Oral SERDs alone or in combination with CDK 4/6 inhibitors in breast cancer: Current perspectives and clinical trials.

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents.

Chemotherapy response score as a predictor of survival in ovarian cancer patients.

OBJECTIVE: The chemotherapy response score (CRS) has been widely adopted as a predictive tool for ovarian cancer survival. In the present study, we seek to define differences in survival rates among patients grouped in the traditionally established three-tiered system and those who have not been offered debulking surgery. STUDY DESIGN: We designed a retrospective cohort study involving women treated with chemotherapy and offered interval or late debulking surgery for ovarian cancer. Twenty-eight women were not considered for a debulking procedure for various reasons. Of the 89 women who were finally offered interval debulking or late debulking surgery, 28 had a CRS 1 score, 34 had a CRS 2 score and 27 had a CRS 3 score. RESULTS: Significant differences were noted in the progression-free survival (PFS) and overall survival (OS) of patients based on the CRS stratification, although survival rates were considerably longer for all three groups compared to those of patients who were not offered surgery. Cox regression univariate analysis revealed that suboptimal debulking and CRS 1 or no surgery had a significant negative impact on PFS and OS rates. The binary stratification of CRS (CRS 1-2 vs CRS 3) revealed comparable differences in the PFS and OS to those in the groups that were stratified as platinum resistant and platinum sensitive. CONCLUSION: The chemotherapy response score is a significant determinant of ovarian cancer survival that helps evaluate the risk of early disease relapse and death and may soon be useful in guiding patient-tailored treatment.

An open-label phase 2 study treating patients with first or second relapse of multiple myeloma with carfilzomib, pomalidomide, and dexamethasone (KPd): SELECT study.

Once-weekly carfilzomib at 56 mg/m2 plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple myeloma (RRMM). The phase 2 SELECT study (NCT04191616) evaluated efficacy/safety of weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in early RRMM patients refractory to lenalidomide. All 52 treated patients were refractory to prior treatment, and 19 (37%) were triple-class refractory. Overall response rate (ORR; primary endpoint) was 58% (35% ≥ very good partial response, 6% ≥ complete response); median response duration was 20.3 months. Minimal residual disease negativity (10-5) was achieved in 10% of patients. Median progression-free survival was 11.1 months; median overall survival was 18.8 months. Adverse events (AEs) were consistent with the known safety profile including grade ≥3 treatment-emergent AEs reported in 67% of patients. Although the primary endpoint of ORR was not met, KPd showed meaningful clinical benefits in lenalidomide-refractory RRMM patients, including those who were daratumumab-refractory and/or triple-class refractory.

Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin.

Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem's cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem's cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study.

Not available.

Cardiovascular complications of ribociclib in breast cancer patients.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have unprecedentedly advanced hormone-dependent breast cancer treatment paradigm. In the metastatic setting, ribociclib has consistently demonstrated survival benefit in pre-, peri-, and postmenopausal patients, conjugating efficacy with health-related quality of life preservation. Accordingly, the emergence of cardiac and/or vascular adverse events related to this novel targeted agent is gaining significant interest. This narrative review provides an overview of the incidence and spectrum of cardiovascular toxicity, in both clinical trial framework and real-world evidence. The potential pathogenetic mechanism, along with the available diagnostic parameters including biomarkers, and proper management, are also summarized.

Small RNA-seq and clinical evaluation of tRNA-derived fragments in multiple myeloma: Loss of mitochondrial i-tRFHisGTG results in patients' poor treatment outcome.

Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA-derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM-related tRFs in ameliorating MM prognosis and risk stratification. Small RNA-seq was performed to profile tRFs in bone marrow CD138+ plasma cells, revealing the significant deregulation of the mitochondrial internal tRFHisGTG (mt-i-tRFHisGTG ) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt-i-tRFHisGTG levels were quantified by RT-qPCR. Disease progression was assessed as clinical end-point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt-i-tRFHisGTG levels with patients' bone disease (p = 0.010), osteolysis (p = 0.023) and with significantly higher risk for short-term disease progression following first-line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt-i-tRFHisGTG -fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease-established markers. Notably, our study highlighted mt-i-tRFHisGTG loss as a powerful independent indicator of post-treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.

Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies.

Inflammasomes are multimeric protein complexes, sensors of intracellular danger signals, and crucial components of the innate immune system, with the NLRP3 inflammasome being the best characterized among them. The increasing scientific interest in the mechanisms interconnecting inflammation and tumorigenesis has led to the study of the NLRP3 inflammasome in the setting of various neoplasms. Despite a plethora of data regarding solid tumors, NLRP3 inflammasome's implication in the pathogenesis of hematological malignancies only recently gained attention. In this review, we investigate its role in normal lymphopoiesis and lymphomagenesis. Considering that lymphomas comprise a heterogeneous group of hematologic neoplasms, both tumor-promoting and tumor-suppressing properties were attributed to the NLRP3 inflammasome, affecting neoplastic cells and immune cells in the tumor microenvironment. NLRP3 inflammasome-related proteins were associated with disease characteristics, response to treatment, and prognosis. Few studies assess the efficacy of NLRP3 inflammasome therapeutic targeting with encouraging results, though most are still at the preclinical level. Further understanding of the mechanisms regulating NLRP3 inflammasome activation during lymphoma development and progression can contribute to the investigation of novel treatment approaches to cover unmet needs in lymphoma therapeutics.

Left Ventricular Myocardial Work Improves in Response to Treatment and is Associated with Survival Among Patients with Light-Chain Cardiac Amyloidosis.

AIMS: Complete hematologic response to treatment for light chain cardiac amyloidosis (AL-CA) may lead to improvement of myocardial function and better outcomes. We sought to evaluate the effect of response to treatment for AL-CA on echocardiographic indices of myocardial deformation and work, and their prognostic significance. METHODS AND RESULTS: Sixty-one patients treated for AL were enrolled and underwent echocardiographic assessment at baseline and at 1-year. Patients were stratified according to hematologic response as complete or not complete responders. A significant reduction in median NT-proBNP (2,771 to 1,486 pg/mL; p < 0.001), posterior wall thickness (PWT) (13 to 12 mm; p = 0.002), and an increase in global work index (GWI) (1,115 to 1,356 mmHg%; p = 0.018) was observed at 1-year. Patients with complete response (CR) had a more pronounced decrease in intraventricular septum thickness (14.2 to 12.0 mm; p = 0.006), improved global longitudinal strain (GLS) (-11.6 to -13.1%; p for interaction = 0.045), increased global constructive work (1,245 to 1,436 mmHg%; p = 0.008) and global work index (926 to 1250 mmHg%, p = 0.002) compared to non-CR. Furthermore, deltaGLS (ρspearman = 0.35; p < 0.001) and deltaGWI (ρspearman = -0.32; p = 0.02) correlated with delta NT-proBNP. Importantly, patients with GLS and GWI response had a better prognosis (log-rank p = 0.048 and log-rank p = 0.007, respectively). After adjustment for Mayo stage, gender, and response status, deltaGLS (HR = 1.404, p = 0.046 per 1% increase) and deltaGWI (HR = 0.996, p = 0.042 per 1mmHg% increase) were independent predictors of survival. CONCLUSIONS: Complete hematologic response to treatment is associated with improved left ventricular myocardial work indices and their change is associated with improved survival in AL-CA.

Tenofovir-Induced Fanconi Syndrome Presenting with Life-Threatening Hypokalemia: Review of the Literature and Recommendations for Early Detection.

Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor that has been widely used for the treatment of patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. However, in the HBV monoinfection scenario, only five cases of TDF-associated Fanconi syndrome have been reported thus far, two of them providing a confirmatory kidney biopsy. Here, we describe the case of a 68-year-old woman with chronic hepatitis B (CHB) who developed TDF-induced Fanconi syndrome that reverted after TDF withdrawal from tenofovir alafenamide. Though the overall risk of TDF-associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular functions should be monitored in patients exposed to TDF.

Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study.

BACKGROUND: Multiple myeloma remains incurable, and heavily pretreated patients with relapsed or refractory disease have few good treatment options. Belantamab mafodotin showed promising results in a phase 2 study of patients with relapsed or refractory multiple myeloma at second or later relapse and a manageable adverse event profile. We aimed to assess the safety and efficacy of belantamab mafodotin in a phase 3 setting. METHODS: In the DREAMM-3 open-label phase 3 study, conducted at 108 sites across 18 countries, adult patients were enrolled who had confirmed multiple myeloma (International Myeloma Working Group criteria), ECOG performance status of 0-2, had received two or more previous lines of therapy, including two or more consecutive cycles of both lenalidomide and a proteasome inhibitor, and progressed on, or within, 60 days of completion of the previous treatment. Participants were randomly allocated using a central interactive response technology system (2:1) to receive belantamab mafodotin 2·5 mg/kg intravenously every 21 days, or oral pomalidomide 4·0 mg daily (days 1-21) and dexamethasone 40·0 mg (20·0 mg if >75 years) weekly in a 28-day cycle. Randomisation was stratified by previous anti-CD38 therapy, International Staging System stage, and number of previous therapies. The primary endpoint was progression-free survival in all patients who were randomly allocated. The safety population included all randomly allocated patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04162210, and is ongoing. Data cutoff for this analysis was Sept 12, 2022. FINDINGS: Patients were recruited between April 2, 2020, and April 18, 2022. As of September, 2022, 325 patients were randomly allocated (218 to the belantamab mafodotin group and 107 to the pomalidomide-dexamethasone group); 184 (57%) of 325 were male and 141 (43%) of 325 were female, 246 (78%) of 316 were White. Median age was 68 years (IQR 60-74). Median follow-up was 11·5 months (5·5-17·6) for belantamab mafodotin and 10·8 months (5·6-17·1) for pomalidomide-dexamethasone. Median progression-free survival was 11·2 months (95% CI 6·4-14·5) for belantamab mafodotin and 7·0 months (4·6-10·6) for pomalidomide-dexamethasone (hazard ratio 1·03 [0·72-1·47]; p=0·56). Most common grade 3-4 adverse events were thrombocytopenia (49 [23%] of 217) and anaemia (35 [16%]) for belantamab mafodotin, and neutropenia (34 [33%] of 102) and anaemia (18[18%]) for pomalidomide-dexamethasone. Serious adverse events occurred in 94 (43%) of 217 and 40 (39%) of 102 patients, respectively. There were no treatment-related deaths in the belantamab mafodotin group and one (1%) in the pomalidomide-dexamethasone group due to sepsis. INTERPRETATION: Belantamab mafodotin was not associated with statistically improved progression-free survival compared with standard-of-care, but there were no new safety signals associated with its use. Belantamab mafodotin is being tested in combination regimens for relapsed or refractory multiple myeloma. FUNDING: GSK (study number 207495).

Impact of daratumumab on stem cell mobilization and collection, engraftment and early post-transplant complications among multiple myeloma patients undergoing autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) remains a standard therapy for multiple myeloma (MM) patients. Our study aimed to assess the impact of daratumumab-containing induction on stem cell (SC) mobilization, apheresis and hospitalization. We evaluated 200 newly diagnosed MM patients that were mobilized for SC collection and which received induction with (N = 40) or without daratumumab (N = 160). Dara group patients required more frequent use of plerixafor, larger collection volumes, and had lower SC yield. 87.5% (35/40) of dara group patients achieved the planned yield of ≥ 5 × 10^6 CD34+/kg for at least one transplant compared to 96.2% (154/160) of patients in the non-dara group. Dara group patients had delayed hematopoietic recovery (11 vs 10 days for PMN > 0.5 × 10E9/l), required more transfusions (4 vs 2 plts), prolonged hospitalization (20 vs 18 days), more febrile episodes and prolonged antibiotic administration. Despite daratumumab effect patients finally achieved a successful stem cell collection and proceeded to transplant.

Tixagevimab/Cilgavimab as Pre-Exposure Prophylaxis against COVID-19 for Multiple Myeloma Patients: A Prospective Study in the Omicron Era.

Background: tixagevimab/cilgavimab, distributed under the name "Evusheld", was the first available pre-exposure prophylaxis for COVID-19 other than vaccination. It received an EUA from the FDA after sufficient trial data showed efficacy in preventing SARS-CoV-2 infections and subsequent severe disease. Its potential benefits for high-risk immunocompromised patients generated a lot of interest. Individuals with multiple myeloma fall into this category, as they are characterized by attenuated immune responses and, in some cases, vaccines have limited efficacy. Methods: this single-center, prospective study included consecutive patients with multiple myeloma. All individuals were considered high-risk for COVID-19 due to their underlying disease. Baseline demographic and clinical characteristics, as well as data regarding COVID-19 infection and antibodies, were collected. Patients were administered two intramuscular 150 mg doses of Evusheld and were monitored during the follow-up period. Results: one hundred and eleven multiple myeloma patients were included in this analysis, with a median age of 64 years (range 58-69) and fifty-three were females (47.7%). Fourteen patients (12.6%) had a prior history of COVID-19 and all patients were vaccinated with either three or four doses of mRNA-based vaccines. An increase was observed in the median neutralizing-antibody levels before and after tixagevimab/cilgavimab administration, from 92.6% to 97.3%. The high levels were sustainable, with a median neutralizing-antibody level of 95.4% at 3 months post Evusheld administration. Overall, nine patients (8.1%) were diagnosed with COVID-19 during the follow-up period, at a median of 31 days. There were no SARS-CoV-2- infection-related hospitalizations or deaths. The monoclonal antibody combination was well tolerated, with no infusion-related reactions or major adverse events, and pain at the injection site only was reported by 33 patients (30%). Conclusions: tixagevimab/cilgavimab (Evusheld) seemed beneficial for patients with multiple myeloma, who presented high neutralizing-antibody levels and a low incidence of COVID-19 during the initial Omicron wave. No new safety concerns emerged. However, novel combinations of monoclonal antibodies against the new circulating variants of SARS-CoV-2 are deemed necessary in view of the emergence of immune tolerance.

Metabolomics Point out the Effects of Carfilzomib on Aromatic Amino Acid Biosynthesis and Degradation.

(1) Carfilzomib (Cfz) is an antineoplastic agent indicated for the treatment of multiple myeloma. However, its beneficial action is attenuated by the occurrence of cardiotoxicity and nephrotoxicity as the most common adverse effects. Presently, there is well-established knowledge on the pathomechanisms related to these side effects; however, the research on the metabolic alterations provoked by the drug is limited. (2) An in vivo simulation of Cfz-induced toxicity was developed in (i) Cfz-treated and (ii) control mice. An RP-HRMS-based protocol and an advanced statistical treatment were used to investigate the impact of Cfz on the non-polar metabolome. (3) The differential analysis classified the Cfz-treated and control mice and resulted in a significant number of identified biomarkers with AUC > 0.9. The drug impaired the biosynthesis and degradation of aromatic amino acids (AAA) and led to alterations of uremic toxins in the renal and urine levels. Furthermore, the renal degradation of tryptophan was affected, inducing its degradation via the kynurenine pathway. (4) The renal levels of metabolites showed impaired excretion and degradation of AAAs. Cfz was, finally, correlated with the biosynthesis of renal dopamine, explaining the biochemical causes of water and ion retention and the increase in systolic pressure.

EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets.

Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary.

Optimal Time Interval between Neoadjuvant Platinum-Based Chemotherapy and Interval Debulking Surgery in High-Grade Serous Ovarian Cancer.

BACKGROUND: There is limited data on the optimal time interval between the last dose of neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) in high-grade serous ovarian carcinoma (HGSC). METHODS: We retrospectively identified patients with stage IIIC/IV HGSC who received NACT followed by IDS during a 15-year period (January 2003-December 2018) in our Institution. RESULTS: Overall, 115 patients with stage IIIC/IV HGSC were included. The median age of diagnosis was 62.7 years (IQR: 14.0). A total of 76.5% (88/115) of patients were diagnosed with IIIC HGSC and 23.5% (27/115) with IV HGSC. Median PFS was 15.7 months (95% CI: 13.0-18.5), and median OS was 44.7 months (95% CI: 38.8-50.5). Patients were categorized in groups according to the time interval from NACT to IDS: <4 weeks (group A); 4-5 weeks (group B); 5-6 weeks (group C); >6 weeks (group D). Patients with a time interval IDS to NACT ≥4 weeks had significantly shorter PFS (p = 0.004) and OS (p = 0.002). Median PFS was 26.6 months (95% CI: 24-29.2) for patients undergoing IDS <4 weeks after NACT vs. 14.4 months (95% CI: 12.6-16.2) for those undergoing IDS later (p = 0.004). Accordingly, median OS was 66.3 months (95% CI: 39.1-93.4) vs. 39.4 months (95% CI: 31.8-47.0) in the <4 week vs. >4 week time interval NACT to IDS groups (p = 0.002). On multivariate analysis, the short time interval (<4 weeks) from NACT to IDS was an independent factor of PFS (p = 0.004) and OS (p = 0.003). CONCLUSION: We have demonstrated that performing IDS within four weeks after NACT may be associated with better survival outcomes. Multidisciplinary coordination among ovarian cancer patients is required to avoid any unnecessary delays.

Real-World Effectiveness and Safety of Belantamab Mafodotin Monotherapy in Triple-Class Refractory Multiple Myeloma.

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM). The aim of this study was to assess the effectiveness and tolerability of monotherapy with the conjugated anti-BCMA monoclonal antibody belantamab mafodotin in triple-class refractory patients with MM in real-world practice. Patients refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 monoclonal antibody received belantamab mafodotin at 2.5 mg/kg intravenously every 3 weeks. Overall, 27 patients with a median age of 65 years (range 41-81) were included. Of these, 52% were male and the median number of prior lines of treatment was 5 (4-10). The overall response rate (partial response or better) was 52%, whereas the disease control rate (stable disease or better) was 70%. The median progression-free survival (PFS) was 2 months (95%CI: 0-7), whereas the median PFS among the responders was 12 months (95%CI: 6-18). Regarding the toxicity profile, the most common toxicity was eye toxicity, in 44% of the patients. Keratopathy grade 2-3 was reported in 33.3% of the patients. In conclusion, belantamab mafodotin showed a safety and efficacy profile consistent with the results of the registrational study. Importantly, heavily pretreated patients who responded to treatment derived a substantial survival benefit.

Impact of CDK4/6 Inhibitors on Aromatase Inhibitor-Associated Musculoskeletal Syndrome (AIMSS) in the Adjuvant Setting.

Background: Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a well-tolerated therapy, AI-induced musculoskeletal symptoms are common and may be accused for treatment discontinuation. Recently, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors changed the therapeutic setting, and currently, ribociclib, palbociclib, and abemaciclib are all approved in combination with nonsteroidal AIs in patients with ER-positive, HER2-negative advanced or metastatic breast cancer. This systematic review aims to identify the frequency of aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) in the adjuvant setting in patients under AI monotherapy compared to patients under combination therapy with AIs and CDK4/6 inhibitors and demonstrate the underlying mechanism of action. Methods: This study was performed in accordance with PRISMA guidelines. The literature search and data extraction from all randomized clinical trials (RCTs) were done by two independent investigators. Eligible articles were identified by a search of MEDLINE and ClinicalTrial.gov database concerning the period 2000/01/01-2021/05/01. Results: Arthralgia was reported in 13.2 to 68.7% of patients receiving AIs for early-stage breast cancer, while arthralgia induced by CDK4/6 inhibitors occurred in a much lower rate [20.5-41.2%]. Bone pain (5-28.7% vs. 2.2-17.2%), back pain (2-13.4% vs. 8-11.2%), and arthritis (3.6-33.6% vs. 0.32%) were reported less frequently in patients receiving the combination of CDK4/6 inhibitors with ET. Conclusions: CDK4/6 inhibitors might have a protective effect against joint inflammation and arthralgia occurrence. Further studies are warranted to investigate arthralgia incidence in this population.