Статинское воздействие после многократного диагностирования миеломы и риск полной смертности, венозного тромбоэмболизма, патологических переломов и острых повреждений почек: ретроспективное когортное исследование.

Introduction

Multiple myeloma (MM) is a hematologic malignancy defined by clonal plasma cell proliferation and clinically important end-organ damage. At diagnosis, osteolytic bone disease is present in roughly 77% of symptomatic patients, renal impairment in up to 24.6%, and anemia in nearly half [ 1 , 2 ] . Fractures carry a direct survival penalty. In a Swedish cohort of 14 013 patients, fracture after diagnosis doubled the risk of death (HR ~ 2.00, 95% CI: 1.90–2.10) [ 3 ] . Venous thromboembolism (VTE) compounds this burden. A population-based study of 18 627 patients found that the hazard ratio (HR) for VTE was 7.5 (95% CI: 6.4–8.9) in the first year after MM diagnosis relative to matched controls [ 4 ] . The introduction of novel agents has meaningfully improved survival. Patients experienced a 50% improvement in median overall survival, from 29.9 to 44.8 months [ 5 ] . Five-year relative survival in Sweden rose from 0.28 to 0.41 across successive calendar periods [ 6 ] . Yet some mainstay therapies themselves amplify complication risk. In a landmark trial, deep-vein thrombosis occurred in 26% of patients receiving lenalidomide with high-dose dexamethasone, compared with 12% in the low-dose arm ( P = 0.0003) [ 7 ] . A meta-analysis confirmed that the pooled VTE incidence with contemporary lenalidomide-based regimens remains 6.0% (95% CI: 5.1–7.1%) despite thromboprophylaxis [ 8 ] . These findings underscore the need for safe, widely available adjunctive strategies that could reduce major complications in routine MM care.

HIGHLIGHTS

Retrospective cohort study to evaluate the effects of post-diagnosis statin exposure on all-cause mortality, venous thromboembolic events, pathological fractures, and AKI in multiple myeloma.

Post-diagnosis statin exposure significantly reduced all-cause mortality, venous thromboembolism, and pathological fracture.

Modest time-to-event benefit in the incidence of AKI was noted.

Prospective studies are required to further establish the association.

Statins are one such candidate. Beyond cardiovascular risk reduction, statins possess anti-inflammatory, immunomodulatory, and anti-thrombotic properties [ 9 ] . Preclinical work has demonstrated that myeloma cells with dysregulated mevalonate pathways are sensitive to statin-induced apoptosis, and fluvastatin potentiated bortezomib activity in vivo [ 10 ] . Translational data further suggest that background statin use may enhance response to venetoclax in relapsed or refractory MM [ 11 ] . Two large observational studies have examined post-diagnosis statin exposure. In a U.S. veteran cohort of 4957 patients, statin use was associated with a 21% reduction in all-cause mortality (aHR = 0.79, 95% CI: 0.73–0.86) and a 31% reduction in skeletal-related events (aHR = 0.69, 95% CI: 0.59–0.80) [ 9 ] . A Swedish population-based study of 4315 patients reported a similar signal, with MM-specific mortality HRs declining from 0.83 for pre-diagnosis use to 0.65 across the full follow-up period [ 12 ] . Despite this biological plausibility and early clinical evidence, existing studies have not simultaneously evaluated the association of statin exposure with VTE, pathological fractures, and acute kidney injury (AKI) in a single cohort. Moreover, much of the statin-MM literature has focused on incidence rather than post-diagnosis outcomes. A recent meta-analysis of 10 studies found a pooled odds ratio (OR) of 0.80 (95% CI: 0.68–0.93) for MM development among statin recipients but did not address survival or complications after diagnosis [ 13 ] .

Patients with MM continue to experience serious, sometimes treatment-exacerbated complications. Thrombosis, skeletal events, and renal injury remain common even in the modern therapeutic era [ 8 , 14 ] . If a generally well-tolerated and widely prescribed medication class is associated with improved outcomes, such findings could rapidly inform supportive care strategies in hematology and oncology. Without real-world evidence addressing multiple complication endpoints simultaneously, clinicians will lack guidance on whether statin therapy meaningfully modifies key MM outcomes beyond its cardiovascular indications. Our study, therefore, aimed to evaluate the association between statin exposure following MM diagnosis and 5-year all-cause mortality, VTE, pathological fractures, and AKI.

This retrospective cohort study has been reported in line with the STROCSS guidelines [ 15 ] .

Methods

Study design and data source

We conducted a retrospective cohort study using the TriNetX Linked Network, a global federated health research network of electronic medical records from 39 participating healthcare organizations. The database was queried on 16 January 2026. Per the platform’s standard event lookback, eligible index events could have occurred up to 20 years before the query date (approximately December 2005 to January 2026). Because TriNetX provides de-identified, aggregated data, this study was exempt from institutional review board review and informed consent requirements.

Study population

We identified adults (≥18 years) with MM based on the ICD-10-CM diagnosis code C90.0. Two cohorts were constructed. The statin-exposed cohort included patients with any statin exposure, identified using RxNorm codes for rosuvastatin, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, or pitavastatin, where the first qualifying statin record occurred on or after the first MM diagnosis. Prior statin use before MM diagnosis was permitted if a qualifying statin record was also present during cancer care. The comparator cohort included adults with MM who had no recorded statin exposure at any point following their diagnosis.

The index date was defined as the first qualifying statin exposure date for the statin cohort and as the MM diagnosis date for the non-statin cohort. For each outcome-specific analysis, patients with documentation of the outcome of interest before the start of the outcome assessment window were excluded to restrict analyses to incident events.

Exposure, covariates, and outcomes

Exposure

The primary exposure was statin use after MM diagnosis, defined as any qualifying statin record on or after the date of the first MM diagnosis.

Covariates

We matched cohorts on 59 baseline covariates assessed at any time prior to the index date, including demographics (age, sex, and race), key comorbidities (e.g., hypertension, hyperlipidemia, and chronic kidney disease), and concurrent MM-directed or adjunctive therapies (e.g., dexamethasone, bortezomib, lenalidomide, apixaban, and aspirin). Missing categorical demographic data (e.g., race) were retained as an “Unknown” category and matched as a separate level to preserve sample size.

Outcomes

The primary outcome was all-cause mortality, captured using the TriNetX “Deceased” demographic flag. Secondary outcomes were VTE (ICD-10-CM I26, I82), pathological fractures (ICD-10-CM M84.4, M84.5), and AKI (ICD-10-CM N17). The time-at-risk window began 1 day after the index date and extended through 1825 days (5 years) after the index date.

Statistical analysis

We applied 1:1 propensity score matching to reduce confounding attributable to measured baseline differences between statin-exposed and non-exposed patients. Matching was performed using greedy nearest-neighbor matching without replacement, with the platform’s standard caliper of 0.1 pooled standard deviations. Covariate balance was evaluated using the absolute standardized mean difference (ASMD), with values <0.1 indicating adequate balance.

For each endpoint, time-to-event distributions were estimated using Kaplan–Meier methods and compared between cohorts using log-rank tests. We quantified associations using HRs and 95% confidence intervals (CIs) from marginal, unadjusted Cox proportional hazards models fit to the propensity-matched cohorts. E -values were calculated to account for possible unmeasured confounders. Patients were censored at the last recorded encounter in the electronic medical record or at the end of the 5-year follow-up window, whichever occurred first. Statistical significance was defined as a two-sided P < 0.05. All analyses were conducted within the TriNetX analytical platform.

Results

Patient selection and baseline characteristics

A total of 43 543 adults with MM were identified in the TriNetX Linked network, including 8756 patients with post-diagnosis statin exposure and 34 787 patients without statin exposure (Fig. 1 ). Before matching, the statin cohort was older (mean 64.4 years, SD 11.7) than the non-statin cohort (mean 61.6 years, SD 14.6) (Table 1 ). Several comorbidities were more common in the statin cohort, including essential hypertension (73.9% vs. 59.6%), hyperlipidemia (52.5% vs. 45.4%), and chronic ischemic heart disease (29.1% vs. 22.8%) (Table 1 ). Concurrent medications also differed, including bortezomib (18.7% vs. 1.2%) and lenalidomide (18.3% vs. 2.5%) (Table 1 ).

Propensity score matching and covariate balance

After 1:1 propensity score matching, 7167 patients remained in each cohort (Table 1 ). In the matched sample, the mean age was 64.4 years (SD 12.1) in the statin cohort and 64.8 years (SD 13.7) in the non-statin cohort. Matching achieved strong baseline balance across all measured covariates; all 59 covariates met the prespecified balance criterion (ASMD < 0.1 after matching) (Fig. 2 ). Key comorbidities were closely aligned, including essential hypertension (72.0% vs. 72.5%), type 2 diabetes (40.3% vs. 40.2%), chronic kidney disease (29.1% vs. 29.4%), and chronic ischemic heart disease (28.7% vs. 28.7%) (Table 1 ). Concurrent medication use was similarly balanced, including dexamethasone (35.9% vs. 36.8%), bortezomib (5.0% vs. 5.3%), lenalidomide (7.3% vs. 7.0%), aspirin (19.8% vs. 20.6%), and apixaban (4.7% vs. 4.8%) (Table 1 ).

All-cause mortality

For mortality, the analytic sample included 7015 statin-exposed patients and 6987 non-exposed patients after excluding those who died before the follow-up window began ( n = 152 and n = 180, respectively). All-cause mortality at 5 years occurred in 17.5% (1225/7015) of the statin cohort and 26.0% (1819/6987) of the non-statin cohort (Table 2 ). Cox proportional hazards analysis demonstrated a significantly lower hazard of death with statin exposure (HR = 0.591, 95% CI: 0.549–0.635; log-rank P < 0.001) (Fig. 3 ). Kaplan–Meier estimates showed higher 5-year survival in the statin cohort (76.8%) compared with the non-statin cohort (65.1%), with separation of survival curves consistent with the direction and magnitude of the HR (Fig. 4 ).

VTE, pathological fractures, and acute kidney injury

For VTE, the analytic sample included 6197 statin-exposed patients and 6317 non-exposed patients (Table 2 ). The 5-year cumulative incidence was 9.2% (572/6197) in the statin cohort versus 12.0% (755/6317) in the non-statin cohort. Time-to-event analysis demonstrated a lower hazard of VTE with statin exposure (HR = 0.688, 95% CI: 0.617–0.767; log-rank P < 0.001) (Fig. 3 ). For pathological fractures, analyses included 6696 statin-exposed patients and 6654 non-exposed patients. Fractures occurred in 4.6% (305/6696) of the statin cohort and 7.6% (504/6654) of the non-statin cohort (Table 2 ). Statin exposure was associated with a significantly lower fracture hazard (HR = 0.541, 95% CI: 0.469–0.623; log-rank P < 0.001) (Fig. 3 ). For AKI, analyses included 5438 statin-exposed patients and 5181 non-exposed patients (Table 2 ). The 5-year absolute risk was similar between cohorts (19.3% vs. 19.7%; risk difference −0.4%; P = 0.606). In contrast, Kaplan–Meier and Cox analyses identified a modest reduction in the hazard of AKI with statin exposure (HR = 0.900, 95% CI: 0.825–0.981; log-rank P = 0.016) (Figs. 3 and 4 ).

Sensitivity analysis for unmeasured confounding (E-values)

Point estimate E -value for all-cause mortality was 2.774. It was 2.265 for VTE, 3.101 for pathological fracture, and 1.462 for AKI. Corresponding E -values for the CI closest to null were 2.526 for all-cause mortality, 1.850 for VTEs, 2.449 for pathological fracture, and 1.165 for AKI (Table 3 , Fig. 5 ).

Discussion

Our propensity score-matched retrospective cohort study of 14 334 patients with MM demonstrates that statin exposure on or after diagnosis is associated with substantially improved 5-year survival, fewer venous thromboembolic events, and fewer pathological fractures, alongside a modest time-to-event benefit for AKI. Statin-exposed patients had a 41% lower hazard of death (HR = 0.591, 95% CI: 0.549–0.635), a 31% lower hazard of VTE (HR = 0.688, 95% CI: 0.617–0.767), and a 46% lower hazard of pathological fractures (HR = 0.541, 95% CI: 0.469–0.623). For AKI, absolute 5-year incidence was nearly identical between groups (19.3% vs. 19.7%), yet time-to-event analysis revealed a modest hazard reduction (HR = 0.900, 95% CI: 0.825–0.981). Taken together, these results suggest that statins may confer clinically meaningful benefits across several morbidity domains in MM, though the observational design warrants cautious interpretation.

The survival association is the most striking finding and carries the greatest potential clinical relevance. A Veterans Health Administration cohort of 4957 treated MM patients similarly reported lower all-cause mortality among statin users (adjusted HR = 0.79, 95% CI: 0.73–0.86), with the association persisting in 12-month landmark analyses designed to mitigate immortal time bias [ 9 ] . A Swedish population-based study of 4315 incident MM cases corroborated this pattern, demonstrating lower MM-specific mortality for post-diagnosis statin exposure (HR = 0.73, 95% CI: 0.60–0.89) with a suggestive dose–response gradient [ 12 ] . Beyond MM, a large meta-analysis of cancer survival studies encompassing over 990 000 participants found that statin use was associated with lower all-cause mortality (HR = 0.81, 95% CI: 0.72–0.91) [ 16 ] . A pooled analysis of four randomized CLL/SLL trials also showed improved overall survival among statin users (adjusted HR = 0.62, 95% CI: 0.48–0.79), extending the signal to another treated hematologic malignancy [ 17 ] . Biologic plausibility for these observations rests on mevalonate pathway inhibition. Preclinical work has shown that t (4;14)-positive MM cells are preferentially sensitive to statin-mediated pathway blockade, with geranylgeranyl pyrophosphate rescue experiments localizing the effect to protein prenylation [ 10 ] . Earlier mechanistic studies demonstrated that lovastatin induces apoptosis in roughly half of genetically distinct MM cell lines through isoprenylation-dependent pathways [ 18 ] , and that geranylgeranylation inhibition reduces Mcl-1 protein levels, a key survival factor in myeloma plasma cells [ 19 ] . Simvastatin has also been shown to suppress myeloma-cell growth in a dose-dependent manner across 12 of 13 cell lines, with additive effects when combined with dexamethasone [ 20 ] . These laboratory findings offer a coherent mechanistic framework. However, the magnitude of the survival benefit observed in our study and in prior observational cohorts must be interpreted with restraint. A meta-analysis of 10 randomized trials adding statins to standard anticancer therapy in advanced cancers found no significant survival improvement (pooled HR = 0.94, 95% CI: 0.85–1.04) [ 21 ] . This discrepancy between observational and randomized evidence raises the possibility that healthy-user effects, confounding by indication, and differential access to care inflate the apparent benefit. A Veterans Health Administration study of frailty in older MM patients further underscores this concern, as frailty was strongly associated with mortality independent of statin use, and unmeasured differences in health status may partly explain the observed survival advantage [ 22 ] .

The VTE finding is particularly relevant given the high thrombotic burden in MM, driven by disease biology, immunomodulatory drug (IMiD) exposure, and patient comorbidities. In our matched cohort, statin-exposed patients experienced fewer VTE events (9.2% vs. 12.0%). This observation aligns with a large Korean nationwide nested case-control study of 455 805 cancer patients, in which statin treatment was associated with lower VTE risk (adjusted OR = 0.71, 95% CI = 0.67–0.75) [ 23 ] . A narrative review of the broader VTE-prevention literature noted that observational studies generally suggest statin-associated reductions in incident VTE of approximately 30%, and the randomized JUPITER trial demonstrated a 43% relative reduction with rosuvastatin [ 24 ] . Plausible mechanisms include anti-inflammatory effects, endothelial stabilization, and modulation of platelet and coagulation pathways. Preclinical MM data also suggest that statins suppress MIP-1α expression through Ras/ERK and Ras/Akt pathway inhibition, which may attenuate the prothrombotic microenvironmental milieu [ 25 ] . Importantly, this potential benefit should be viewed as complementary to, not a replacement for, established thromboprophylaxis. A randomized substudy of 342 newly diagnosed MM patients receiving lenalidomide demonstrated VTE rates of only 2.27% with aspirin and 1.20% with enoxaparin [ 26 ] . An expert consensus paper pooling four apixaban studies in 306 MM patients reported only two VTE events (0.6%) during prophylaxis [ 27 ] . These low event rates with dedicated prophylaxis indicate that any statin-associated reduction would represent an adjunctive layer of protection rather than a substitute intervention. The VTE risk prediction models developed specifically for MM, including the IMPEDE VTE score validated in over 8700 patients [ 28 ] and the PRISM score incorporating cytogenetics [ 29 ] , further highlight that baseline thrombotic risk is heterogeneous and driven by disease-specific factors that Electronic Health Record (EHR)-based matching cannot fully capture.

The association with fewer pathological fractures (4.6% vs. 7.6%; HR = 0.541) is notable, given the substantial morbidity and quality-of-life impact of skeletal events in MM. The Veterans Health Administration MM cohort reported a concordant 31% lower risk of skeletal-related events among statin users (adjusted HR = 0.69, 95% CI: 0.59–0.80) [ 9 ] . A meta-analysis of observational studies in older adults found that statin treatment was associated with lower fracture risk overall (relative risk (RR) = 0.80, 95% CI: 0.72–0.88), with particularly strong signals for hip fractures [ 30 ] . Two plausible pathways may underlie this association. Indirectly, improved disease control through mevalonate pathway inhibition could reduce osteolytic tumor burden; preclinical evidence supports this in MM, with statins shown to inhibit MIP-1α, a mediator implicated in myeloma-driven osteolysis [ 25 ] , and simvastatin demonstrated protective effects on osteoblasts exposed to myeloma-conditioned media [ 31 ] . Directly, statins may modulate osteoblast and osteoclast activity independently of tumor effects. However, a meta-analysis restricted to seven randomized controlled trials found that statins increased bone mineral density modestly but did not significantly reduce fracture risk (pooled HR = 1.00, 95% CI: 0.87–1.15) [ 32 ] . This discordance between observational and randomized fracture data mirrors the survival literature and tempers causal inference. The MRC Myeloma IX trial demonstrated that zoledronic acid reduced skeletal-related events by 26% relative to clodronic acid (HR = 0.74, 95% CI: 0.62–0.87) [ 33 ] , and a Cochrane network meta-analysis confirmed that bisphosphonates reduce pathological vertebral fractures (RR = 0.74, 95% CI: 0.62–0.89) [ 34 ] . Whether statins provide incremental skeletal protection beyond these established agents remains unknown and warrants prospective evaluation. Post hoc E analysis demonstrates that any single unknown confounder is unlikely to cause such significant effects for all-cause mortality, VTE, and pathological fractures.

The AKI results require careful interpretation. E -values suggest greater vulnerability to residual confounding compared to mortality, VTE, and pathological fractures. Despite nearly identical absolute 5-year incidence (19.3% vs. 19.7%), time-to-event analysis suggested a modest delay in AKI onset among statin-exposed patients (HR = 0.900, 95% CI: 0.825–0.981). A similar pattern has been reported in a hospitalized chronic kidney disease cohort, where crude AKI rates were comparable between statin users and nonusers, yet adjusted analyses favored statin exposure [ 35 ] . A large surgical cohort study also found lower adjusted odds of AKI with preoperative statin use (OR = 0.84, 95% CI: 0.79–0.90) [ 36 ] . Preclinical data suggest that statins may attenuate renal microvascular injury and tubular hypoxia through endothelial-stabilizing mechanisms [ 37 ] . However, several lines of evidence argue against a robust renoprotective class effect. A meta-analysis of eight randomized cardiac surgery trials found no AKI reduction with perioperative statins (RR = 1.02, 95% CI: 0.82–1.28) [ 38 ] , and a nationwide French cohort of over 8 million adults reported that high-potency statins were associated with increased AKI risk in men (HR = 1.19, 95% CI: 1.08–1.31) [ 39 ] . AKI in MM is multifactorial, arising from light-chain deposition, hypercalcemia, dehydration, and nephrotoxic therapies. Multiple studies have shown that renal recovery depends primarily on the depth and rapidity of hematologic response [ 40 , 41 ] . It is therefore plausible that the modest hazard signal reflects improved overall disease control or correlated supportive-care behaviors rather than a direct renoprotective statin effect.

From a clinical standpoint, these associations suggest that statins may have value as an adjunctive strategy in routine MM care. Statins are inexpensive, widely prescribed, and generally well-tolerated. If even a fraction of the observed benefit is causal, the public health implications would be substantial. However, the current observational evidence is insufficient to recommend statin initiation solely for MM outcomes. Candidate populations for future prospective testing include newly diagnosed patients, those at high baseline VTE risk, and those with an elevated skeletal event burden. The pragmatic accessibility of statins makes them an attractive candidate for evaluation within randomized or emulated target trial frameworks.

Strengths and limitations

Several strengths support the validity of our findings. The TriNetX network provided a large, geographically diverse real-world cohort spanning 39 healthcare organizations. Propensity score matching on 59 baseline covariates achieved strong measured balance, and we assessed four clinically meaningful endpoints over a 5-year horizon, addressing a gap in prior literature where outcomes were evaluated individually rather than simultaneously.

Important limitations must be acknowledged. The observational EHR design cannot exclude residual and unmeasured confounding. Key MM prognostic factors – including International Staging System stage, cytogenetic risk profile, and specific lines of therapy – were not uniformly available for matching, creating uncertainty about whether associations reflect true statin effects or systematic differences in disease biology and treatment intensity. Statin dose, specific agent, duration, and adherence were not captured, and our exposure definition encompasses both continuation of pre-existing prescriptions and new initiations on or after diagnosis; this heterogeneity in exposure timing and intensity may bias hazard estimates in either direction. Time-related bias is also a concern depending on how index events were anchored. Finally, outcome misclassification is inherent in routine care data, particularly for AKI and pathological fractures, where coding practices vary across institutions. These estimates should therefore be interpreted as associations rather than causal effects, and the direction of residual confounding likely favors statin-exposed patients who may be healthier, more engaged with care, and more likely to receive guideline-concordant MM therapy.

Conclusions

Statin exposure on or after MM diagnosis was associated with improved 5-year survival and lower risks of VTE and pathological fractures in this large propensity score-matched real-world cohort. The AKI signal was modest and nuanced, with concordant time-to-event but not absolute-risk differences. These findings are biologically plausible and consistent with prior observational MM cohorts, yet the gap between observational and randomized evidence in oncology demands prospective confirmation. Future work should include randomized trials or carefully emulated target trials testing intentional statin initiation in MM, analyses incorporating granular disease risk features such as cytogenetics and staging, and evaluation of statin intensity and duration. Interaction studies with thromboprophylaxis and bone-modifying agents would further clarify whether statins provide incremental benefit beyond current standard supportive care.

Acknowledgements

The authors thank the participating healthcare organizations within the TriNetX network for contributing de-identified data used in this analysis.

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Contributor Information

Naveen Gautam, Email: ngautam661@gmail.com.

Krishna Kandel, Email: kkandel75@gmail.com.

Jyoti Sharma, Email: jyotisharma121119@gmail.com.

Ethical approval

All procedures involving human subjects were carried out according to the ethical guidelines outlined in the World Medical Association’s Declaration of Helsinki. Because the TriNetX platform utilizes aggregated, fully de-identified patient data, Institutional Review Board (IRB) approval and informed patient consent were waived per institutional and TriNetX determinations.

Consent

Not applicable; no individually identifiable patient information is reported.

Sources of funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author contributions

N.G.: Conceptualization, methodology, formal analysis, and writing – review and editing. K.K.: Conceptualization, methodology, writing – original draft, and writing – review and editing. Jyoti Sharma: Writing – original draft and writing – review and editing.

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Research registration unique identifying number (UIN)

This study has been registered in the Research Registry with the Unique Identification Number (UIN) research registry 11902.

Guarantor

Krishna Kandel.

Provenance and peer review

Not applicable.

Data availability statement

The data that support the findings of this study are available from TriNetX, LLC, but restrictions apply to the availability of these data, which were used under license for the current study and, therefore, are not publicly available. Data, however, are available from the author upon reasonable request and with the permission of TriNetX.

Preprint/prior dissemination

None.

Permissions

All figures and tables are original to the authors, or permissions have been obtained where required.

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Associated Data

Data Availability Statement

The data that support the findings of this study are available from TriNetX, LLC, but restrictions apply to the availability of these data, which were used under license for the current study and, therefore, are not publicly available. Data, however, are available from the author upon reasonable request and with the permission of TriNetX.