divided the patients into two groups according to whether they did or did not use Dara before ASCT (Dara + group: 162 patients (6.2%); Dara- group: 2464 patients (93.8%)). There were no significant differences between the two groups in regard to patient age at ASCT, gender, performance status (PS) at ASCT, ISS categorization at diagnosis, and MM type of heavy or light chain (Table 1). However, the following characteristics differed significantly between the two groups: cytogenic abnormalities, the interval between the diagnosis and ASCT, and the follow-up period of survivors (Table 1). The median interval from the diagnosis of MM to ASCT was 210 days in the Dara + group and 275.5 days in the Dara- group. The median follow-up times of the survivors in the Dara- and Dara + groups were 680 days and 405 days, respectively.

We compared the PFS and OS of the Dara- group and Dara + group and found that the PFS and OS of the Dara- group were significantly superior to those of the Dara + group (Fig. 1A-B; p = 0.006 and p < 0.001, respectively). The 1-year PFS rates of the Dara- and Dara + groups were 87.4% (95%CI:85.9–88.7) and 77.3% (95%CI: 62.9–83.4), respectively, and the 1-year OS rates of the Dara- and Dara + groups were 96.7% (95%CI: 95.9–97.4) and 90.0% (95%CI: 83.2–94.1), respectively.

The other factors associated with superior PFS in the univariate analysis were age < 65 years at the time of ASCT (p = 0.010), low ISS stage (p < 0.001), good performance status (p = 0.046), absence of unfavorable cytogenic abnormalities (p < 0.001), and obtaining complete response (CR) or very good partial response (VGPR) before ASCT (p < 0.001; Table 2). When we performed the univariate analysis for OS, the following factors showed superior OS: age < 65 years at the time of ASCT (p = 0.029), female gender (p = 0.048), low ISS stage (p < 0.001), good performance status at ASCT (p = 0.032), absence of unfavorable cytogenic abnormalities (p < 0.001), and obtaining CR or VGPR before ASCT (p = 0.003; Table 3).

Next, we performed a multivariate analysis of PFS and OS in relation to all the baseline factors. The factors that were independently associated with superior PFS were age < 65 years (p = 0.015), low ISS stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.037) and a good treatment response before ASCT (p < 0.001, Table 2). The factors that were independently associated with superior OS were age < 65 years (p = 0.033), low ISS stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.007) and good treatment response before ASCT (p < 0.001, Table 3). These results demonstrated that the use of Dara before ASCT was associated with a worse prognosis independently of the traditional risk factors (such as older age, high ISS stage, unfavorable cytogenetic abnormalities, and poor pre-ASCT response).

3.2. Comparing the clinical outcome of the Dara + and Dara- groups by a matched pair analysis

To further clarify the impact of receiving Dara before ASCT, we performed a matched pair analysis (1 to 5 ratio) by matching the following factors between the two groups: the age of ASCT, international staging system (ISS) stage at diagnosis, and cytogenic abnormalities (Table S1 and S2). The PFS and OS of the Dara- group were still significantly superior to those of the Dara + group in this matched pair analysis (p = 0.011 and p = 0.004, significantly; Figure S1A-B). As the disease status before ASCT had an impact on the prognosis after ASCT, we compared the PFS and OS of the Dara- and the Dara + groups according to the disease status before ASCT treatment (Fig. 1C-F). The PFS and OS of the patients who had achieved CR or VGPR before ASCT did not change between the Dara- and Dara + groups (Fig. 1C-D). However, the PFS and OS of the patients who had only achieved a partial response (PR) or stable disease (SD) to progressive disease (PD) before ASCT were significantly superior in the Dara- group to those in the Dara + group (p = 0.050 and p < 0.001, respectively; Fig. 1E-F).

We then divided the patients into two groups according to the interval between the day of diagnosis and the day of ASCT: less than 6 months and 6 months or more. The PFS of the Dara- group was not different from that of the Dara + group with the patients who had received ASCT within 6 months after the diagnosis (Figure S2A). However, the PFS of the Dara- group was significantly superior to that of the Dara + group with the patients who had taken 6 months or longer to receive ASCT after the diagnosis (p = 0.007; Figure S2B). When we compared the pre-ASCT response, CR and VGPR rates in the Dara + group were higher in the patients who had received ASCT within 6 months after the diagnosis compared to the patients who had received ASCT 6 months or later after the diagnosis (71.5% and 58.3%, respectively; Fig. 2A). The CR and VGPR rates in the Dara- group were similar between the patients who had received ASCT within 6 months after the diagnosis and the patients who had received ASCT 6 months or later after the diagnosis (63.1% and 56.9%, respectively; Fig. 2B). Finally, we performed an additional analysis of the OS from the day of diagnosis instead of the day of ASCT and found that the OS of the patients who had only achieved PR or SD to PD was significantly superior in the Dara- group compared to the Dara + group (Figure S3A-B).

Collectively, our results showed that MM patients who obtained CR or VGPR by treatment with Dara before ASCT had significant improvements in both PFS and OS (Figure S4A-B).

In Japan, MM patients who are eligible for ASCT are first treated with bortezomib, lenalidomide, and dexamethasone or bortezomib-containing regimens, recommended by the practical guidelines for hematological malignancy, Japanese Society of Hematology³. None of the patients have received daratumumab as a first-line treatment in this cohort. Here, we demonstrated that the prognosis of the Dara- group was superior to that of the Dara + group. This result might seem to contradict previous studies that demonstrated the usefulness of Dara administration before ASCT^11–14. However, the situation in our study was distinct from that in previous studies. In our study, the patients who could not obtain a sufficient response by the induction therapy were included in the Dara + group. Therefore, our results indicate that MM patients who can obtain CR or VGPR by Dara treatment before ASCT will exhibit significant improvement in both PFS and OS. On the other hand, in MM patients who can not achieve CR or VGPR by Dara treatment before ASCT, treatment with Dara will result in significantly inferior PFS and OS. These results could be interpreted as meaning that a better response before ASCT led to an improvement of the prognosis after ASCT. Indeed, the importance of pre-ASCT response for the prognosis post-ASCT has been reported by others ²³.

Several points are different between our study and the previous studies. First, the backgrounds of enrolled patients were different. Dara was used for newly diagnosed MM patients in the GRIFFIN and CASSIOPEIA studies^13,14. On the other hand, Dara was used as a second or later line of treatment in our retrospective analysis. Second, the pre-ASCT responses seen in the GRIFFIN and CASSIOPEIA studies were superior to the pre-ASCT response in our cohort. Third, the OS of our total cohort was inferior to the OS of the GRIFFIN and CASSIOPEIA studies. This might indicate that more treatment-resistant cases were included in our study compared to the GRIFFIN and CASSIOPEIA studies. Although there are differences between the previous studies and our cohort, our study indicates that the patients who will benefit from Dara treatment before ASCT as a second or later-line therapy are those who achieve VGPR or CR before ASCT.

When we compared the PFS of patients who had received ASCT 6 months or later after the diagnosis, the PFS of Dara + patients was inferior to that of Dara- patients. However, the PFS of patients who had received ASCT within 6 months after the diagnosis was not significantly different between Dara + and Dara- patients. As the CR and VGPR rate in the Dara + group were higher in the patients who had received ASCT within 6 months after the diagnosis compared to the patients who had received ASCT 6 months or later after the diagnosis (Fig. 2A), it may be that changing the treatment to a Dara-containing regimen at an earlier time point would lead to an improvement of the prognosis after ASCT.

There are several limitations in this study. First, this was a retrospective observation study in which the individual physicians decided on the treatment. We could not know the reasons why the physicians had chosen to use Dara before ASCT. Therefore, a potential selection bias for choosing Dara treatment before ASCT could not be ruled out. We adapted matched pair analysis to align the background factors between the Dara- group and the Dara + group, but it will also be necessary to confirm our results with other cohorts. Second, as the interval between the day of diagnosis and the day of ASCT was longer in the Dara + group compared to the Dara- group, more patients with initial treatment resistance may have been included in the Dara + group. Because it was technically difficult to extract the patients with initial treatment resistance from the database, we used the pre-ASCT response as a factor to infer resistance to treatment. Also, we could not compensate for the longer interval from the diagnosis to ASCT in the Dara + group. Therefore, we performed an additional analysis in which the OS was calculated from the day of diagnosis instead of the day of ASCT, but the results were the same as using the standard OS. Third, the lack of information regarding post-ASCT treatment prevented us from analyzing whether Dara or other specific treatments after ASCT could affect the prognosis of MM patients. Fourth, as this was a retrospective observation study, we do not know whether we could change the prognosis of MM patients by adding further treatments before ASCT to improve the disease status before ASCT.

Despite these limitations, we demonstrated that the PFS and OS of the patients who could only achieve PR or SD to PD before ASCT in the Dara + group were significantly inferior to those of the patients in the Dara- group. However, for the MM patients who could obtain CR or VGPR by Dara treatment before ASCT, both the PFS and OS were significantly improved.

Financial disclosure: This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development (Grant 18ek0510023h0002).

Acknowledgments:

This study was conducted with the support of the MM working group in JSTCT.

Ethical approval:

All procedures performed in this study involving the patient were in accordance with the ethical standards of Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (approval no. R1437) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The informed consent from the patient was obtained by the physicians in each institution.

Disclosure Statement

All the authors declare no conflicts of interest except K. Suzuki, T. Kikuchi, N. Tsukada, S. Kako, S. Ota, K. Kataoka, M. Sawa, and Y. Kanda received an honorarium from Janssen Pharmaceutical K.K. and Y. Atsuta received lecture fee from Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical CO., Ltd., Novartis Pharma KK, and AbbVie GK. and honorarium from Meiji Seika Pharma Co, Ltd. and a consultant fee from JCR Pharmaceuticals Co., Ltd. and Kyowa Kirin Co., Ltd.

Author contributions

Yutaka Shimazu: Conceptualization; methodology; formal analysis; writing-original draft. Junya Kanda: Methodology; formal analysis; writing-reviewing and editing. Kazuhito Suzuki, Akinori Wada, Taku Kikuchi, Takashi Ikeda: Methodology; formal analysis; writing-reviewing and editing. Nobuhiro Tsukada, Akiyoshi Miwa, Mitsuhiro Itagaki, Shinichi Kako, Kaichi Nishiwaki, Shuichi Ota, Shin-ichiro Fujiwara, Keisuke Kataoka, Noriko Doki, Masashi Sawa, Nobuhiro Hiramoto, Akinori Nishikawa, Toshi Imai, Tatsuo Ichinohe, Yoshinobu Kanda, Yoshiko Astuta and Koji Kawamura: Data collection; writing-reviewing and editing.

Data availability statement

The data of this study are not publicly available due to ethical restrictions that exceed the scope of the recipient/donor’s consent for research use in the registry.

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Tables 1-3 are available in the Supplementary Files section.

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The impact of daratumumab pretreatment on multiple myeloma patients undergoing autologous transplantation

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Abstract

Figures

1. Introduction

2. Subjects and methods

2.1. Data source and patients

2.2. Statistical analyses

3. Results

3.2. Comparing the clinical outcome of the Dara + and Dara- groups by a matched pair analysis

4. Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

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