Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016–2021)

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4–72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6–93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0–64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs. Supplementary Information The online version contains supplementary material available at 10.1007/s12185-024-03754-8.


Introduction
According to data from the Japan National Cancer Registry, there were 7130 newly diagnosed multiple myeloma (NDMM) patients in 2015, comprising 3736 males and 3394 females.4135 patients, consisting of 2030 males and 2105 females, passed away (1).The annual incidence rate of multiple myeloma gradually increased from 5.0 per 100,000 persons in 2010 to 6.0 in 2019 [1].The estimated 5-year overall survival (OS) rate between 2009 and 2011 was 42.8% [1].
Multiple novel anti-myeloma drugs, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), have been developed and approved by the Pharmaceuticals and Medical Devices Agency (PMDA) for the treatment of multiple myeloma (MM) patients under the coverage of the national health insurance system in Japan.Initially, bortezomib was approved in 2006 for the treatment of relapsed and/or refractory multiple myeloma (RRMM).Subsequently, thalidomide and lenalidomide were approved for RRMM in 2008 and 2010, respectively.Based on the pivotal phase 3 VISTA [2] and FIRST [3] trials, bortezomib and lenalidomide were further approved for the treatment of newly diagnosed multiple myeloma (NDMM) in 2011 and 2015, respectively.In subsequent years, pomalidomide, carfilzomib and elotuzumab, ixazomib and daratumumab, and isatuximab were, respectively, approved for the treatment of RRMM in 2015, 2016, 2017, and 2020.Notably, daratumumab was also approved for the treatment of NDMM in 2019 based on the primary analyses of phase 3 trials, namely, ALCYONE [4,5] and MAIA [6,7].
Although the Japan National Cancer Registry operated by the National Cancer Center and the hematologic diseases registry operated by the Japanese Society of Hematology Extended author information available on the last page of the article (JSH) exist, these registries do not gather sufficient data to conduct in-depth analyses of patient characteristics and outcomes.In 2015, Ozaki et al. provided a comprehensive overview of patient demographics and prognosis for Japanese multiple myeloma (MM) patients treated at hospitals where members of the Japanese Society of Myeloma (JSM) were employed [8].The study retrospectively collected and analyzed real-world data from two cohorts: the 1990-2000 cohort consisting of 1208 patients and the 2001-2012 cohort consisting of 2234 patients, in collaboration with the JSM [8].The analysis revealed a notable improvement in the 5-year overall survival (OS) rate, which increased from 31.2% in the 1990-2000 cohort to 50.3% in the 2001-2012 cohort.Furthermore, within the latter cohort, a subset of patients received treatment with novel drugs such as bortezomib, thalidomide, and lenalidomide, leading to a remarkable improvement in their prognosis.Since no national survey of Japanese MM patients has been conducted since the aforementioned report, we have undertaken a prospective collection and analysis of real-world data from the 2016-2018 cohort, in collaboration with the JSH, to elucidate the effects of novel anti-myeloma drugs.

Study design
The study described was a non-interventional, multicenter, prospective cohort study of the patients with plasma cell neoplasms (PCN) conducted in Japan, overseen by the Japanese Society of Hematology (UMIN000022099).The study adhered to the ethical principles outlined in the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research.The study protocol received approval from the institutional review boards (IRB) at all participating sites.

Patients and treatments
A total of 67 sites across Japan participated in this study.Patients who were diagnosed with PCN between January 2016 and December 2018 were registered and followed up until the end of December 2021, patient withdrawal, or death.The PCN group encompassed both symptomatic conditions (such as symptomatic multiple myeloma, nonsecretory multiple myeloma, multiple plasmacytoma, and plasma cell leukemia) and non-symptomatic conditions (such as monoclonal gammopathy of undetermined significance [MGUS], smoldering multiple myeloma, solitary plasmacytoma of bone, and extramedullary plasmacytoma), as per the diagnostic criteria of the International Myeloma Working Group (IMWG) [9,10].Patients with symptomatic PCN received treatment with drugs approved by the Pharmaceuticals and Medical Devices Agency (PMDA) based on the physician's discretion.

Endpoints
The primary endpoint of this study was the 3-year overall survival (OS) of newly diagnosed patients with symptomatic PCN who were treated with systemic chemotherapy.Secondary endpoints included progression-free survival (PFS), time to next treatment (TNT), treatment-free interval (TFI), and the best overall response rates (ORR) based on the International Myeloma Working Group (IMWG) uniform response criteria [11] as determined by the first-line treatment.The definitions of OS, PFS, TNT, and TFI can be found in Supplementary Method S1.

Statistical analysis
In the United States, where novel anti-myeloma drugs were widely utilized, the real-world data showed a 3-year OS rate of 70% [12].To achieve a 3-year survival rate with a 95% confidence interval (CI) range of less than 7%, a sample size of 800 patients with symptomatic PCN would be required.Accounting for non-symptomatic PCN and potential dropouts, the number of patients in this study was set at 1100.The analysis focused on patients diagnosed with symptomatic PCN who received treatment with anti-myeloma drugs, as well as patients initially diagnosed with non-symptomatic PCN at registration but progressed to symptomatic PCN requiring treatment during the study period.Baseline patient characteristics were summarized using descriptive statistics.PFS, OS, TNT, and TFI were estimated using the Kaplan-Meier method, and the 95% CI was calculated using the Greenwood formula.Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the association between OS or PFS and clinically significant baseline factors, providing hazard ratios (HR) and their corresponding 95% CI.All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Patient characteristics
Between January 2016 and December 2018, a total of 1951 patients with PCN were registered from 67 hospitals across Japan.After excluding 52 patients due to ineligibility or insufficient data, 1899 patients were included in the analysis.Among them, 1349 patients were diagnosed with symptomatic PCN and required some form of treatment, while the remaining 550 patients were initially diagnosed with nonsymptomatic PCN.During the study period, 59 patients with non-symptomatic PCN progressed to symptomatic PCN, with 36 of them experiencing this progression by December 2018.Therefore, a total of 1385 patients with symptomatic PCN (1349 plus 36) were analyzed in this report.Among these patients, 1274 were diagnosed with symptomatic multiple myeloma (MM), 14 with non-secretary MM, 70 with multiple plasmacytoma, and 27 with plasma cell leukemia (PCL) (Fig. 1).
In Table 1, the median age of the patients was 71 years (ranging from 33 to 96 years), and 1044 (75.4%) patients were 65 years or older.Female patients constituted 47.7% of the cohort.Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores were distributed as 78.1% for 0-2 and 21.9% for 3-4.Regarding the ISS, 20.1%, 35.8%, and 40.1% of patients were classified into stages 1, 2, and 3, respectively.The M-protein types were IgG in 55.9% of cases and non-IgG in 40.4%.Various symptoms were observed in the patients, with hypercalcemia in 13.0%, renal insufficiency in 25.3%, anemia in 61.4%, and bone diseases in 61.5% of cases.Accompanying symptoms such as AL amyloidosis, extramedullary tumors, and central nervous system (CNS) invasion were observed in 6.1%, 8.4%, and 0.6% of the patients, respectively.The distribution of Freiburg comorbidity index (FCI) scores [13] was as follows: 61.7% had an FCI of 0, 29.2% had an FCI of 1, 7.9% had an FCI of 2, and 1.1% had an FCI of 3.
In Table 2, we showed the clinical characteristics of the patients treated with and without autologous stem cell transplantation (ASCT).Nine-hundred and twenty-two patients received the initial induction therapy but did not undergo ASCT (non-ASCT-Group), while the remining 342 patients underwent ASCT within 1 year from the start of the initial induction therapy (ASCT-Group).The patients who received no initial induction therapies (n = 101), that who received an allogeneic transplant (n = 1), or those who underwent ASCT after 1 year from the start date of the initial therapy (n = 19) were not included in either group.The median ages (range) were 75 (37-92) in non-ASCT-G and 60 (33-73) in ASCT-G, respectively.91% and 31.9% of the patients of non-ASCT-G and ASCT-G were over 65 years.ECOG PS 0-2/3-4 in non-ASCT-G and in ASCT-G were 77.

Response rates
As first-line therapies, 604 patients received PI, 250 patients received a combination of PI and IMiD, 238 patients received IMiD alone, and 68 patients received conventional chemotherapies.Regarding overall response rates, including partial response (PR) or better and very good PR or better, the combination of PI and IMiD exhibited the highest rate (Fig. 3a).Notably, in both patient groups, those who received ASCT and those who did not receive ASCT, the combination regimens involving both PI and IMiD as the first-line therapy demonstrated better response rates compared to PI-based or IMiD-based regimens (Fig. 3b).Furthermore, ASCT-G showed higher rates of deeper responses represented by very good PR (VGPR) or better than non-ASCT-G regardless of the kinds of the induction regimens (Fig. 3b).
In the ASCT group, the median PFS was 53.4 months (95%CI 44.6-65.0),whereas in the non-ASCT group, it was   5 and 6 present the results of multivariable analysis.In the patient group who received ASCT, no factors were significantly associated with PFS.However, in the patient group who did not undergo ASCT, induction treatment with IMiD was associated with better PFS compared to conventional chemotherapy, with an HR of 0.70 (95%CI 0.50-0.97).As unfavorable prognostic factors, ISS 3 was found to be associated with poorer PFS compared to ISS 1, with an HR of 1.83 (95%CI 1.40-2.38)(Fig. 4c).In addition, the presence of extramedullary tumors was significantly associated with a worse PFS rate, with an HR of 1.87 (95%CI 1.42-2.46)(Fig. 4d).

Time to next treatment (TNT) and treatment free interval (TFI)
The median TNT for all symptomatic patients with PCN was 30.9 months with a 95% CI of 28.7 to 33.7 months.
The median TFI for all symptomatic PCN patients was 1.2 months with a 95% CI of 1.0 to 1.4 months.Among patients who received ASCT, the median TFI was 2.8 months (95%CI 2.1-8.8),while for those who did not receive ASCT, it was 1.0 month (95%CI 0.8-1.1)(data not shown).

Discussion
In this prospective observational study conducted in Japan from 2016 to 2018, the overall survival (OS) rate of patients with PCN was found to be 70.0%at 3 years.This OS rate Furthermore, the Mayo Clinic study also showed that the 3-year OS rate was 77% in patients receiving one of the novel drugs, such as thalidomide, lenalidomide, or bortezomib, as their initial therapy, compared to 67% in patients who did not receive these drugs.Similarly, in our cohort, until the approval of daratumumab for newly diagnosed MM in 2019, only bortezomib and lenalidomide among the novel drugs were approved for the patients with newly diagnosed MM.As a result, approximately 94% of the patients in our cohort received bortezomib and/or lenalidomide as their initial therapy, which contributed to achieving similar outcomes to that of the Mayo Clinic cohort in the 2006-2010 period.This study clearly demonstrates that the use of novel drugs has significantly improved the outcomes of Japanese patients with PCN.
The previous retrospective study of the real-world outcomes of Japanese patients with symptomatic MM reported by S. Ozaki et al. showed that the 3-year OS rates improved from 55% in the 1990-2000 cohort to 70% in the 2001-2012 cohort [8].They also demonstrated that the 3-year OS rates were 70% in the patients receiving the novel drugs and 58% in the patients receiving the conventional chemotherapies alone in 2001-2012 cohort.In our current prospective study (2016-2018 cohort), we found a 3-year OS rate of 70.0% for patients with symptomatic PCN who received any kinds of treatment.Although there were differences in the median age (67 years and 71 years, respectively) and rates of patients receiving ASCT (32.3% and 27.1%, respectively) between the previous study and our current study, the 3-year OS rates at 3 years were similar.However, it is important to note that our current study enrolled patients prospectively from various kinds of hospitals, including those with general hematologists belonging to the Japanese Society of Hematology (JSH), representing a broader real-world population of symptomatic PCN patients.Based on this perspective, our current study's findings suggest that the real-world outcomes of MM treatment have continued to improve further in 2016-2018 compared to the previous period (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012).This improvement may be attributed to the wider availability and use of novel drugs in the treatment of symptomatic PCN patients during this study period.
Our study showed that the OS, PFS rates and TNT of patients who received ASCT showed better outcome.clinical trials will continue to shape the treatment landscape for MM patients, and the role of upfront ASCT will be better understood in the context of novel drug therapies and patient selection criteria.This study has revealed valuable insights into the factors influencing OS and PFS in patients with PCN, particularly those who did or did not receive upfront ASCT.Currently, upfront ASCT is one of the alternative choices for the patients aged 65-70 years as reported by a retrospective study conducted by Japanese Society of Myeloma and European Myeloma Network [16].However, this study showed in patients who received upfront ASCT, the primary factor affecting OS was age.Specifically, the study found that patients aged 65 or older had an unfavorable OS, highlighting the need for careful patient selection when considering upfront ASCT, especially in elderly patients.This finding emphasizes the importance of considering age-related factors and potential treatment-related risks when deciding on treatment strategies for older MM patients.Conversely, in patients who did not receive ASCT, several risk factors were associated with unfavorable outcomes, including the treatment regimen of conventional chemotherapies, ISS stages 2/3, the presence of extramedullary tumors, and FCI stages 2/3.These factors did not include age in the group of patients who did not receive ASCT, indicating that other clinical factors play a more significant role in predicting OS in this subgroup.The study's findings have important implications for clinical decision-making, especially when considering upfront ASCT as an alternative treatment choice for elderly patients, particularly those aged at 65 or older.The results underscore the need for a personalized and comprehensive assessment of individual patient characteristics, including age, comorbidities, disease stage, and treatment response, when determining the appropriateness of upfront ASCT.This approach ensures that the potential benefits of ASCT are balanced against the individual patient's overall health status and potential risk factors.
It was confirmed that the use of novel drugs, particularly bortezomib and lenalidomide, as initial therapies has led to better ORR and improved OS compared to conventional chemotherapies in non-ASCT group.This improvement is noteworthy, even though the number of patients treated with conventional chemotherapies was limited.Among the novel drug options, the combination of bortezomib and lenalidomide emerged as particularly effective, as evidenced by the highest ORR and a deeper response with VGPR or higher.In non-ASCT group, it was observed that factors such as ISS stage 3 and the presence of extramedullary tumors were associated with unfavorable OS and PFS even in the era of novel drugs.This suggests that the current treatment approaches with bortezomib and/or lenalidomide may not be sufficient for these specific high-risk TIE patients.This highlights the need for alternative treatment strategies, such as incorporating daratumumab-containing therapies, such as D-MPB or D-Ld, which have shown more favorable results in the context of high-risk MM patients.In addition, the study's findings emphasize that it's not just chronological age, but comorbidities, that significantly influence OS in TIE patients.This suggests that older patients who are otherwise fit and without significant comorbidities can still benefit from bortezomib and/or lenalidomide-based regimens.Individualized treatment decisions based on a patient's overall health status, beyond just age, are crucial for optimizing outcomes.While the study did not conduct a multivariable analysis for baseline prognostic factors related to FISH analyses due to the small number of patients, the mention of high-risk cytogenetics (such as t(4;14), t(14;16), or del(17p)) aligns with previous reports that these cytogenetic abnormalities can negatively impact both PFS and OS [17,18].This underscores the importance of developing novel immune-based therapies, such as chimeric antigen receptor-T (CAR-T) cell therapy and bispecific antibodies, to address these high-risk cases and further improve treatment outcomes [19,20].Overall, this study identifies several areas where additional research and novel therapeutic approaches are needed to address the specific challenges faced by highrisk TIE patients with MM.This underscores the ongoing unmet need to improve treatment strategies for this patient population.
It's clear that while this study provides valuable insights into the outcomes of patients with PCN, there are certain limitations that should be considered.One significant limitation is the lack of comprehensive safety data beyond the occurrence of second primary malignancies.Detailed safety data, adverse events, and the relative dose intensities of the drugs used could provide a more complete picture of the treatment landscape and potential challenges faced by patients.The observational nature of this study, with treatment decisions being based on physicians' choice and the availability of national health insurance, introduces variability in the treatments and examinations received by patients.This variability can impact the comprehensiveness of data collected, such as the limited availability of baseline chromosomal analysis like FISH, which in turn affects the ability to conduct multivariable analyses.Despite these limitations, the study's reliance on real-world data collected from a national survey is still highly valuable.This type of data is particularly important in rapidly evolving fields like multiple myeloma, where treatment strategies are continually changing due to the emergence of new therapies.Real-world data can provide insights into the effectiveness of these treatments in actual clinical practice, and it also enables international comparisons.The commitment to continuing this type of survey in collaboration with the Japanese Society of Hematology demonstrates a dedication to advancing the understanding of plasma cell neoplasms and improving patient outcomes.The approach of using real-world data to identify unresolved clinical questions and guide future research is an essential step toward refining treatment strategies and ultimately enhancing the prognosis of patients with these conditions.

Fig. 2
Fig. 2 Survival curves of the symptomatic PCN patients who needed any kinds of treatments (n = 1284) are shown.a Three-year overall survival (OS) rate was 70.0% (95%CI 67.4-72.6%).The median OS period was 69.3 months (95%CI 67.1-NE).b Three-year OS rates of the patients who received upfront ASCT (n = 342, blue line) and

Fig. 3
Fig. 3 Best responses according to the first line therapies are shown.a All patients, b patients who received upfront ASCT (ASCT) and those who did not receive ASCT (non-ASCT)

Table 1
Clinical characteristics of MM patients enrolled in this studya Most of the patients whose M protein typing was not conducted by immunofixation or immuno-electrophoresis possessed measurable levels of free light chains of abnormal kappa/lambda ratios

Table 2
Clinical characteristics of MM patients with and without autologous stem cell transplantation Patients who received no initial treatment (n = 101), that who received an allogeneic stem cell transplant (n = 1), or those who received an autologous transplant after 1 year of initial treatment (n = 19) were not included in either group a Patients who received initial induction therapy without any transplant b Patients who underwent autologous stem cell transplant within 1 year of initial induction therapy

Table 3
Univariable and multivariable analyses for OS in MM patients receiving ASCT Each cytogenetic abnormality was not applied for multivariable analysis, as it was examined only in a fraction of the patients ISS: International Staging System; CA: chromosomal abnormalities; FCI: Freiburg Comorbidity Index; HR: hazard ratio; CI: confidence interval a ISS stage 1 is reference category b FCI 0 is reference category IMiD: immunomodulatory drug; PI: proteasome inhibitor: ISS: International Staging System; CA: chromosomal abnormalities; FCI: Freiburg Comorbidity Index; HR: hazard ratio; CI: confidence interval a ISS stage 1 is reference category b FCI 0 is reference category

Table 5
Univariable and multivariable analyses for PFS in MM patients receiving ASCT Each cytogenetic abnormality was not applied for multivariable analysis, as it was examined only in a fraction of the patients IMID: immunomodulatory drug; PI: proteasome inhibitor: ISS: International Staging System; CA: chromosomal abnormalities; FCI: Freiburg Comorbidity Index; HR: hazard ratio; CI: confidence interval a ISS stage 1 is reference category

Table 6
Univariable and multivariable analyses for PFS in MM patients not receiving ASCTEach cytogenetic abnormality was not applied for multivariable analysis, as it was examined only in a fraction of the patients IMiD: immunomodulatory drug; PI: proteasome inhibitor; ISS: International staging system; CA: chromosomal abnormalities; FCI: Freiburg Comorbidity Index; HR: hazard ratio; CI: confidence interval a ISS stage 1 is reference category b ECOG PS 0-1 is reference category c FCI 0 is reference category