Search

Objective: We aimed to explore the efficacy and safety of Selinexor combined bortezomib, lenalidomide, and dexamethasone (XVRd) protocol in newly diagnosed multiple myeloma with extramedullary disease., Methods: This is a single-arm, open, observational clinical study. For induction/consolidation(21-day cycles), patients received 8 cycles of XVRd protocol. In maintenance (28-day cycles), patients received XR (Selinexor + Lenalidomide) at least 2 years until disease progression, death or withdrawal. The primary endpoints were overall response rates and minimal residual disease negative rates., Results: The median age of the 10 patients was 62 (range 55-81) years. R-ISS stage 3 was present in 2 (20%) patients. 3 patients had high risk cytogenetic and 1 patient with plasma cell leukocyte. According to IMWG criteria, the ORR of 10 patients with NDMM was 100%, including 2 stringent complete response (sCR), 2 complete remission (CR), 4 very good partial response (VGPR) and 2 partial response (PR). Median progression-free survival and overall survival were not achieved. The most common grade 3-4 treatment-emergent adverse events (occurring in 10% of patients) were thrombocytopenia. The most common non-hematological adverse events were grade 1 or 2, including nausea (30%), fatigue (40%), and anorexia (20%). Overall, the severe toxicities were manageable., Conclusion: The XVRd regimen had good efficacy and safety in newly diagnosed multiple myeloma with extramedullary disease., Competing Interests: Declarations Ethics statement This study was conducted in accordance with the Declaration of Helsinki and was approved by the independent ethics committee of Qingdao Municipal Hospital (No. 2022Y042). Patient consent All patients provided written informed consent. Clinical trial registration ChiCTR2200062860. Competing interests The authors declare no competing interests. Conflict of interest The authors declare no conflict of interest., (© 2024. The Author(s).)

Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear., Methods: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response., Results: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups., Conclusions: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.)., (Copyright © 2024 Massachusetts Medical Society.)

This case report describes the clinical course of a patient with relapsed IgA kappa multiple myeloma with high-risk cytogenetics. Initially treated with daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD) then transitioned to lenalidomide maintenance. However, he experienced a relapse and was treated with carfilzomib-based therapy (CFZ) but developed drug-induced thrombotic microangiopathy (DI-TMA). Despite receiving eculizumab and supportive care, the patient's condition worsened, leading to encephalopathy and refractory gastrointestinal bleeding in the setting of persistent thrombocytopenia. Ultimately, the decision was made to transition to comfort-focused care. DI-TMA has been documented with various proteasome inhibitors such as ixazomib and bortezomib. Additionally, other medications such as cyclosporine, tacrolimus, clopidogrel, ticlopidine, and interferon have been associated with DI-TMA as well (Pisoni et al. (Drug Saf 24:491-501, 2001) [18]). Here we discuss a case of carfilzomib-induced TMA (CFZ-TMA) refractory to eculizumab as well as a review of the published literature., (© 2024. The Author(s).)

We present the case of a man in his 50s with multiple myeloma who developed foot drop after receiving bortezomib-dexamethasone combination chemotherapy. Diagnostic evaluations, including haematological parameters, nerve conduction studies and imaging, were performed to confirm the diagnosis and assess the extent of neuropathy. He was managed conservatively with analgesics and vitamin supplements, and bortezomib was temporarily withheld. The neuropathy gradually improved, and bortezomib was successfully reintroduced without recurrence of foot drop. Bortezomib-induced foot drop is a rare complication of bortezomib-based therapy in patients with multiple myeloma. Early recognition and intervention are crucial to minimise impact on quality of life. This case report emphasises the safe reintroduction of bortezomib post-neuropathy resolution, emphasising the importance of early recognition and multidisciplinary management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Bortezomib-induced neuropathic pain (BINP) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BINP susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BINP development in Korean MM patients while evaluating the reproducibility of variants from Caucasians. Clinical data and buffy coat samples from 185 MM patients on bortezomib were collected. The cohort was split into discovery and validation cohorts through random stratification of clinical risk factors for BINP. Genome-wide association study was performed on the discovery cohort (n = 74) with Infinium Global Screening Array-24 v3.0 BeadChip (654,027 single nucleotide polymorphism [SNPs]). Relevant biological pathways were identified using the pathway scoring algorithm. The top 20 SNPs were validated in the validation cohort (n = 111). Previously reported SNPs were validated in the entire cohort (n = 185). Pathway analysis of the genome-wide association study results identified 31 relevant pathways, including immune systems and endosomal vacuolar pathways. Among the top 20 SNPs from the discovery cohort, 16 were replicated, which included intronic variants in ASIC2 and SMOC2, recently implicated in nociception, as well as intergenic variants or long noncoding RNAs. None of the 17 previously reported SNPs remained significant in our cohort (rs2274578, P = .085). This study represents the first investigation of novel genetic loci and biological pathways associated with BINP occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms. PERSPECTIVE: This article is the first to explore novel genetic loci and pathways linked to BINP in Korean MM patients, offering novel insights beyond the existing research focused on Caucasian populations into personalized risk assessment and therapeutic strategies of BINP., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

The ubiquitin-proteasome pathway (UPP) regulates protein stability and normal cellular functions with the help of autocatalytic proteasome complex. Studies have linked aberrant proteasome activity to malignant cells and found that proteasome inhibitors play a significant role as therapeutic drugs for various types of cancer, specifically multiple myeloma and mantle cell lymphoma. Bortezomib, the first FDA-approved proteasome inhibitor for treating different stages of multiple myeloma, acts on cancer cells by inhibiting the 26S proteasome, modulating NF-κB, phosphorylating Bcl-2, upregulating of NOXA, blocking p53 degradation, activating caspase, generating reactive oxygen species (ROS), and inhibiting angiogenesis. However, its efficacy is limited due to side effects such as peripheral neuropathy (PN), thrombotic microangiopathy (TMA), and acute interstitial nephritis (AIN). Therefore, a better understanding of its precise mechanism of action may help mitigate these side effects. In this review, we have discussed the proposed mechanisms of action and off target effects of Bortezomib, along with the prospects of next generation potential proteasome inhibitor drugs in the treatment of cancer., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies., Methods: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status., Results: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved., Conclusions: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse., Methods: In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed., Results: A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group., Conclusions: Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.)., (Copyright © 2024 Massachusetts Medical Society.)

The present study is an overview of systematic reviews focusing on adverse events of antimyeloma treatments. It provides a systematic description of adverse events as they are reported in the systematic reviews as well as a critical appraisal of included reviews. We conducted a comprehensive literature search in the most widely used electronic databases looking for systematic reviews that had an adverse event of an antimyeloma treatment intervention as primary outcome. Two independent reviewers conducted selection of included studies and data extraction on predesigned online forms and assessed study quality using AMSTAR 2. Overall corrected covered area (CCA) was calculated to examine the overlap of primary studies across systematic reviews. After screening eligible studies, 23 systematic reviews were included in this overview. Seven reviews with overall CCA of 14.7% examined cardiovascular adverse events of different drugs, including immunomodulatory drugs and proteasome inhibitors (mainly carfilzomib). Nine focused on infections, presenting with overall CCA of 5.8%, each one focused on a different drug or drug class. Three studied thromboembolism in patients treated either with lenalidomide, any immunomodulatory drug, or with daratumumab and had an overall CCA equal to 1.5%. Four more reviews focused on bortezomib-associated neurotoxicity, carfilzomib-associated renal toxicity, or second primary malignancies as an adverse event of lenalidomide or anti-CD38 monoclonal antibody treatment. The quality of included studies as judged by AMSTAR 2 was mostly critically low. Absence of a priori registered protocol and formal assessment of risk of bias of included primary studies were the most common shortcomings. Reporting of antimyeloma drug-associated toxicity is supported by multiple systematic reviews; nevertheless, methodological quality of existing reviews is mostly low., (© 2023. The Author(s).)

Purpose: Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib., Methods: We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events., Results: Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048)., Conclusion: While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences., (© 2024. The Author(s).)

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease., (© 2024 John Wiley & Sons Ltd.)

Background: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH., Methods: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials., Results: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min -1 ·m -2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib., Conclusion: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely., Competing Interests: Conflict of interest: X. Jaïs reports grants from Acceleron, Janssen, MSD and Bayer HealthCare, lecture honoraria from Janssen and MSD, and travel support from MSD, outside the submitted work. L. Savale reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Bayer, Janssen and Merck, and lecture honoraria from Janssen and Merck, outside the submitted work. M. Jevnikar reports consulting fees from Janssen, and travel support from MSD and Janssen, outside the submitted work. A. Boucly reports grants from Acceleron, Janssen and MSD, and lecture honoraria and travel support from Janssen, Merck, AOP Orphan and Ferrer, outside the submitted work. G. Simonneau reports consulting fees and lecture honoraria from Actelion, Jansen, Bayer and MSD, travel support from Janssen, and advisory board participation with Acceleron, outside the submitted work. O. Sitbon reports grants from Acceleron (now MSD), AOP Orphan, Janssen (formerly Actelion) and MSD, consulting fees from Acceleron (now MSD), Altavant (now Enzyvant), AOP Orphan, Ferrer, Gossamer Bio, Janssen (formerly Actelion) and MSD, lecture honoraria from AOP Orphan, Janssen (formerly Actelion), Ferrer and MSD, and advisory board participation with Altavant (now Enzyvant), Gossamer Bio, Janssen (formerly Actelion) and MSD, outside the submitted work. M. Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, Morphogen-IX, Shou Ti and United Therapeutics, lecture honoraria from Janssen and Merck, and advisory board participation with Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck MSD, consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, and lecture honoraria from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Both humoral and cell-mediated immunity of the patient affected by multiple myeloma (MM) are impaired; thus, infection is the main cause of the onset of symptoms and death caused by MM. Bortezomib is a first-line drug approved for patients with multiple myeloma (MM) and has significantly increased their overall survival. However, bortezomib-induced peripheral neuropathy (PN) remains a significant side effect that has led to its discontinuation in some patients. Guillain-Barre syndrome (GBS) is thought to be related to immune damage, and most patients have cytomegalovirus (CMV), Epstein-Barr virus (EBV), or mycoplasma infection before onset. Cases of GBS secondary to MM are rare., Methods: We provide a case of GBS caused by cytomegalovirus infection after MM treatment, and briefly review the existing literature., Results: Secondary GBS after MM. This patient received active treatment. The clinical symptoms are gradually improving., Conclusions: The use of bortezomib has the risk of reactivating the virus. It is more about the reactivation of hep-atitis B virus. Nonetheless, cytomegalovirus and Epstein-Barr virus shall have our attention. Patients with MM need to monitor CMV, regularly, especially during the treatment of bortezomib. At the same time, they also need to closely monitor the symptoms and signs of the nervous system to guard against the occurrence of GBS.

Background: Capsaicin is a highly selective agonist of the transient receptor potential vanilloid 1. The adhesive capsaicin patch provides a high capsaicin concentration (8%) directly in the painful area - its efficacy in benign peripheral neuropathic pain (diabetic neuropathy or postherpetic neuralgia) has recently been described in the literature. However, there is scant evidence of its efficacy in chemotherapy-induced peripheral neuropathy (CIPN). This is a concern for patients with multiple myeloma, who suffer from peripheral neuropathic pain induced by first-line treatments (bortezomib or thalidomide)., Aim: To describe improved control of CIPN in patients with multiple myeloma using adhesive capsaicin 8% patch., Methods: We opted for a retrospective observational case series. Between October 2017 and October 2020, we collected clinical data from adult multiple myeloma patients affected by CIPN who were administered the capsaicin 8% patch in our palliative care outpatient clinic. We compiled Numerical Pain Rating Scale (NPRS) scores, patients' medication needs and performance status before and after patch application., Results: Two women and five men with an average age of 62.85 years received bortezomib. Two patients (28.57% of the sample) also received thalidomide. The average NPRS score before patch application was 6.42/10. Five of the seven patients (71.42%) received a mean daily oral morphine dose of 52.85 mg/day, five (71.42%) received gabapentinoids and one (14.28%) received antidepressants. The average NPRS score decreased to 4/10 seven days after patch application, while the mean daily oral morphine dose remained stable. Performance status improved slightly in two patients (28.57%) and remained stable in the rest. One patient (14.28%) required an extra analgesic dose during patch application., Conclusions: Capsaicin 8% patch application appears to reduce pain intensity in patients with multiple myeloma suffering from CIPN., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Thrombosis represents a frequent and potentially severe complication in individuals diagnosed with multiple myeloma (MM). These events can be driven by both the disease as well as the therapies themselves. Overall, available evidence is inconclusive about the differential thrombogenicity of carfilzomib/lenalidomide/dexamethasone (KRd) and bortezomib/lenalidomide/dexamethasone (VRd). This meta-analysis compares the risk for venous thromboembolism (VTE; including deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE; including myocardial infarction and ischemic stroke) with KRd versus VRd as primary therapy for newly diagnosed MM (NDMM). Out of 510 studies identified after deduplication, one randomized controlled trial and five retrospective cohort studies were included. We analyzed 2304 patients (VRd: 1380; KRd: 924) for VTE events and 2179 patients (VRd: 1316; KRd: 863) for ATE events. Lower rates of VTE were observed in the VRd group when compared with the KRd group (6.16% vs. 8.87%; odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.88; p = .01). Both treatment groups exhibited minimal ATE incidence, with no significant difference between them (0.91% vs. 1.16%; OR, 1.01; 95% CI, 0.24-4.20; p = .99). In view of potential biases from retrospective studies, heterogeneity of baseline population characteristics, and limited access to patient-level data (e.g., VTE risk stratification and type of thromboprophylaxis regimen used) inherent to this meta-analysis, additional research is warranted to further validate our findings and refine strategies for thrombosis prevention in MM., (© 2024 Wiley Periodicals LLC.)

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events. In summary, these findings suggest a benefit of D-RVd front-line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients., (© 2024 Janssen Scientific Affairs, LLC. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens., Methods: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity., Results: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia., Conclusion: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Bortezomib is the first-line standard and most effective chemotherapeutic for multiple myeloma; however, bortezomib-induced peripheral neuropathy (BIPN) severely affects the chemotherapy regimen and has long-term impact on patients under maintenance therapy. The pathogenesis of BIPN is poorly understood, and basic research and development of BIPN management drugs are in early stages. Besides chemotherapy dose reduction and regimen modification, no recommended prevention and treatment approaches are available for BIPN apart from the International Myeloma Working Group guidelines for peripheral neuropathy in myeloma. An in-depth exploration of the pathogenesis of BIPN, development of additional therapeutic approaches, and identification of risk factors are needed. Optimizing effective and standardized BIPN treatment plans and providing more decision-making evidence for clinical diagnosis and treatment of BIPN are necessary. This article reviews the recent advances in BIPN research; provides an overview of clinical features, underlying molecular mechanisms, and therapeutic approaches; and highlights areas for future studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A 60-year-old patient was diagnosed with multiple myeloma in November 2020, and started treatment in December 2020 with bortezomib, dexamethasone, and thalidomide. Four months later, he presented to the ophthalmology emergency department with inflammation and pain in the left eye. Examination of the anterior segment revealed severe, mixed anterior squamous blepharitis with significant bilateral palpebral inflammation, dysfunction of the meibomian glands, and several styes on both eyelids bilaterally. A peripheral ulcerative keratopathy was detected while examining the left eye cornea, with an inferior infiltrate and significant thinning, approximately 5 mm in length, at the limbal margin (Figure 1). Tear break-up time was shortened bilaterally. In addition to palpebral hygiene and oral treatment with doxycycline 100 mg every 24 hours, the patient was prescribed the following topical treatment without preservatives: artificial tears with lipid emulsion, netilmicin 0,3% 0,4 ml eye drops every 6 hours and dexamethasone 1 mg/ml every 8 hours.

Background: Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with multiple myeloma. As thalidomide toxicity is dose-dependent, identifying the most appropriate dose for each patient is essential., Aims: This study aimed to investigate the effects of a thalidomide dose step-up strategy on treatment response and progression-free survival (PFS)., Methods and Results: This prospective observational study included 93 patients with newly diagnosed multiple myeloma (NDMM) who received bortezomib, thalidomide, and dexamethasone (VTD). The present study assessed the incidence of thalidomide dose reduction and discontinuation, the overall dose intensity, and their effects on therapeutic efficacy. Furthermore, this study used Cox proportional hazard models to analyze the factors contributing to thalidomide intolerability. The results showed the overall response rates in all patients and the evaluable patients were 78.5% and 98.7%, respectively. The median PFS in the study cohort was not reached. The most common thalidomide-related AEs were constipation (32.3%) and skin rash (23.7%), resulting in dose reduction and discontinuation rates of 22.6% and 21.5%, respectively. The responders had a significantly higher average thalidomide dose intensity than the nonresponders (88.6% vs. 42.9%, p < .001)., Conclusion: The thalidomide dose step-up approach is a viable option for patients with NDMM receiving VTD induction therapy with satisfactory efficacy and tolerability. However, thalidomide intolerance may lead to dose reduction or discontinuation due to unpredictable AEs, leading to lower dose intensity and potentially inferior treatment outcomes. In addition to a dose step-up strategy, optimal supportive care is critical for patients with multiple myeloma receiving VTD induction therapy., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Background: Bortezomib results in peripheral neuropathy (PN) in approximately 50% of patients, during multiple myeloma (MM) treatment, a complication known as Bortezomib-induced peripheral neuropathy (BIPN). The drug response varies among individuals. Genetic factor may play an important role in BIPN., Methods: A next-generation sequencing (NGS) panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy. mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR (RT-qPCR). Serum homocysteine (Hcy) levels were detected in 40 samples by chemiluminescent microparticle immunoassay (CMIA)., Results: Compared with the non-BIPN group (n = 89), a total of 8 significantly associated single nucleotide polymorphisms (SNPs) were identified in the BIPN group (n = 115): MTHFR (rs1801131, rs1801133, rs17421511), EPHX1 (rs1051740), MME (rs2016848), ALDH1A1 (rs6151031), HTR7 (rs1935349) and CYP2A6 (rs8192720). The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment (NP group) was lower than that of newly diagnosed patients without peripheral neuritis after treatment (NnP group) (1.70 ± 0.77 vs . 2.81 ± 0.97, p = 0.009). Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group (11.66 ± 1.79 μmol/L vs . 8.52 ± 3.29 μmol/L, p = 0.016) and healthy controls (11.66 ± 1.79 μmol/L vs . 8.55 ± 2.13 μmol/L, p ≤ 0.001)., Conclusion: CYP2A6, EPHX1, MTHFR, ALDH1A1, HTR7, MME and BIPN are linked in Chinese MM patients. BIPN is more likely to occur in patients with lower MTHFR mRNA expression, which might result in higher serum Hcy levels., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 Zhang et al.)

Background: Currently, there is no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). This study aimed to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs., Methods: A pre- and post-intervention study was conducted from February 2017 through June 2019 at Siriraj Hospital (Bangkok, Thailand). Five patients were invited to receive once-weekly BTZ (1.3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/d) for 4 months. The primary outcomes were the difference in antibody level at 8 and 48 weeks compared with baseline and the incidence of serious adverse events (AEs). The secondary outcome was the occurrence of opportunistic infections (OIs) during the 72 weeks after starting BTZ., Results: The median patient age was 46 years (range, 34-53). All patients had 3-5 OIs prior to enrollment. All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment. There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.73 ± 0.72) or 48 weeks (3.74 ± 0.53) compared with baseline (3.84 ± 0.49; P = .336 and P = .555, respectively). However, after serum dilution, the antibody titer nonsignificantly decreased 8-16 weeks after BTZ initiation (P = .345). Ten OIs were observed 24-72 weeks after BTZ initiation., Conclusions: Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and 10 OIs were observed during 24-72 weeks of BTZ treatment. No serious AEs were observed. Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells. Clinical Trials Registration. NCT03103555., Competing Interests: Potential conflicts of interest. N. A. reports honoraria for speaking engagements from AstraZeneca (Thailand), Takeda (Thailand), and Janssen (Thailand). M. P. reports honoraria for speaking engagements from Oxford Nanopore, Rocher (Thailand), and ThermoFisher. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma (MM)., Methods: A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022. Among the 32 patients, 15 patients were relapsed and refractory multiple myeloma (R/RMM) (R/RMM group), 17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events (AE) or other reasons (conversion treatment group). The treatment included IPD regimen (ixazomib+pomalidomide+dexamethasone), IRD regimen (ixazomib+lenalidomide+dexamethasone), ICD regimen (ixazomib+cyclophosphamide+dexamethasone), ID regimen (ixazomib+dexamethasone)., Results: Of 15 R/RMM patients, overall response rate (ORR) was 53.3%(8/15), among them, 1 achieved complete response (CR), 2 achieved very good partial response (VGPR) and 5 achieved partial response (PR). The ORR of the IPD, IRD, ICD and ID regimen group were 100%（3/3）, 42.9%（3/7）, 33.3%（1/3）, 50%（1/2）， respectively， there was no statistically significant difference in ORR between four groups (χ 2 =3.375, P =0.452). The ORR of patients was 50% after first-line therapy, 42.9% after second line therapy, 60% after third line therapy or more, with no statistically significant difference among them (χ 2 =2.164, P =0.730). In conversion treatment group, ORR was 88.2%(15/17), among them, 6 patients achieved CR, 5 patients achieved VGPR and 4 patients achieved PR. There was no statistically significant difference in ORR between the IPD（100%， 3/3）, IRD（100%， 6/6）, ICD（100%， 3/3） and ID（60%， 3/5） regimen groups (χ 2 =3.737， P =0.184). The median progression-free survival (PFS) time of R/RMM patients was 9 months (95% CI : 6.6-11.4 months), the median overall survival (OS) time was 18 months (95% CI : 11.8-24.4 months). The median PFS time of conversion treatment group was 15 months (95% CI : 7.3-22.7 months), the median OS time not reached. A total of 10 patients suffered grade 3- 4 adverse event (AE). The common hematological toxicities were leukocytopenia, anemia, thrombocytopenia. The common non-hematological toxicities were gastrointestinal symptoms (diarrhea, nausea and vomit), peripheral neuropathy, fatigue and infections. Grade 1-2 peripheral neurotoxicity occurred in 7 patients., Conclusion: The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy, particularly for conversion patients who are effective for bortezomib therapy. The AE was manageable and safe.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM., (© 2024. The Author(s).)

Background: Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking., Objectives: Evaluate the real-world experience of the VCD regimen., Design: Retrospective., Setting: Tumor registry database of tertiary cancer care center., Patients and Methods: newly diagnosed MM patients who received VCD induction and underwent autologous stem cell transplant (ASCT) from July 2007 to July 2020., Main Outcome Measures: response evaluation, progression-free survival (PFS) and overall survival (OS)., Sample Size: 87 patients., Results: Of 102 patients who started induction with VCd, 87 patients experienced a partial response or more overall response rate of 85%). The median age of these 87 patients at diagnosis was 52 years, of which 29.9% presented with renal impairment and 60.3% of patients had stage 2 by the Revised International Staging System (R-ISS). Patients with a standard cytogenetic risk achieved a better response compared to those with a poor cytogenetic risk ( P =.044). The post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively. The median PFS was 49 months and 5 years OS was 84%. PFS was better in patients who achieved sCR vs PR (83 vs 35 months, P =.037). High LDH, high-risk cytogenetic and stage 3 R-ISS showed a worse median PFS and OS., Conclusions: VCD induction in newly diagnosed MM is highly effective, convenient, tolerable and affordable regimen, especially in low and middle-income countries with limited resources, also with favorable outcomes and survival. while those who did not respond successfully shifted to VRD or VTD., Limitations: The usual limitations of a retrospective analysis using registry-level data, no data on quality of life., Competing Interests: CONFLICT OF INTEREST: None.

This report describes a case of a patient with active multiple myeloma who was started on bortezomib, cyclophosphamide and dexamethasone and subsequently presented to the emergency department with acute intestinal obstruction one week later. The patient underwent exploratory laparotomy, but no mechanical cause of the obstruction was found. The patient later developed sepsis and eventually died. The possible cause of the intestinal obstruction was attributed to bortezomib, and the paper discusses the potential mechanism of this side effect and its management based on available literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To test if Patient Reported Outcomes (PRO) data can replace physical on-site consultation in determining if patients with multiple myeloma, AL amyloidosis, or plasma cell leukemia are ready for their next bortezomib treatment without dose reduction., Methods: We developed an online questionnaire addressing common side effects to bortezomib and an algorithm stratifying patients according to their responses and asked them to complete the questionnaire the day before attending the clinic. Applying a mixed-method study design of PRO data, time registrations, and interviews with patients and healthcare professionals, we tested the usability of electronic PRO data forming the basis of decision-making on whether patients are physically fit for the next treatment with an unchanged dose., Results: The questionnaire and the associated algorithm were able to identify patients who were physically fit for treatment without need for further consultation, with a positive predictive value of 98 %. The method proved to be feasible for all groups of patients regardless of age and educational level. Patients and healthcare professionals found the online questionnaire to be advantageous and flexible., Conclusion: The use of PRO data to evaluate patients prior to bortezomib treatment is safe and feasible. Patients prefer to report their side effects themselves as it provides them with more freedom during their treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma., Methods: GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18-70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0-3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m 2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1-2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, and on days 1 and 11 for cycles 3-4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m 2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1-28 for cycles 1-3; thereafter, up to 15 mg orally on days 1-28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1-6, and on day 1 for cycles 7-26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed., Findings: Between June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7-55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61-77), 69% (61-76), 66% (58-74), and 67% (59-75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both., Interpretation: Addition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma., Funding: Bristol Myers Squibb/Celgene and Chugai., Competing Interests: Declaration of interests EKM reports consulting or advisory role with Bristol Myers Squibb (BMS)/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi Aventis, Stemline, and Takeda; honoraria from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi Aventis, Stemline, and Takeda; research funding from Sanofi Aventis; and travel accommodation and expenses from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi Aventis, Stemline, and Takeda. HG reports support for the present manuscript from BMS/Celgene, Chugai, and HD6 funding; consulting or advisory role with Amgen, BMS, Janssen, Sanofi, and Adaptive Biotechnology; honoraria from Amgen, BMS, Chugai, GlaxoSmithKline, Janssen, Novartis, Sanofi, and Pfizer; research funding from Amgen, BMS, Celgene, GlycoMimetics, GlaxoSmithKline, Heidelberg Pharma, Hoffmann-La Roche, Karyopharm, Janssen, Incyte Corporation, Millenium Pharmaceuticals, Molecular Partners, Merck Sharp and Dohme, MorphoSys, Pfizer, Sanofi, Takeda, and Novartis; travel accommodations and expenses from Amgen, BMS, GlaxoSmithKline, Janssen, Novartis, Sanofi, and Pfizer; and grants or provision of Investigational Medicinal Products from Amgen, Array Biopharma/Pfizer, BMS/Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, Mundipharma, and Sanofi. MHä reports consulting or advisory role with Novartis, BMS/Celgene, Gilead Sciences, Sanofi/Aventis, Roche, Amgen, SOBI, Janssen, Takeda, GlaxoSmithKline, Jazz Pharmaceuticals, Bayer Vital, and BMS. RF reports Honoraria from Amgen, BMS/Celgene, Janssen, Sanofi, and Takeda; and travel accommodations and expenses from BMS/Celgene, Janssen, and GSK. MM reports consulting or Advisory Role with Janssen, BMS, Abbvie, Sanofi, GlaxoSmithKline, Oncopeptides, Takeda, and Stemline; honoraria from Amgen, BMS, GlaxoSmithKline, Janssen, and Takeda; and travel accommodations and expenses from Amgen. JD reports honoraria from Sanofi, BMS, Janssen, AstraZeneca, Beigene; and travel accommodation and expenses from Amgen, BMS, Beigene, and Amgen. CM reports Consulting or Advisory Role from Celgene, BMS, and Janssen. CS reports consulting or advisory role from BMS, GlaxoSmithKline, Janssen, Pfizer, Roche, and Takeda; honoraria from Amgen, BMS/GlaxoSmithKline, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda; research funding from Janssen, and Takeda; and travel accommodation and expenses from BMS, Janssen, Sanofi Aventis, and Takeda. RS reports consulting or advisory role with BMS/Celgene, GlaxoSmithKline, Janssen, Kite/Gilead, and Sanofi; and honoraria from Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Kite/Gilead, Sanofi, and Takeda. IvM reports consulting or advisory role with Sanofi, Amgen, Janssen, Takeda, Stemline, GSK, BMS, Oncopeptides, Pfizer, and AstraZeneca. PR reports honoraria from BMS and travel accommodation and expenses from BMS. UG reports consulting or advisory role with Amgen, Boehringer Ingelheim, BMS, Celtrion, Ipsen, Sanofi, and MSD; and honoraria from Amgen, AstraZeneca, and Novartis. SK reports travel accommodation and expenses from AbbVie. UMM reports consulting or advisory role with Sanofi-Aventis, BMS, Roche, GSK, Novartis, Pierre Fabre, MSD, and Guardant Health; and travel accommodation and expenses from Pierre Fabre, Ipsen, and Janssen. CK reports travel accommodation and expenses from European Hematology Association. KCW reports consulting or advisory role with Abbvie, Amgen, Adaptive Biotech, BMS/Celgene, BeiGene, Janssen, GlaxoSmithKline, Karyopharm, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Takeda, and Menarini; honoraria from Abbvie, Amgen, Adaptive Biotech, Astra Zeneca, BMS/Celgene, BeiGene, Janssen, GlaxoSmithKline, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Stemline, Takeda, and Menarini; and research funding from Abbvie, Amgen, BMS/Celgene, Janssen, GlaxoSmithKline, Sanofi, and Takeda. MSR reports consulting or advisory role with BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie, Novartis, and Roche; research funding from Sanofi; travel accommodation and expenses from BMS, AbbVie, Janssen, Sanofi, GSK; Honoraria from BMS, Janssen, GSK, AbbVie, and Sanofi; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Novartis, Sanofi. HJS reports consulting or advisory role with Amgen, AstraZeneca, BMS/Celgene, Genzyme, GSK, Janssen Cilag, Oncopeptides, Pfizer, Sanofi, and Stemline; honoraria from Abbvie, Amgen, AstraZeneca, BMS/Celgene, Genzyme, GSK, Janssen Cilag, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; and travel accommodation and expenses from Amgen, BMS/Celgene, Janssen Cilag, and Sanofi. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed., Methods: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status., Results: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group., Conclusions: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)., (Copyright © 2023 Massachusetts Medical Society.)

Proton pump inhibitors (PPIs) are commonly used in cancer patients, but their impact on treatment outcomes in multiple myeloma (MM) patients remains unclear. This study investigated the association of PPI use with survival and adverse effects in MM patients across three randomized-control trials initiating daratumumab, lenalidomide, or bortezomib combination treatments. Cox proportional hazard analysis and logistic regression were employed to assess the associations with treatment outcomes, while adjusting for age, sex, weight, MM international staging system stage, ECOG-performance status, comorbidity count, and presence of gastrointestinal disorders. Pooled data involving 1804 patients revealed that 557 (32%) used PPIs at baseline. PPI use was independently associated with worse overall survival (adjusted HR [95% CI] 1.32 [1.08-1.62], P = 0.007) and grade ≥ 3 adverse events (adjusted OR [95% CI] 1.39 [1.03-1.88], P = 0.030). However, the association with progression-free survival did not reach statistical significance (adjusted HR [95% CI] 1.14 [0.97-1.33], P = 0.112). Findings were consistent across trials and treatment arms. PPI use was identified as a negative prognostic factor in MM patients, potentially enhancing clinical decisions regarding its use. Further research is needed to fully comprehend the impacts and safety of PPI use in MM patients., (© 2024. The Author(s).)

Aim: To compare the effectiveness of in -class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73.2% with IRd versus 57.5% with V-based therapy (p < 0.0001). Median duration of treatment was 10.8 versus 5.3 months (p < 0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration : US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3-4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting., (© 2023. The Author(s).)

TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30-50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent., (© 2023. The Author(s).)

Objective: To research the effects of autonomic neuropathy of the digestive system induced by bortezomib on clinical efficacy and quality of life., Methods: A total of 150 patients with newly diagnosed multiple myeloma (MM) were hospitalized in our department from January 2018 to December 2021, and treated with bortezomib-based combination regimens. To observe the incidence of autonomic neuropathy of the digestive system and analyse the correlations between the severity of autonomic neuropathy and the efficacy, survival, age, underlying diseases and personal history., Results: The incidence of autonomic neuropathy of the digestive system was 60.0%. The overall response rate (ORR), 2-year progression-free survival (PFS) rate and 2-year overall survival (OS) rate in the grade 3 group of autonomic neuropathy were significantly lower than those in the grade 1-2 group, and the differences were statistically significant ( P  < 0.05). Age, constipation, diabetes, fracture/spinal cord compression in bed and history of alcoholism were positively correlated with the risk of autonomic neuropathy of the digestive system ( P  < 0.05). The autonomic neuropathy of the digestive system was significantly alleviated in most patients after the timely adjustment of the treatment regimen, and bortezomib could continue to be administered., Conclusions: The incidence of autonomic neuropathy of the digestive system induced by bortezomib is high, and its severity is closely related to efficacy, advanced age, constipation, diabetes, fracture/spinal cord compression in bed and history of alcoholism. Early detection and early treatment are necessary to better treat the disease and reverse the autonomic neuropathy.

Aim: To study the dynamics of calculated indices [neutrophil-lymphocyte ratio (NLR); systemic inflammation index (SIV)] and biomarkers of systemic inflammation [interleukin-1β (IL-1β); high-sensitivity C-reactive protein (hsCRP)], parameters of the structure-and-function state of the myocardium and intracardiac hemodynamics, and their relationship in patients newly diagnosed with multiple myeloma (MM) at the onset of the disease and after 6 courses of chemotherapy (CT) containing the proteasome inhibitor bortezomib., Material and Methods: This prospective study included 30 patients aged 63.8±10.0 years diagnosed with MM; 17 (56.7 %) of them were men. The following tests were performed for all patients: measurement of IL-1β and hsCRP, calculation of the inflammation indexes NLR and SIV, transthoracic echocardiography before and after 6 courses of bortezomib-containing CT. At the time of study completion, 9 patients dropped out due to reasons not related to cardiovascular complications of CT., Results: The antitumor therapy was associated with increases of immune-inflammation indexes: NLR increased from 1.54 [1.02; 1.83] to 2.9 [1.9; 4.35] (p=0.009) and SIV increased from 402.95 [230.5; 534.0] to 1102.2 [453.1; 1307.9] (р=0.014). IL-1β increased from 5.15 [4.05; 5.77] to 6.22 [5.66; 6.52] pg/ml remaining within the reference range (p=0.142) whereas hsCRP decreased from 1.02 [0.02; 2.71] to 0.02 [0.02; 0.82] IU/l (p=0.138). Statistically significant changes in parameters of heart remodeling and clinical picture of cardiovascular complications were not observed. A correlation analysis showed significant inverse correlations of hsCRP with left ventricular ejection fraction (LV EF) (r= -0.557; p=0.003), the number of plasma cells (PC) with LV EF (r= -0.443; p=0.023), and a direct correlation of the number of PC with hsCRP (r=0.433; p=0.022)., Conclusion: During the study, the accepted criteria for cardiotoxicity of bortezomib-containing chemotherapy in patients with MM, were not met. The identified correlations between the level of markers for acute inflammation, indexes of intracardiac hemodynamics, and the immediate MM substrate may indicate the role of chronic low-intensity inflammation in the pathogenesis of myocardial remodeling in patients with MM. This necessitates further studies on larger samples of patients to assess the prognostic significance.

Background: Multiple myeloma (MM), as well as some treatments for MM, increase the risk of venous thromboembolism (VTE). Prior literature suggests carfilzomib, lenalidomide, and dexamethasone (KRd) may have a higher incidence of thromboembolic events compared with bortezomib, lenalidomide, and dexamethasone (VRd). We aimed to evaluate VTE risk with KRd induction compared to VRd at a large academic medical center in the United States., Materials and Methods: We retrospectively reviewed patients with newly diagnosed MM presenting at a single institution. Patients were followed for objectively diagnosed VTE events for 6 months following the start of induction therapy., Results: A total of 209 patients were included, with 69 (33%) receiving KRd and 140 (67%) receiving VRd. Overall, 18 patients (9%) had a VTE event, with 5 (7%) in the KRd cohort and 13 (9%) in the VRd cohort (P = .80). Treatment with KRd was not associated with an increased risk of VTE compared to VRd (HR 0.74; 95% CI 0.26-2.08; P = .57)., Conclusion: In this cohort, KRd was not associated with an increase in VTE risk compared to VRd, contrary to prior literature., Competing Interests: Disclosure Angela Vickroy has consulted for Janssen Advisory Board. Mark Schroeder has received consultancy fees or honoraria from Advarra, Incyte, StemLine, and GSK. Ravi Vij has received consultancy fees or honoraria from Oncopeptides, Janssen, Takeda, BMS, GSK, Sanofi, Beigene, and Adaptive Biotechnologies. Sanofi. Kristen Sanfilippo has received research funding and loan repayment from NHLBI NIH, research funding from ACS-IRG, consultancy from Health Services Advisory Group, and expert case review from Quinn Johnston and Covington & Burling LLP., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Bortezomib-induced peripheral neuropathy in patients with multiple myeloma is an undesirable and sometimes severe side effect. Our study aimed to examine whether there was a difference in bortezomib-induced peripheral neuropathy between multiple myeloma patients with normal and abnormal genetic characteristics., Methods: This retrospective analysis is based on the assessment of bortezomib-induced peripheral neuropathy frequency in newly-diagnosed multiple myeloma patients with normal ( n  = 68) and abnormal ( n  = 45) genetic profiles. A total of 113 patients diagnosed with multiple myeloma according to the International Myeloma Working Group criteria, between 2016 and 2021, were included in this study., Results: Neuropathy was detected in 42 (37.1%) patients. The most common genetic anomalies were 13q del (in 28.9%), t (4.14) (in 22.2%), and trisomy 7 (in 20.0%). When patients with and without bortezomib-induced peripheral neuropathy were compared, the only significant differences were observed for age ( p  = 0.032) and genetic grouping ( p  = 0.001); whereas other characteristics that could be associated with bortezomib-induced peripheral neuropathy were similarly distributed in both groups. Bortezomib-induced peripheral neuropathy was significantly more frequent in multiple myeloma patients with normal genetic characteristics ( p  = 0.001)., Conclusion: As a result of our study, it was observed that the frequency of bortezomib neuropathy was significantly higher in patients with normal genetic features compared to those with abnormal genetic features. This result suggested that factors other than genetic factors should be investigated to clarify the etiology of bortezomib-associated neuropathy in patients with multiple myeloma., Competing Interests: Declaration of conflicting interestsThe authors) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis., Methods: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m 2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022., Findings: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy., Interpretation: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies., Funding: Janssen Oncology., Competing Interests: Declaration of interests PMV served as a consultant for, served on an advisory board for, and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Sanofi, and Secura Bio. DWS served as a consultant or in an advisory role for GlaxoSmithKline, AbbVie, Sanofi, Bristol Myers Squibb, Janssen, and Pfizer. JLK served as a consultant for AbbVie, Bristol Myers Squibb, Janssen, Roche/Genentech, and Tecnopharma; received research funding from AbbVie, Amgen, Bristol Myers Squibb, Fortis Therapeutics, Heidelberg Pharma, Janssen, Novartis, Roche/Genentech, Sutro Biopharma, and Takeda; received honoraria from AbbVie, Janssen, Roche/Genentech, and Tecnopharma; and served on an advisory board for Incyte and TG Therapeutics. BR received honoraria from Incyte, Bristol Myers Squibb, and PharmaEssentia. CR served as a consultant and on a speakers bureau for Janssen, Takeda, Bristol Myers Squibb, Amgen, and Karyopharm Therapeutics. ACh served as a consultant or in an advisory role for Amgen, Janssen Oncology, Seattle Genetics, Karyopharm Therapeutics, Genzyme, Oncopeptides, Takeda, Antengene, GlaxoSmithKline, Secura Bio, Shattuck Labs, Genentech, AbbVie, and Bristol Myers Squibb/Celgene; and received research funding from Celgene, Janssen, Amgen, Seattle Genetics, Takeda, and Pharmacyclics. RS served as a consultant or in an advisory role for Sanofi/Aventis, Janssen Oncology, and Oncopeptides; and received research funding from Sanofi. LJC served as a consultant or in an advisory role for AbbVie, Amgen, Celgene, Karyopharm Therapeutics, and Sanofi; served on a speakers bureau for Amgen and Sanofi; received honoraria from Amgen, Celgene, Janssen, Karyopharm Therapeutics, and Sanofi; and received research funding from Amgen and Janssen. LDA served as a consultant or in an advisory role for and received honoraria from GlaxoSmithKline, Bristol Myers Squibb, Celgene, Janssen, Amgen, Oncopeptides, Karyopharm Therapeutics, AbbVie, BeiGene, Cellectar, and Sanofi. NS served as a consultant for Amgen, CareDx, CSL Behring, GlaxoSmithKline, Indapta Therapeutics, Karyopharm Therapeutics, Kite, Oncopeptides, and Sanofi; and received research funding from bluebird bio, Bristol Myers Squibb/Celgene, Janssen, Nektar, Poseida, Precision BioSciences, Sutro Biopharma, and TeneoBio. NB received honoraria from OncLive; and served as a consultant or in an advisory role and on a speakers bureau for Janssen, Sanofi Genzyme, and Oncopeptides. YAE received research funding, received honoraria, and served on a speakers bureau for Janssen, Takeda, Oncopeptides, GlaxoSmithKline, Pfizer, Sanofi, and Bristol Myers Squibb. SAH served as a consultant for Bristol Myers Squibb/Celgene, Janssen, Takeda, Oncopeptides, GlaxoSmithKline, Secura Bio, and Sanofi; and received research funding from Oncopeptides. CC received honoraria from Takeda, Bristol Myers Squibb, Pfizer, and Janssen. AJ served as a consultant or in an advisory role for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, and Sanofi. TMW served as a consultant for Janssen, Carevive, and Sanofi. RZO holds stock and other ownership interests in Asylia Therapeutics; received honoraria from and served as a consultant or in an advisory role for AbbVie, Biotheryx, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides, Regeneron, Sanofi, and Takeda; received research funding from Asylia Therapeutics, Biotheryx, and Heidelberg Pharma; and holds patents, royalties, or other intellectual property for Asylia Therapeutics. KHS served on an advisory board for AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, and Janssen; received research funding from AbbVie and Karyopharm Therapeutics; served on a speakers bureau for Adaptive Biotechnologies Corporation, Amgen, Bristol Myers Squibb, Janssen, and Sanofi Genzyme; served as a consultant for Adaptive Biotechnologies Corporation, Novartis, and Sanofi Genzyme; and received honoraria from Karyopharm Therapeutics. AJC served as a consultant for Janssen, Bristol Myers Squibb, EUSA Pharma, AbbVie, Sanofi, Cellectar, GlaxoSmithKline, and Secura Bio; and received research funding from Janssen, AbbVie, Sanofi, Harpoon, Bristol Myers Squibb, Adaptive Biotechnologies, and Nektar. SD is the Executive Officer for Alliance Foundation Trials for Clinical Trials. HP, ACo, and SP are employees of and hold stock and other ownership in Janssen. TSL is an employee of Janssen. SZU served as a consultant or in an advisory role for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GlaxoSmithKline, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol Myers Squibb/Celgene; served on a speakers bureau for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol Myers Squibb/Celgene; and received research funding from Celgene and Array BioPharma. PGR received research funding from Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, and Karyopharm Therapeutics; and served on an advisory committee for Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, Karyopharm Therapeutics, Janssen, Sanofi, Secura Bio, GlaxoSmithKline, Regeneron, AstraZeneca, and Protocol Intelligence. JL and NN declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aim of this study is to analyze the efficacy and safety of sequential therapy with bortezomib-based triplet regimens without lenalidomide (PXD, including VTD, PAD, and VCD) followed by continuous lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone (Vd) treatment. The main objective is to evaluate the advantages of PXD followed by Rd compared to the combinations of bortezomib-lenalidomide-dexamethasone (VRd) in newly diagnosed multiple myeloma (NDMM). Fifty-eight nontransplant NDMM patients who were admitted to our department from 2017 to 2019 were included in this study. Bortezomib-based triplet regimens were initially selected and followed by Rd or Vd as continuous treatment once the patients achieved partial remission (PR) or better response. The efficacy and safety of the patients were observed. The Rd continuous treatment cohort was compared with historical data from the EVOLUTION trial on continuous VRd treatment. In our cohort, the overall survival rate was 100%, and progression-free survival (PFS) was 38.5% after a median of 19 (4-36) cycles of Rd continuous therapy was applied. During the follow-up period, the best outcome assessments achieved were 53.8% complete response (CR) and 84.6% excellent partial response (VGPR). A total of 23.1% had grade 3-4 or higher drug-related adverse reactions, mainly hematological toxicity, and no patients died of adverse reactions. Compared with the Vd group, the Rd group had a better PFS and VGPR rate (2-year PFS: 92.3% vs. 56.3%, P = 0.002; 3-year PFS: 69.2% vs. 8.0%, P < 0.001; VGPR: 84.6% vs. 69.2%, P = 0.02). No significant differences were found in ORR (100% vs. 92.3%) or CR (53.8% vs. 35.7%, P = 0.082). Compared with the EVOLUTION study, patients in the Rd group had a more advanced disease stage (stage III rate of 40% vs. 19%, P = 0.039) and worse physical status (KPS 50-60 rate of 25.0% vs. 2.0%, P = 0.000). However, a higher proportion of ORR (100% vs. 73.0%, P < 0.001), VGPR or better (75.0% vs. 32.0%, P < 0.001), and PFS at 12 months (90.0% vs. 68%, P = 0.011) were achieved. Sequential administration of bortezomib-based triplet regimens without lenalidomide as an initial therapy followed by Rd as a continuous treatment may not be inferior to VRd for first-line treatment in NDMM patients., (© 2022. The Author(s).)

Purpose: The incidence of multiple myeloma (MM) is two to three times higher in Black patients compared with other races, making it the most common hematologic malignancy in this patient population. Current treatment guidelines recommend the combination of a proteasome inhibitor, an immunomodulatory agent, and a corticosteroid as preferred induction therapy. Bortezomib use comes with the risk of peripheral neuropathy (PN) and potential need for dose reduction, therapy interruption, and additional supportive medications. Known risk factors for bortezomib-induced peripheral neuropathy (BIPN) include diabetes mellitus, previous thalidomide, advanced age, and obesity. We aimed to determine the potential association between Black race and incidence of BIPN., Patients and Methods: We identified a cohort of 748 patients with newly diagnosed MM who received induction with bortezomib, lenalidomide, and dexamethasone from 2007 to 2016. One hundred forty Black patients were matched with 140 non-Black patients on age, sex, BMI, and route of bortezomib administration. Incidence of BIPN was a binary event defined as new use of a neuropathy medication, bortezomib dose reduction, dose omission, or discontinuation because of PN., Results: The incidence of BIPN was higher in Black patients (46%) compared with non-Black patients (34%; P = .05) in both univariate (odds ratio [OR], 1.61; 95% CI, 1.00 to 2.61; P = .052) and multivariable analyses (OR, 1.64; 95% CI, 1.01 to 2.67; P = .047). No significant differences in BIPN were seen when stratified by route of administration., Conclusion: These data indicate that Black race is an independent risk factor for the development of BIPN. Additional prevention strategies, close monitoring, and appropriate supportive care measures are warranted for these patients.

Background: The nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been elucidated, although tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been reported to increase after introduction of the drug. This study compared the incidence and risk factors for acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate drug-related nephrotoxicity., Methods: From 2006 to 2017, 276 patients who underwent a first cycle of bortezomib-based chemotherapy for MM were identified in a single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network criteria within 7 days of the first chemotherapy., Results: The median (interquartile range) age was 65 (56-72) years, and baseline estimated glomerular filtration rate (eGFR) was 61.3 (34.1-89.1) mL/min/1.73 m2. The incidences of AKI and laboratory TLS were 17% (n = 47) and 13% (n = 36), respectively. Ten (3.6%) subjects met both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category [30-59, odds ratio (OR) 3.005 (95% confidence interval 1.163-7.976); 15-29, OR 4.225 (1.183-15.000); <15, OR 16.154 (3.831-70.920) vs ≥60, P < .001], lower serum albumin level [per 1 increase, OR 0.479 (0.256-0.871), P = .018], renal amyloidosis [OR 13.039 (4.108-44.041), P < .001] and use of acyclovir during bortezomib treatment [OR 3.689 (1.133-14.469), P = .042] were predictors of AKI. MM stages and β-2-microglobulin were not associated with increased risk of AKI. Regarding laboratory TLS, MM stage and β-2-microglobulin were higher in those with TLS than in others. In multivariate analyses, β-2-microglobulin level [OR 1.204 (1.005-1.461), P = .038] and absence of high-risk chromosome abnormalities [OR 0.143 (0.022-0.588), P = .016] were associated with higher risk of TLS., Conclusions: Development of AKI was often observed in the absence of TLS in patients with MM after treatment with bortezomib. In addition, the risk factors for AKI and TLS varied widely. These findings indicate the potential nephrotoxicity of bortezomib irrespective of TLS in patients with decreased kidney function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

An 83-year-old man presented with visual disturbance and right hemiparalysis, one month after daratumumab, bortezomib, and dexamethasone administration for multiple myeloma (MM). Blood screens revealed a CD4+ T-lymphocyte count of 132/μl. Diffusion weighted and fluid-attenuated inversion-recovery MR imaging showed high intensity signals in the both occipital lobes and left precentral area. The patient had no history of human immunodeficiency virus infection. Cerebrospinal fluid (CSF) JC virus (JCV) was positive (83 copies/ml), as indicated by PCR. The patient was diagnosed with progressive multifocal leukoencephalopathy (PML). MM treatment was discontinued, and mefloquine and mirtazapine therapy was started. However, the CSF JCV-DNA PCR count did not improve (111 copies/ml) after 30 days from starting mefloquine and mirtazapine therapy. The patient died six months after symptom onset. Conclusively, patients with decreased CD4+ T lymphocyte counts following DBd therapy for MM, the possibility of PML should be considered.