Первичная линия Daratumumab, линалидомид и дексаметасон у пациентов старше 80 Годы с недавно диагностированной множественной миеломой: износостойкость лечения, инфекционные осложнения и пищевая уязвимость.

Introduction

Multiple myeloma (MM) predominantly affects older adults; however, despite recent therapeutic advances, the management of patients aged > 80 years remains challenging because of heterogeneity in the physiologic reserve, frailty, and tolerance to continuous therapy.

In transplant-ineligible newly diagnosed MM (Ti-NDMM), the combination of daratumumab, lenalidomide (LEN), and dexamethasone (DEX) (DRd) has been established as a frontline regimen based on results from the MAIA trial [ 1 ] and is widely used owing to the favorable efficacy and tolerability profile. Long-term follow-up of the MAIA trial has demonstrated sustained progression-free survival (PFS) and overall survival (OS) benefits with DRd, including in patients aged ≥ 80 years [ 2 ]. However, the applicability of these findings to the highly heterogeneous very elderly population encountered in routine practice remains uncertain. Furthermore, frailty subgroup analyses of the MAIA trial has suggested that the relative benefit of DRd is attenuated in frail patients, partly because of more frequent early treatment discontinuation [ 3 ]. These findings highlight the importance of identifying patients at risk of early treatment interruption; however, the factors contributing to treatment interruption during frontline DRd therapy remain unclear.

Treatment durability is particularly important in very elderly patients with MM because many have limited opportunities to receive subsequent lines of therapy. Real-world studies have suggested that a substantial proportion of very elderly patients do not proceed to second-line treatment [ 4 ], underscoring the importance of maintaining frontline therapy. In clinical practice, infectious complications may substantially compromise the treatment continuation in vulnerable very elderly patients [ 5 ]. However, factors associated with treatment durability in very elderly patients receiving DRd remain poorly understood.

Frailty assessment has become an integral component of risk stratification in elderly patients with MM, because frailty is associated with treatment-related toxicity, treatment discontinuation, and poor survival outcomes [ 6 , 7 ]. However, older adults with MM represent a highly heterogeneous population, and conventional frailty assessment tools may provide limited discrimination among very elderly patients. Furthermore, recent prospective geriatric assessment studies have demonstrated variability in frailty classification across assessment methods, highlighting the need for complementary markers of clinically meaningful vulnerability [ 8 ]. Among these markers, nutritional and immunologic indices may provide additional prognostic information. The Prognostic Nutritional Index (PNI) and Geriatric Nutritional Risk Index (GNRI) have been associated with survival outcomes in MM and reflect nutritional and immunologic vulnerabilities beyond conventional frailty assessments [ 9 , 10 ]. However, the clinical relevance of these nutritional indices in patients aged > 80 years who receive DRd remains unclear. Therefore, we retrospectively investigated patients aged > 80 years with Ti-NDMM who received frontline DRd, to evaluate real-world outcomes and explore the factors associated with the treatment durability, particularly infectious complications and baseline nutritional vulnerability.

Materials and methods

Study design and patients

This retrospective, single-center study was conducted at Kitasato University Hospital. Consecutive patients aged > 80 years with Ti-NDMM diagnosed between December 1, 2019, and October 31, 2025, who received frontline DRd were included. Follow-up continued until January 26, 2026, or death. DRd was administered in 28-day cycles, with cycle intervals extended according to the clinical circumstances. All patients received trimethoprim-sulfamethoxazole prophylaxis. Routine quinolone antibacterial, antiviral, and antifungal prophylaxes were not administered. LEN and DEX dosing, including DEX tapering and granulocyte colony-stimulating factor (G-CSF) administration, were individualized according to clinical judgment. The relative dose intensity (RDI) was calculated as the cumulative administered dose divided by the cumulative planned dose based on the initial prescribed dose and intended treatment schedule, multiplied by 100. Because dose escalation of LEN was permitted according to clinical conditions, a LEN RDI > 100% was possible. Immunoglobulin replacement therapy (IgRT) was not routinely administered but was considered at the discretion of the treating physician for patients with severe hypogammaglobulinemia and recurrent infections.

The study protocol was approved by the Kitasato University Hospital Ethics Committee (approval no. B25-153) and conducted in accordance with the principles of the Declaration of Helsinki. Owing to the retrospective nature of the study, the requirement for written informed consent was waived by the ethics committee.

Baseline clinical assessment, frailty, and nutritional status

The baseline demographic, clinical, laboratory, and disease-related characteristics were collected at the time of diagnosis. Frailty was assessed using a simplified frailty score based on the age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group Performance Status (ECOG PS), as described by Facon et al. [ 7 ]. This scale was used routinely throughout the study period.

Nutritional and immunological statuses were evaluated using the PNI and GNRI. The PNI was calculated using the following formula: 10 × serum albumin level (g/dL) + 0.005 × total lymphocyte count (/μL) [ 11 ]. The GNRI was calculated, as follows: (14.89 × serum albumin level [g/dL]) + (41.7 × actual body weight/ideal body weight). The ideal body weight was defined as 22 × height (m) 2 [ 12 ], and the actual-to-ideal body weight ratio was capped at 1.0 when the actual body weight exceeded the ideal body weight according to the original GNRI definition.

Cytogenetic analysis and risk definitions

Interphase fluorescence in situ hybridization (iFISH) was performed on diagnostic bone marrow samples to evaluate t(4;14), t(14;16), del(17p), chromosome 1q21 abnormalities, t(11;14), and del(13q). Gain of 1q21 was defined as three copies and amplification as ≥ 4 copies, with a positivity threshold of ≥ 3% of nuclei. Traditional high-risk cytogenetic abnormalities (HRCAs) included t(4;14), t(14;16), and del(17p), whereas expanded HRCAs additionally included 1q21 gain or amplification. Plasma cell enrichment was not routinely performed.

Response and safety assessment

Hematologic responses were evaluated according to the International Myeloma Working Group (IMWG) response criteria [ 13 ]. The minimal residual disease (MRD) status was assessed using multicolor flow cytometry (sensitivity, 10⁻ 5 ) in patients who achieved a complete response, which was confirmed by at least two consecutive negative immunofixation electrophoresis (IFE) results.

Serial serum immunoglobulin G (IgG) levels were collected during treatment and analyzed according to the myeloma subtype.

Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Grade ≥ 2 infectious events were identified by reviewing the electronic medical records and classified according to the clinical diagnosis, microbiological findings, CTCAE grade, and presence or absence of concomitant neutropenia. The timing of each infectious event relative to the DRd treatment was also recorded. Grade ≥ 3 adverse events, particularly hematologic toxicity and infections, were evaluated. The reasons for treatment discontinuation were also recorded.

Statistical analysis

Categorical variables were compared using Fisher’s exact test, and continuous variables were compared using the Mann–Whitney U test. The duration of treatment (DOT), time to next treatment (TTNT), PFS, and OS were measured from the time of DRd initiation. DOT was defined as the time from DRd initiation to the permanent discontinuation of DRd for any reason, including disease progression, adverse events, death, physician decision, and patient preference. TTNT was defined as the time to second-line therapy or death. PFS was defined as the time until disease progression or death. OS was defined as the time from DRd initiation to death from any cause. Because death was considered an event in both the TTNT and PFS analyses, deaths unrelated to myeloma progression were not treated as competing risks. Patients without events were censored at the last follow-up visit. Patients who were transferred without subsequent follow-up were censored at the time of transfer. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Exploratory analyses of the treatment durability were performed according to baseline nutritional indices, including the PNI and GNRI. The exact two-sided 95% confidence intervals (CIs) for key response rates were calculated using the Clopper–Pearson method. All statistical tests were two-sided, and p < 0.05 was considered statistically significant. Statistical analyses were performed using EZR (version 2.9–1; Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 14 ].

Results

Patient cohort and treatment selection

During the study period, 24 patients aged > 80 years with Ti-NDMM were identified, of whom 15 received frontline DRd and were included in the analysis. Among the nine patients who did not receive frontline DRd, four received bortezomib plus DEX (Vd), one received LEN plus DEX (Rd), three received best supportive care (BSC), and one died before treatment initiation. Vd was selected for three patients during the early study period, when institutional experience with DRd was limited, and for one patient because of severe renal impairment (estimated glomerular filtration rate < 10 mL/min/1.73 m 2 ), which precluded the safe use of LEN. The patient treated with Rd declined the hospitalization required for DRd initiation. BSC was selected according to the patient or family preference in three cases. The patient who died before treatment initiation had an ECOG PS of 4 and developed fatal pneumonia shortly after diagnosis. The baseline characteristics of the patients who did and did not receive frontline DRd are summarized in Table 1 .

Baseline characteristics of DRd-treated patients

The characteristics of the 15 patients who received frontline DRd are summarized in Table 1 . The median age was 83 (range: 81–92) years, and 12 patients (80.0%) had an ECOG PS of 0–1. The median PNI and GNRI were 43.1 (range: 23.0–56.4) and 88.9 (range: 57.8–107.2), respectively. Myeloma bone disease was present in 13 patients (86.7%), soft tissue extramedullary disease in 1 (6.7%), chromosome 1q21 abnormalities in 6 (40.0%), and traditional HRCAs in 5 (33.3%), including del(17p) in 4 (26.7%) and t(4;14) in 1 (6.7%). Two patients (13.3%) had ≥ 2 expanded HRCAs, and according to the Second Revision of the International Staging System (R2-ISS), 7 (46.7%) and 2 (13.3%) patients were classified as stage III and IV, respectively.

Treatment response and survival outcomes

The best hematologic responses included complete response (CR) in four patients, very good partial response (VGPR) in four, partial response (PR) in six, and stable disease (SD) in one, resulting in an overall response rate of 93.3% (95% CI: 68.1%–99.8%) and a VGPR or better rate of 53.3% (95% CI: 26.6%–78.7%). MRD assessment was performed in four patients with CR and sustained IFE negativity, all of whom were MRD negative.

The median starting doses of LEN and DEX were 10 (range: 5–15) mg/day and 20 (range: 4–20) mg/week, respectively. The median LEN and DEX RDIs were 88.6% and 31.3%, respectively (Table S1). DEX was frequently tapered during the first 12 treatment cycles according to the clinical condition and treatment tolerance. None of the patients permanently discontinued DEX while continuing the remaining components of DRd. Instead, DEX was progressively tapered to lower doses, with many patients receiving only 2–4 mg per cycle during prolonged treatment (Fig. S1). The median time to PR and VGPR was 1.1 (range: 0.5–2.8) and 4.5 (range: 0.7–11.8) months, respectively. Additional data are summarized in Table S1.

During the median follow-up of 23.1 (range, 0.4–58.0) months, 6 DOT, 5 TTNT, 5 PFS, and 2 OS events occurred. The estimated median DOT and TTNT were 36.7 (95% CI: 12.5 to not reached) and 44.6 (95% CI: 12.5 to not reached) months, respectively. The estimated median PFS was 40.0 (95% CI: 15.8 to not reached) months, whereas the estimated median OS was not reached (Fig. 1 ). Additional fixed-time estimates are provided in Table S2.

At the data cutoff, eight patients remained on DRd therapy at our institution. One additional patient was transferred to a community-affiliated hospital while continuing DRd because of persistent functional decline requiring prolonged hospitalization and was subsequently lost to follow-up. Treatment was permanently discontinued in six patients because of progressive disease ( n = 2) or infection-related events ( n = 4).

Safety and infectious complications

Grade ≥ 2 infusion-related reactions (IRRs) occurred in three patients (20.0%), including one grade 3 event with transient oxygen desaturation. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 12 (80.0%) and 2 (13.3%) patients, respectively. Filgrastim was administered to seven patients, and no platelet transfusions were required. None of the patients received antiviral prophylaxis or IgRT during DRd treatment.

A total of 23 grade ≥ 2 infectious episodes occurred in 11 of 15 patients (73.3%), including 13 grade 2 episodes and 10 grade 3–5 episodes. Respiratory, urinary, and biliary infections were common. Five episodes had microbiological etiologies: SARS-CoV-2 ( n = 2), Klebsiella oxytoca complex ( n = 1), Streptococcus constellatus ( n = 1), and Escherichia coli ( n = 1). No fungal or bloodstream infections were detected. The median time to the first grade 3–5 infection was 1.6 (range: 0.4–32.6) months. Most grade 3–5 infections occurred within the first 12 months after DRd initiation, whereas recurrent grade 2 respiratory or urinary tract infections were observed in several patients during prolonged treatment (Fig. 2 ). The serial serum IgG profiles are presented in Fig. S2. Detailed infectious event characteristics are provided in Table S3. The DEX exposure according to a grade 3–5 infection status is summarized in Table S4. No significant differences were observed in the DEX RDI or final DEX dose, whereas the cumulative DEX exposure was numerically lower in patients with grade 3–5 infections. Infection-related events leading to DRd discontinuation occurred in four patients, including two infection-related deaths and two infection-triggered treatment discontinuations or regimen switches. One patient died of aspiration pneumonia during DRd treatment, whereas the other died approximately two months after DRd discontinuation, following the development of a grade 4 cervical abscess.

Exploratory analyses of treatment durability according to baseline nutritional status

Patients were dichotomized according to the median baseline PNI (43.1). Compared with patients with a high PNI, those with a low PNI tended to have a poorer performance status, higher frailty scores, lower albumin levels and lymphocyte counts, and a trend toward a greater disease burden, including greater bone marrow plasma cell infiltration and a more advanced R-ISS stage distribution (Table S5).

The hematologic response depth, treatment intensity, response kinetics, and cumulative treatment exposure were comparable between the groups (Table S6). However, a low PNI was associated with a shorter treatment durability than that of a high PNI (median DOT: 30.8 months vs. not reached, p = 0.049; Fig. 3 A). The associations with TTNT, PFS, and OS did not reach statistical significance (Fig. S3). Patients with a low PNI more frequently experienced grade 3–5 infections (71.4% vs. 12.5%, p = 0.041) and grade 3–5 infectious complications within six months after DRd initiation (57.1% vs. 0.0%, p = 0.026) than those with a high PNI (Table S7). These findings are illustrated in a swimmer plot (Fig. 4 ).

Patients were also dichotomized according to the median baseline GNRI (88.9). Patients with a low GNRI had lower albumin levels and tended to have a poorer functional status and greater disease burden (Table S8). A low GNRI was associated with a shorter DOT (30.8 months vs. not reached, p = 0.026; Fig. 3 B) and TTNT (30.8 months vs. not reached, p = 0.009; Fig. S3). Although a low GNRI also tended to be associated with a shorter PFS and OS, the differences were not statistically significant (Fig. S3).

Discussion

In this retrospective, single-center study of patients aged > 80 years with Ti-NDMM, frontline DRd demonstrated favorable effectiveness and meaningful treatment durability in routine clinical practice. Infectious complications emerged as major barriers to treatment continuation, particularly during the first year of therapy. Exploratory analyses suggested that a lower baseline PNI was associated with severe infectious complications and a shorter treatment durability. These associations should be interpreted with caution because of the limited sample size and potential residual confounding factors.

DRd has become a standard frontline treatment for Ti-NDMM based on results from the MAIA trial, which demonstrated substantial improvements in survival outcomes compared with Rd alone and durable benefits even among patients aged ≥ 80 years [ 1 – 3 ]. However, the very elderly patients encountered in routine clinical practice are often a more heterogeneous population than that enrolled in clinical trials. Our findings should be interpreted as representing outcomes in carefully selected patients who were considered appropriate to receive frontline DRd, rather than in all patients aged > 80 years with Ti-NDMM. These findings support the feasibility of frontline DRd in selected very elderly patients.

Our findings emphasize that the treatment durability is an important therapeutic goal, because many very elderly patients do not receive subsequent lines of therapy [ 4 ]. Therefore, maintaining frontline disease control is important. Although the PFS remains the conventional efficacy endpoint, the DOT provides a complementary real-world measure that incorporates disease control, tolerability, toxicity, physician decision-making, and patient preference. Although this limits its interpretation as a pure efficacy endpoint, it also makes DOT particularly relevant for patients aged > 80 years.

In our cohort, progressive disease accounted for only a minority of treatment discontinuations, whereas infection-related events represented the major competing causes, including fatal infections and treatment discontinuation or switching to another regimen. Accordingly, infection has emerged as a major barrier to treatment durability. Severe infections occurred predominantly within the first year after DRd initiation, which is consistent with the results of the pooled MAIA and ALCYONE analyses, highlighting the need for intensified surveillance and supportive care during the early phase of daratumumab-based therapy [ 15 ].

Another finding was the frequent use of DEX tapering in routine clinical practice. DEX was commonly reduced during the early treatment phase according to tolerance and physician judgment. This practice is consistent with the increasing recognition that prolonged corticosteroid exposure may contribute to infectious complications, metabolic toxicity, functional decline, and treatment intolerance in older adults with frailty [ 16 ]. In the IFM2017-03 trial, daratumumab plus LEN, with DEX limited to the first two cycles, achieved superior PFS and lower treatment discontinuation rates than continuous Rd in patients with frailty [ 17 ]. In our exploratory analyses, the overall DEX RDI and DEX dose at the final administered cycle were similar, regardless of the grade 3–5 infection status, whereas the cumulative DEX exposure was numerically lower among patients who developed severe infections, likely reflecting earlier treatment discontinuation after infection-related events. These findings suggest that severe infections are a major barrier to treatment continuation despite DEX tapering and that factors beyond corticosteroid exposure may contribute to infectious vulnerability. Frailty assessment is considered essential in elderly patients with MM [ 18 ]; however, among patients aged > 80 years, conventional frailty classifications may not fully capture clinically meaningful heterogeneity because many individuals are categorized within the frailty spectrum. In this context, nutritional and immunologic vulnerabilities may provide complementary information regarding the physiologic reserve. Previous studies have demonstrated that both the PNI and GNRI are associated with survival outcomes in MM, supporting their role as markers of the host vulnerability beyond the tumor burden alone [ 9 , 10 ]. In our exploratory analyses, patients with a lower baseline PNI experienced a reduced treatment durability. Early severe infectious complications were also more frequent in this group, despite comparable treatment intensities, response kinetics, and hematologic response depths. These findings raise the possibility that a reduced treatment durability reflects the host vulnerability despite comparable antimyeloma responses.

The association between a low PNI and poor treatment durability is plausible. Nevertheless, given the limited sample size, cohort-specific median cutoffs, and absence of multivariate adjustment, these findings should not be interpreted as demonstrating an independent effect of PNI. Residual confounding factors such as the disease burden, frailty, performance status, and systemic inflammation cannot be excluded. The PNI reflects both the nutritional reserve and immune competence and may therefore identify patients with reduced physiologic reserve who are more vulnerable to treatment-disrupting infectious complications rather than disease aggressiveness alone [ 9 , 19 , 20 ]. In contrast, the GNRI showed weaker associations with infectious complications, despite similar trends toward reduced treatment durability. Together, these findings suggest that nutritional and immunologic vulnerabilities may contribute to heterogeneity, even within this very elderly population.

Severe infections occur predominantly during the first year, and careful surveillance, supportive care, and appropriate dose modifications are important during this period [ 16 , 18 ]. A lower baseline PNI may indicate a subgroup that could benefit from closer clinical monitoring. However, its clinical utility requires validation in larger prospective studies.

This study had several limitations. First, this was a retrospective single-center study with a limited sample size, which restricted the statistical power and precluded multivariate analyses. Because few patients remained at risk during the later follow-up period, the estimated median time-to-event outcomes and later Kaplan–Meier estimates were imprecise and should be interpreted cautiously. Second, treatment selection bias was unavoidable because this study included only patients who received frontline DRd. The characterization of patients who did not receive frontline DRd showed that the treatment allocation reflected multiple factors, including patient or family preferences, physician judgment, severe renal impairment, and limited institutional experience with DRd. Therefore, our findings should be interpreted as reflecting the outcomes of selected patients and may not be generalizable to a broader population of patients aged > 80 years with Ti-NDMM. Third, the PNI and GNRI analyses, as well as the analyses of infectious complications and corticosteroid exposure, were exploratory and based on a small number of events. They also relied on cohort-specific median cutoffs and multiple unadjusted comparisons without multivariate adjustments. Therefore, residual confounding could not be excluded, and these findings should be considered hypothesis generating and require prospective validation. Fourth, plasma cell enrichment was not routinely performed before iFISH, which may have reduced the sensitivity for detecting cytogenetic abnormalities. Fifth, selective MRD assessments precluded estimations of the overall MRD negativity rate. Sixth, infections and treatment discontinuation are multifactorial. Therefore, the present study could not establish a causal relationship between nutritional vulnerability and treatment durability. In addition, the DEX dose modification was individualized rather than protocol defined, which may have introduced heterogeneity in the corticosteroid exposure. Furthermore, the vaccination status documentation was incomplete. Although most patients received multiple COVID-19 vaccinations, the number and timing of vaccinations were not systematically documented, precluding a reliable evaluation of their potential influence on infectious complications. Finally, the DOT is a composite real-world outcome influenced by the efficacy, toxicity, physician and institutional practices, and patient preferences and should not be interpreted as a substitute for the PFS.

In conclusion, frontline DRd demonstrated favorable effectiveness and a clinically meaningful treatment durability in selected patients aged > 80 years with Ti-NDMM. However, infectious complications frequently compromised the treatment continuation, particularly in the early treatment period. These hypothesis-generating findings suggest that a lower baseline PNI may be associated with severe infectious complications and a shorter treatment durability, which warrants further validation in prospective studies.

Supplementary Information

Supplementary Material 1: Fig. S1 Dexamethasone exposure during the first 12 cycles of frontline DRd therapy. Heat map showing dexamethasone exposure during the first 12 cycles of frontline DRd therapy. Each row represents an individual patient, arranged in descending order of treatment duration. Colors indicate the dexamethasone dose administered during each treatment cycle. The color strip on the left indicates the baseline PNI status (high versus low). Circles indicate grade 3–5 infectious complications. Abbreviations: DRd, daratumumab, lenalidomide, and dexamethasone; PNI, Prognostic Nutritional Index.

Supplementary Material 2: Fig. S2 Longitudinal serum IgG levels during DRd therapy according to myeloma subtype. (A) IgG myeloma. (B) Non-IgG myeloma. Each line represents an individual patient. Abbreviations: DRd, daratumumab, lenalidomide, and dexamethasone.

Supplementary Material 3: Fig. S3 Survival outcomes according to baseline nutritional status. Kaplan–Meier curves for (A) TTNT, (B) PFS, and (C) OS according to baseline PNI, and (D) TTNT, (E) PFS, and (F) OS according to baseline GNRI. The patients were dichotomized according to the median baseline PNI (43.1) and GNRI (88.9). P-values were calculated using the log-rank test. Abbreviations: GNRI, Geriatric Nutritional Risk Index; OS, overall survival; PFS, progression-free survival; PNI, Prognostic Nutritional Index; TTNT, time to next treatment.

Supplementary Material 4: Supplementary Tables S1–S8.

Acknowledgements

The authors thank all staff members of Kitasato University Hospital who contributed to the care of the patients included in this study and supported this research. We also thank the patients and their families.

Authors’ contributions

YH conceived and designed the study, collected, analyzed, and interpreted the data, performed the statistical analyses, prepared the tables and figures, and drafted the manuscript. KM supervised the study and critically revised the manuscript. KE, NT, KH, HK, and TS contributed to data collection and reviewed the manuscript. All authors reviewed and approved the final manuscript.

Funding

This research did not receive funding.

Data availability

The datasets analyzed during the current study are not publicly available because they contain information that could compromise the privacy of research participants. The datasets are available from the corresponding author upon reasonable request and with permission of the Kitasato University Hospital Ethics Committee.

Declarations

Competing interests

YH received honoraria from Janssen, Bristol Myers Squibb, Sanofi, Takeda, Ono Pharmaceutical, CSL Behring, and Pfizer. NT received honoraria from Sanofi and Daiichi Sankyo. KH received honoraria from Bristol Myers Squibb. HK received honoraria from Asahi Kasei, Novartis, Sanofi, Janssen, Bristol Myers Squibb, BeOne Medicines, AbbVie, Ono Pharmaceutical, Takeda, and Daiichi Sankyo. TS received honoraria from Janssen, Bristol Myers Squibb, Sanofi, Takeda, and Ono Pharmaceutical. KM received honoraria from Sanofi and Takeda. KE declares no competing financial interests.

Footnotes

The article has been updated to correct the spelled-out form of abbreviation (IgRT).

Publisher’s Note

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Change history

9/14/2026

A Correction to this paper has been published: https://doi.org/10.1007/s44313-026-00178-7

References

1. Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–15. 10.1056/NEJMoa1817249.

2. Facon T, Moreau P, Weisel K, Goldschmidt H, Usmani SZ, Chari A, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942–50. 10.1038/s41375-024-02505-2.

3. Facon T, Cook G, Usmani SZ, Hulin C, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA. Leukemia. 2022;36(4):1066–77. 10.1038/s41375-021-01488-8.

4. Panitsas F, Kothari J, Vallance G, Djebbari F, Ferguson L, Sultanova M, et al. Treat or palliate: outcomes of very elderly myeloma patients. Haematologica. 2018;103(1):e32–4. 10.3324/haematol.2017.173617.

5. Blimark CH, Carlson K, Day C, Einarsdottir S, Juliusson G, Karma M, et al. Risk of infections in multiple myeloma. A population-based study on 8,672 multiple myeloma patients diagnosed 2008-2021 from the Swedish Myeloma Registry. Haematologica. 2008;110(1):163–72. 10.3324/haematol.2024.285645.

6. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068–74. 10.1182/blood-2014-12-615187.

7. Facon T, Dimopoulos MA, Meuleman N, Belch A, Mohty M, Chen WM, et al. A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial. Leukemia. 2020;34(1):224–33. 10.1038/s41375-019-0539-0.

8. Sobrini-Morillo P, Corral-Tuesta C, Sánchez-Castellano C, Gutiérrez-Blanco T, Palomo-Rumschisky P, Álvarez-Pinheiro CG, et al. Comprehensive geriatric assessment of older patients with multiple myeloma: a prospective observational study. Cancers (Basel). 2025. 10.3390/cancers17172904.

9. Nie Y, Zhang Z, Tang X. Prognostic and clinicopathological value of prognostic nutritional index in patients with multiple myeloma: a meta-analysis. Front Oncol. 2025;15:1545096. 10.3389/fonc.2025.1545096.

10. Suzuki K, Gunji T, Nagao R, Uryu H, Yokoyama H, Katsube A, et al. Geriatric nutritional risk index predicts 10-year survival in patients with multiple myeloma. Jpn J Clin Oncol. 2026. 10.1093/jjco/hyag040.

11. Onodera T, Goseki N, Kosaki G. Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nihon Geka Gakkai Zasshi. 1984;85(9):1001–5.

12. Bouillanne O, Morineau G, Dupont C, Coulombel I, Vincent JP, Nicolis I, et al. Geriatric nutritional risk index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr. 2005;82(4):777–83. 10.1093/ajcn/82.4.777.

13. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–46. 10.1016/s1470-2045(16)30206-6.

14. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8. 10.1038/bmt.2012.244.

15. Bahlis NJ, Facon T, San-Miguel JF, Usmani SZ, Dimopoulos MA, Moreau P, et al. Infections in patients receiving daratumumab for newly diagnosed multiple myeloma: a pooled analysis of MAIA and ALCYONE. Blood Adv. 2026. 10.1182/bloodadvances.2025019323.

16. Jung J. Treatment of transplant-ineligible multiple myeloma. Blood Res. 2025;60(1):53. 10.1007/s44313-025-00102-5.

17. Manier S, Lambert J, Hulin C, Macro M, Laribi K, Araujo C, et al. Safety and efficacy of a dexamethasone-sparing regimen with daratumumab and lenalidomide in patients with frailty and newly diagnosed multiple myeloma (IFM2017-03): a phase 3, open-label, multicentre, randomised, controlled trial. Lancet Oncol. 2025;26(10):1323–33. 10.1016/s1470-2045(25)00280-3.

18. Hicks LK, Messersmith HJ, Al Hadidi S, Banerjee R, Derman BA, Kumar S, et al. Treatment of multiple myeloma: ASCO-Ontario Health (Cancer Care Ontario) living guideline. J Clin Oncol. 2026;44(10):914–41. 10.1200/jco-25-02587.

19. Xiao Y, Wei G, Ma M, Liu D, Chen P, Quan H, et al. Association among prognostic nutritional index, post-operative infection and prognosis of stage II/III gastric cancer patients following radical gastrectomy. Eur J Clin Nutr. 2022;76(10):1449–56. 10.1038/s41430-022-01120-7.

20. Ding Z, He Y, Guo X, Feng R, Ren G, Deng L, et al. Prognostic nutritional index and mortality in pneumonia: a retrospective cohort study in China. Front Nutr. 2025;12:1660457. 10.3389/fnut.2025.1660457.

Associated Data

Supplementary Materials

Supplementary Material 1: Fig. S1 Dexamethasone exposure during the first 12 cycles of frontline DRd therapy. Heat map showing dexamethasone exposure during the first 12 cycles of frontline DRd therapy. Each row represents an individual patient, arranged in descending order of treatment duration. Colors indicate the dexamethasone dose administered during each treatment cycle. The color strip on the left indicates the baseline PNI status (high versus low). Circles indicate grade 3–5 infectious complications. Abbreviations: DRd, daratumumab, lenalidomide, and dexamethasone; PNI, Prognostic Nutritional Index.

Supplementary Material 2: Fig. S2 Longitudinal serum IgG levels during DRd therapy according to myeloma subtype. (A) IgG myeloma. (B) Non-IgG myeloma. Each line represents an individual patient. Abbreviations: DRd, daratumumab, lenalidomide, and dexamethasone.

Supplementary Material 3: Fig. S3 Survival outcomes according to baseline nutritional status. Kaplan–Meier curves for (A) TTNT, (B) PFS, and (C) OS according to baseline PNI, and (D) TTNT, (E) PFS, and (F) OS according to baseline GNRI. The patients were dichotomized according to the median baseline PNI (43.1) and GNRI (88.9). P-values were calculated using the log-rank test. Abbreviations: GNRI, Geriatric Nutritional Risk Index; OS, overall survival; PFS, progression-free survival; PNI, Prognostic Nutritional Index; TTNT, time to next treatment.

Supplementary Material 4: Supplementary Tables S1–S8.

Data Availability Statement

The datasets analyzed during the current study are not publicly available because they contain information that could compromise the privacy of research participants. The datasets are available from the corresponding author upon reasonable request and with permission of the Kitasato University Hospital Ethics Committee.