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IntroductionMedullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.Aim of the studyThis review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC.Materials and methodsWe performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories.ResultsOur search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials.ConclusionWe found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials’ implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients’ outcome and survival.

Simple Summary: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the standard consolidation strategy for patients with newly diagnosed multiple myeloma (MM), as well as for a subset of patients with relapsed/refractory disease. ASCT reduces the duration of myelosuppression induced by HDCT. Chemotherapy agents combined with granulocyte-colony stimulating factors (G-CSF), as well as plerixafor, are key components of currently used stem cell mobilization regimens. However, chemotherapy mobilizing agents are associated with risk of infectious complications and peripheral neuropathy, which is as well a common toxicity of many drugs used in MM treatment. Ixazomib is an oral proteasome inhibitor and has lower neurotoxic potential. We for the first time combined ixazomib with G-CSF (filgrastim) for stem cell mobilization in patients with MM undergoing HDCT and ASCT, and assessed safety and efficacy of this mobilization strategy. Ixazomib was globally well tolerated and no new toxicities have been observed. The combination of ixazomib and G-CSF showed promising stem cell mobilizing activity and led to successful stem cell mobilization in 17 out of 19 (89%) patients. However, 9 (47%) patients required the addition of plerixafor to ensure optimal stem cell collection. Future larger studies might further investigate the role of ixazomib in stem cell mobilization regimens for MM. (1) Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the standard consolidation strategy for patients with newly diagnosed multiple myeloma (MM) and for a subset of patients with relapsed/refractory disease. For stem cell mobilization, G-CSF alone or in combination with chemotherapy mobilizing agents and/or plerixafor are commonly used. Ixazomib is an oral proteasome inhibitor with less neurotoxic potential, which previously showed the ability to mobilize stem cells in preclinical studies. (2) Methods: Prospective single-center phase 1 study assessing the efficacy and safety of stem cell mobilization with ixazomib and G-CSF in patients with newly diagnosed or relapsed/refractory MM undergoing HDCT and ASCT. Primary endpoint was percentage of patients achieving a yield of at least 6.0 × 106/kg CD34+ cells within the first apheresis. G-CSF (filgrastim) 10 μg/kg/day was administered subcutaneously (s.c.) from day 1 to day 5 (planned apheresis) and ixazomib 4 mg orally at day 4. Plerixafor 24 mg s.c. was administered if the stem cell mobilization with ixazomib and G-CSF was not sufficient. (3) Results: 19 patients were treated within the study between 06/2020 and 02/2021. The primary endpoint was reached in 17 (89%) patients, with a median of 7.1 × 106/kg CD34+ cells collected within the first apheresis, comparable to previously published results, and only 2 (11%) patients required a second apheresis. Median number of circulating CD34+ cells was 14.0 × 106/L (2.0–95.2) before the administration of ixazomib, and 33.0 × 106/L (4.2–177.0) pre-apheresis. However, 9 (47%) patients required the addition of plerixafor to ensure optimal stem cell collection. (4) Conclusions: The combination of ixazomib and G-CSF showed promising stem cell mobilizing activity in patients with MM prior to HDCT and ASCT. Future larger studies might further investigate the role of ixazomib in stem cell mobilization regimens for MM. [ABSTRACT FROM AUTHOR]

Objective: Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a rare monoclonal plasma cell proliferation disorder. At present, there is no unified treatment for POEMS syndrome. Here, we describe one case with POEMS syndrome with obvious neurological symptoms diagnosed in September 2020. We made a meta--analysis to assess the efficacy of treatment strategies in recent years. Methods: We retrospectively analyzed the diagnosis and treatment of this patient, and searched relevant articles in PubMed, Embase, and MEDLINE databases using MedicalSubject Headings (MeSH) (eg, POEMS, Therapy, Drug Therapy, Biological Therapy, Combined Modality Therapy, Hematopoietic Stem Cell Transplantation, Immunotherapy, Molecular Targeted Therapy, Chemoradiotherapy, and Salvage Therapy) and free words, and performed the statistical analysis. Results: The patient's efficacy evaluation was complete response (CR) after treatment with ixazomib combined with autologous stem cell transplantation (ASCT). Overall, 20 articles consist of 6 clinical trials, 14 retrospective studies, and 936 patients were included in this meta-analysis. There was no significant difference in complete hematologic response (CRH) rate between people who underwent ASCT and those who did not. However, ASCT might have a better survival rate. Conclusions: Ixazomib combined with ASCT therapy may be a safe and effective method for patients with POEMS syndrome. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) accounts for ∼10% of total hematologic malignancies worldwide. In India, the incidence of MM has increased two-fold with marked heterogeneity. Significant improvements in terms of clinical outcomes have been observed in the management of MM in recent years. However, most patients develop a disease relapse with the first or subsequent treatments. A combination of immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (PIs; bortezomib) has been the mainstay for the therapeutic management of relapsed/refractory multiple myeloma (RRMM). This review highlights the management of RRMM with newer agents such as belantamab, carfilzomib, daratumumab, elotuzumab, ixazomib, mafadotin, selinexor, panobinostat, and venetoclax, with more focus on PIs. As a single agent and in combination with other drugs including dexamethasone and carfilzomib has been studied extensively and approved by the United States, European Union, and India. Clinical trials of these newer agents, either alone or in combination, for the treatment of RRMM in Western countries indicate survival, improved outcomes, and overall well-being. However, evidence in Indian patients is evolving from ongoing studies on carfilzomib and daratumumab, which will ascertain their efficacy and safety. Currently, several guidelines recommend carfilzomib-based, daratumumab-based, and panobinostat-based regimens in RRMM patients. Currently, with more accessible generic versions of these drugs, more Indian patients may attain survival benefits and improved quality of life. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors and immunomodulators (IMiDs), primarily bortezomib and lenalidomide, are essential components of treatment for both newly diagnosed and relapsed/refractory multiple myeloma (MM), producing high response rates and resulting in improved overall survival. However, bortezomib often induces a dose-limiting toxicity in the form of peripheral neuropathy (PN). Neurotoxicity often affects patient’s quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, vitamin B12 deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Usually, bortezomib-induced PN is a sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution while motor neuropathy is less frequently observed. Dose adjustment of bortezomib could be necessary during treatment. Anticonvulsants (pregabalin, gabapentin, carbamazepine, etc.) and tricyclic antidepressants (amitriptyline) are most often used to relieve neurological pain. In this review we focus on the clinical manifestations of bortezomibinduced PN, current understanding of the pathophysiological mechanisms as well as clinical and pharmacological aspects of prevention and management this complication. New proteasome inhibitors such as ixazomib and carfilzomib do not have the neurotoxicity of bortezomib. An early switch within the class of proteasome inhibitors from bortezomib to oral ixazomib appears to be an important approach to prevent severe PN. Our own clinical case of an early switch from bortezomib-based induction to IRd triplet (ixazomib, lenalidomide, dexamethasone) is cited as an illustration of the success of this approach.

Weekly ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression-free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib-Rd in this setting.

Simple Summary: Bone cancer has seen minimal benefits in therapeutic options in the past 30 years. Proteasome inhibitors present a new avenue of research for the treatment of bone cancer. Proteasome inhibitors impair the function of the proteasome, a structure within the cell that removes unwanted and misfolded proteins. Bone cancer cells heavily rely on the proteasome to properly function and survive. Impairing the proteasome function can have detrimental consequences and lead to cell death. This review provides a thorough summary of the in vitro, in vivo, and clinical research that has explored proteasome inhibitors for the treatment of bone cancer. Osteosarcoma (OS) is the most common type of bone cancer, with ~30% of patients developing secondary/metastatic tumors. The molecular complexity of tumor metastasis and the lack of effective therapies for OS has cultivated interest in exploiting the proteasome as a molecular target for anti-cancer therapy. As our understanding towards the behavior of malignant cells expands, it is evident that cancerous cells display a greater reliance on the proteasome to maintain homeostasis and sustain efficient biological activities. This led to the development and approval of first- and second-generation proteasome inhibitors (PIs), which have improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Researchers have since postulated the therapeutic potential of PIs for the treatment of OS. As such, this review aims to summarize the biological effects and latest findings from clinical trials investigating PI-based treatments for OS. Integrating PIs into current treatment regimens may better outcomes for patients diagnosed with OS. [ABSTRACT FROM AUTHOR]

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In this work, the preparation of a PEG@ multi-walled carbon nanotubes (MWCNTs) composite has shown a great potential effect in tumor therapy using graphite powder at room temperature. PEGylated MWCNTs were created and used as a carrier for targeting the antineoplastic drug Ixazomib to myeloma cancer cells (abnormal plasma cells). Ixazomib (MLN2238) was covalently encapsulated into functionalized carbon nanotubes modified with polyethylene glycol (PEG 600) to obtain MWCNTs-PEG-MLN2238. The Ixazomib@ MWCNTs-PEG composite shows promising results as an effective nanocarrier and using a small amount of MWCNTs-PEG-Ixazomib that has a low toxicity compared with that of Ixazomib alone. A multifunctional MWCNTs-PEG-Ixazomib composite is used to test biological effects on multiple myeloma cell lines RPMI 8226 using the MTT assay to enhance treatment efficiency. The cytotoxicity of free Ixazomib citrate (69% cell viability of RPMI8226 cells) was higher than that of MWCNTs-PEG-Ixazomib (91% cell viability) at the same maximum concentration of Ixazomib citrate (50 µg/ml). In this work, we performed a study of preparation of MWCNTs with an acceptable Ixazomib loading efficiency and determination of the drug systemic toxicity for the first time. In this study, the preparation of MWCNTs with acceptable Ixazomib loading efficiency and determination of the drug systemic toxicity was performed for the first time. The MTT assay results show decreasing the toxicity of Ixazomib after loading with the MWCNTs-PEG composite. The MWCNTs-PEG @ Ixazomib show promising results as an effective carrier of Ixazomib and lead to a decrease in the cost of using Ixazomib. [ABSTRACT FROM AUTHOR]

Background: Ixazomib is an orally available proteasome inhibitor for multiple myeloma with adverse effects such as gastrointestinal symptoms, skin rashes, and thrombocytopenia reported in clinical trials and post-marketing surveillance, resulting in treatment discontinuation. However, comprehensive adverse event (AE) assessments for ixazomib are lacking. Objectives: Herein, we aimed to determine the frequency and risk of AEs associated with ixazomib in Japanese patients using the Japanese Adverse Event Reporting Database (JADER). Additionally, the time to onset and post hoc outcomes of unique AEs were clarified. Methods: To investigate the association between ixazomib and AEs, we analyzed the JADER database, comprising voluntary AE reports submitted to the Pharmaceuticals and Medical Devices Agency, between April 2004 and June 2021. AEs with ≥10 reports were included in the analysis, and criteria for the presence of AE signals were defined as meeting the requirements of proportional report ratio ≥2 and χ2 ≥ 4. Characteristic AEs were analyzed considering time to onset and onset outcomes. Results: Of 34 extracted AEs, 18 presented AE signals. The 12 post hoc outcomes with fatality rates ≥10% included septic shock (50.0%), infection (41.2%), heart failure (16.7%), pneumonia (14.2%), and tumor necrosis syndrome (13.3%). A median of the time to onset showed that 11 of the 18 AEs occurred from ixazomib initiation to approximately 1 month later. Conclusion: Our results suggest that ixazomib may increase the incidence of 18 AEs, 11 of which occurred within the first month of treatment. Furthermore, 8 AEs were found to have potentially fatal outcomes at a rate of ≥10%. Therefore, monitoring AEs during the first month of treatment appears necessary. [ABSTRACT FROM AUTHOR]

The emergence of significant arboviruses and their spillover transmission to humans represent a major threat to global public health. No approved drugs are available for the treatment of significant arboviruses in circulation today. The repurposing of clinically approved drugs is one of the most rapid and promising strategies in the identification of effective treatments for diseases caused by arboviruses. Here, we screened small-molecule compounds with anti-tick-borne encephalitis virus, West Nile virus, yellow fever virus and chikungunya virus activity from 2580 FDA-approved drugs. In total, 60 compounds showed antiviral efficacy against all four of the arboviruses in Huh7 cells. Among these compounds, ixazomib and ixazomib citrate (inhibitors of 20S proteasome β5) exerted antiviral effects at a low-micromolar concentration. The time-of-drug-addition assay suggested that ixazomib and ixazomib citrate disturbed multiple processes in viruses' life cycles. Furthermore, ixazomib and ixazomib citrate potently inhibited chikungunya virus replication and relieved virus-induced footpad swelling in a mouse model. These results offer critical information which supports the role of ixazomib as a broad-spectrum agent against arboviruses. [ABSTRACT FROM AUTHOR]

Prolonged survival and expanded treatment options in myeloma patients have led to adverse events associated with treatment getting increased attention. This systematic review and meta-analysis aimed to determine the incidence of ixazomib–associated cardiovascular adverse events (CVAEs) and to compare the rates of ixazomib–associated CVAEs and related therapies. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and high-grade CVAEs and study characteristics were recorded. A total of 266 potentially relevant articles were identified, and 246 were excluded after review. Twenty studies of 1715 patients with multiple myeloma were thus considered in this study. The estimated rates of all-grade and high-grade ixazomib associated CVAEs were 11.2 and 3.7%, respectively. Subgroup analysis showed that median age ≥65 years, none phase 1 trial and combination regimen were associated with higher rates of high-grade ixazomib associated CVAEs. Ixazomib was association with increased high-grade CVAEs risk (RR = 1.679, 95% CI: 1.078–2.615, P = 0.022). Ixazomib was associated with a significant rate of high-grade CVAEs. Future studies are needed to identify patients at high risk for high-grade CVAEs. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a haematological cancer that needs continuous long-term management for improved outcomes and survival. Over the last few decades, medical therapies for myeloma have improved considerably, with several new drug classes becoming available. Oral therapies, especially when used in combinations, are more convenient than intravenous therapies, and limit the number of clinic visits. Oral therapies include thalidomide, lenalidomide, pomalidomide, ixazomib, panobinostat, selinexor, venetoclax, melphalan and cyclophosphamide. Cytopenias were the most common adverse events with the immunomodulatory drugs panobinostat, selinexor and venetoclax, while skin rash was seen commonly with ixazomib and lenalidomide. Oral regimens are imperative during a global pandemic and can be managed over telemedicine visits rather than outpatient infusions and injections, reducing the risk of exposure and infection. It is important that patients monitor their side effects and report them to their healthcare providers at the earliest opportunity. We review available oral regimens and their combinations for effective management of myeloma. [ABSTRACT FROM AUTHOR]

Background: Maintenance therapy with proteasome inhibitors (PIs) can improve outcomes of multiple myeloma (MM) patients, however, the neurotoxicity and parenteral route of bortezomib limit its long‐term use. An efficacious, tolerable, and convenient PI option is needed. Methods: In this single‐center, real‐world study, we retrospectively analyzed the outcome and safety profile of ixazomib‐based maintenance therapy in patients who plateaued with the responses of steady disease or better after bortezomib‐based induction therapy in MM patients not undergoing transplantation. Results: Of all the 71 patients, 37 cases (52.1%) were newly diagnosed MM (NDMM) and 34 cases (47.9%) were relapsed and/or refractory MM (RRMM). The overall response rate (ORR) was 81.7%, including 34 patients (47.9%) with a very good response rate or better (≥VGPR) after a median of nine cycles (6–14) of bortezomib‐based induction therapy. Then the ORR was transformed to 74.6% including 39 patients of ≥VGPR (54.9%) after a median of six courses (2–25) of ixazomib‐based maintenance therapy. Of these, 18 patients (25.4%) exhibited responses deepened. With 26.5 months median follow‐up, median progression‐free survival (PFS) was 28.4 and 16.5 months from the start of bortezomib and 16.2 and 10.0 months from the initiation of ixazomib in NDMM and RRMM group, respectively. Moreover, responses deepened during the maintenance phase (hazard ratio: 0.270, p = 0.007), and responses of ≥VGPR during the induction phase (hazard ratio: 0.218, p < 0.001) were confirmed to independently predict longer PFS after multivariate analyses. Severe adverse events (grade 3/4) were relatively rare. Bortezomib‐emergent peripheral neuritis (PN) was significantly relived after the transition to ixazomib (p < 0.001). Conclusion: This real‐world analysis has demonstrated oral ixazomib is a favorable option of long‐term administration for maintenance with efficacy and feasibility and confirmed the association between deepening responses with ixazomib and prolonged PFS. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a leading cause of cancer-related deaths, primarily as a result of metastases. In this metastasis, the epithelial-to-mesenchymal transition (EMT) is essential. Interaction with the cancer cell microenvironment is primarily dependent on M1- and M2-polarized macrophage. Methods and results: In this study, we revealed the EMT-associated activity of M1, M2a and M2c macrophages in A549 lung cancer cells. We established a co-culture model of A549 lung cancer cells utilizing THP-1-derived M1/M2 polarised macrophages to explore the involvement of macrophages in the immune response, apoptosis, and EMT in lung cancer. Although multiple polarising agents are routinely used for M1 and M2 conversion, we assessed a new possible polarising agent, hydrocortisone. Conclusions: M1 increased A549 cell sensitivity to proteasome inhibitors and decreased A549 cell viability by inducing apoptosis. EMT was induced in the presence of M2c macrophages in A549 cells by the levels of vimentin, fibronectin, E-cadherin, NF-kB, CCL-17. We also revealed the antiproliferative effects of bortezomib and ixazomib on A549 cells in both 2D and 3D cultures. Our findings could help develop an immunotherapeutic strategy by shedding light on a previously undiscovered part of the EMT pathway. Furthermore, additional investigation may reveal that polarising tumour-associated macrophages to M1 and eliminating the M2a or particularly the M2c subtype are effective anti-cancer strategies. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a rare, elusive, and life-threatening condition that is characterized by the pathologic and uncontrolled secondary activation of the cytotoxic T-cells, natural killer cells (NK-cells), and macrophages of the innate immune system. This condition can develop in sporadic or familial contexts associated with hematological malignancies, as a paraneoplastic syndrome, or linked to an infection related to immune system deficiency. This leads to the systemic inflammation responsible for the overall clinical manifestations. Diagnosis should be thorough, and treatment should be initiated as soon as possible. In the current manuscript, we focus on classifying the HLH spectrum, describing the pathophysiology and the tools needed to search for and correctly identify HLH, and the current therapeutic opportunities. We also present the first case of a multiple myeloma patient that developed HLH following therapy with the ixazomib-lenalidomide-dexamethasone protocol. [ABSTRACT FROM AUTHOR]

Introduction and objective Multiple myeloma (MM) is an incurable condition with variable clinical course. The study included a group of patients with especially poor-prognosis, individuals with relapsed/refractory multiple myeloma (RRMM) and specific cytogenetic disorders. Among the currently used therapies the ixazomib-lenalidomid-dexamethasone (IRd) is considered as a candidate to improve outcomes. The aim of the study was to evaluate the safety and efficacy of IRd regimen in the treatment of patients with RMMM. Material and methods Nine patients aged 52–82 years who received ixazomib in the early access programme, were included in the study. All patients met the criteria for recurrent/relapsed MM and had high (t(4:14), t(14:16), del17p or +1q21) risk aberrations. Previous chemotherapy regimens included thalidomide and bortezomib. Median duration of exposure to ixazomib was 12 months. Results One patient with multiple cytogenetic aberrations and extramedullary plasmocytoma died because of progression after two months of treatment. In the remaining patients, the objective response to treatment was reached, and in four cases it was qualified as a very good partial response (VGPR). Observed adverse effects included neutropenia, infections, and oedema (in three cases Grade 3). Eight patients continue treatment, in two cases the decision was made to reduce lenalidomide doses. Conclusions Preliminary results suggest potentially high efficacy and good safety profile of IRd therapy in patients with RRMM and unfavourable cytogenetics.

Abstract Background We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. Methods A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient’s characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. Results In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1–3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51–0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. Conclusions Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.