Search Results (234)

Light-chain (AL) amyloidosis is a rare clonal plasma cell disorder that, if left untreated, carries a high risk of organ damage and mortality. Due to the rarity of the disease and the vulnerability of affected organ systems, treatment requires significant caution and nuance. As a plasma cell dyscrasia, AL amyloidosis treatment regimens are often adapted from those used for related disorders, particularly multiple myeloma. Despite substantial progress in research and drug development, optimal treatment strategies for relapsed/refractory (RR) AL amyloidosis remain unclear, and no FDA-approved therapies currently exist for this setting. B-cell maturation antigen (BCMA) has emerged as a promising immunotherapy target, with associated drug classes including antibody–drug conjugates, bispecific antibodies, and CAR-T cell therapies. These therapies have been extensively studied in relapsed/refractory multiple myeloma (RRMM) and are now being explored in the context of RR AL amyloidosis. This review summarizes the current literature on the efficacy and tolerability of BCMA-directed therapies in AL amyloidosis, with a particular emphasis on CAR-T cell therapy and offers comparisons to outcomes observed in RRMM. Full article

Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression. Full article

Background: Belantamab mafodotin (belamaf) is a BCMA-targeting antibody–drug conjugate used in triple-class refractory multiple myeloma. Despite its efficacy, keratopathy remains a significant dose-limiting toxicity. Following its withdrawal from the U.S. market in 2022, its use in Austria is limited to clinical trials or compassionate use. Methods: In this real-world, retrospective study, we analyzed 36 relapsed/refractory, BCMA-naïve multiple myeloma patients treated at the University Hospital of Vienna (January 2020–June 2024); 42% received a reduced dose (1.9 mg/kg) throughout all treatment cycles. The primary objective was to assess adverse events, particularly keratopathy, and the impact of dose modifications on toxicity and efficacy. Results: The overall response rate was 64%, with responders having significantly fewer prior therapy lines (median 3 vs. 4.5, p = 0.015). Median PFS was 7.3 months, significantly longer in responders (11.1 vs. 1.6 months, p < 0.0001); median OS was 20.1 months, also longer in responders (not reached vs. 18 months, p = 0.031). Keratopathy occurred in 75% of patients; 33% experienced grade 3–4 events. Dose reduction significantly decreased grade 3–4 keratopathy (7% vs. 52%, p = 0.004) and thrombocytopenia (33% vs. 67%, p = 0.048) without compromising efficacy. Conclusions: Belamaf dose reductions improved tolerability without loss of efficacy, supporting reduced dosing in practice. Full article

B-cell maturation antigen (BCMA)-targeted therapies including both chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), have revolutionized the treatment landscape for relapsed/refractory multiple myeloma (MM), offering both deep and durable responses, even in heavily pretreated patients. Despite these advances, most patients ultimately experience relapse. This is likely related to the development of resistance mechanisms that limit the long-term efficacy and durability of BCMA-targeted approaches. In this review, we examine the current landscape of BCMA-directed therapies, including Idecabtagene Vileucel, Ciltacabtagene Autoleucel, Teclistamab, and Elranatamab and explore the multifactorial mechanisms driving resistance. These mechanisms include tumor-intrinsic factors, host-related and tumor-extrinsic factors, and factors related to the tumor-microenvironment itself. We outline emerging strategies to overcome resistance, such as dual-targeting therapies, γ-secretase inhibitors, immune-checkpoint blockade, armored CAR T constructs, and novel combination regimens. Additionally, we discuss the role of therapy sequencing, emphasizing how prior exposure to BsAbs or CAR T-cell therapies may influence the efficacy of subsequent treatments. A deeper understanding of resistance biology, supported by integrated immune and genomic profiling, is essential to optimizing therapeutic durability and ultimately improve patient outcomes for patients with MM. Full article

Background: Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory condition marked by excessive cytokine production, leading to multi-organ dysfunction. It is commonly associated with T-cell-engaging therapies such as chimeric antigen receptor (CAR) T cells, T-cell receptor bispecific molecules, and monoclonal antibodies. Carfilzomib, a proteasome inhibitor, is known to cause a range of adverse effects, primarily hematologic and cardiovascular. However, multiorgan failure grade 5 (fatal), resembling CRS has not been previously reported in association with Carfilzomib. Case Report: A 74-year-old male with relapsed multiple myeloma developed grade 5 multiorgan failure 60 min after the third dose of Carfilzomib, resulting in death within 24 h of symptom onset. The patient tolerated the first doses of Carfilzomib well with only fever and headache developing post infusion. Before the second dose, the patient developed worsening pancytopenia, prompting the discontinuation of Lenalidomide. After the second Carfilzomib infusion, he experienced fever and transient encephalopathy, which resolved with acetaminophen, corticosteroids, and supportive care. However, following the third dose, he rapidly deteriorated—developing fever, tachycardia, hypotension, hypoxia, and encephalopathy. Despite aggressive management with intravenous fluids, broad-spectrum antibiotics, corticosteroids, and tocilizumab, the patient progressed to refractory shock and multi-organ failure, culminating in death within 24 h. A comprehensive infectious workup was negative, ruling out sepsis and suggesting possible Carfilzomib-induced CRS. Conclusion: Grade 5 multiorgan failure with signs and symptoms similar with CRS following Carfilzomib administration is a rare but potentially fatal adverse drug reaction. Further research is needed to better define the risk factors and optimal management strategies for Carfilzomib-induced multiorgan failure and possible CRS. Full article

Serum cereblon (CRBN) has been proposed as a target protein for immunomodulatory drugs (IMiDs). IMiDs are one of the backbone treatment options in multiple myeloma (MM), rendering CRBN an intriguing candidate for use as a biomarker in clinical settings. Ninety-two (92) MM patients, mostly relapsed/refractory and a few at diagnosis, were included in the study, from lenalidomide–dexamethasone (LD) initiation until last follow-up or death. Median CRBN at LD initiation (N = 68) treatment was 247 pg/mL (range, 0–9760 pg/mL), at the time of best response (BR) status (N = 59) 142.5 pg/mL (range, 0–9940 pg/mL) and in patients with relapse/refractory MM to LD regimen (N = 54) 298 pg/mL (range, 0–9840 pg/mL). CRBN in healthy individuals was almost undetectable and significantly lower compared to the CRBN at LD initiation (p = 0.003), at BR to LD (p = 0.012) and at relapse to LD (p = 0.002). CRBN was significantly lower at BR in contrast to LD initiation and relapse to LD (p = 0.04, p = 0.028). High levels of CRBN at treatment initiation correlated with early relapse to LD (≤12 months) (p = 0.03). Seven-year survival was improved in patients with CRBN levels below median measured at the time of LD initiation (p = 0.013) as well as at BR (p = 0.032). CRBN was associated with treatment response and is predictive of survival after LD. Full article

Multiple myeloma (MM or plasma cell myeloma) is a heterogenous B-cell malignant tumor that typically exhibits a high recurrence rate, resistance to drugs, and molecular diversity of tumor subclones. Given the limited efficacy of standard therapy options, cellular immunotherapy featuring a chimeric antigen receptor (CAR) has proven tangible potential in treatment for relapsed and refractory forms of MM. The rational choice of a tumor target which shows high selectivity, stable expression, and biological significance is key to the successful implementation of CAR therapy. This review has summarized and analyzed data from the literature on biological properties, the features of expression, and the clinical development stages of CAR cell products for MM treatment which target BCMA, GPRC5D, FcRH5, SLAMF7, CD38, CD138, TACI, APRIL, CD19, TNFR2, CD44v6, CD70, NKG2D ligands, etc. Special focus is on strategic approaches to overcoming antigenic escape, such as multi-specific CAR constructs, logical activation sequences, and controlled safety systems. The analysis underscores the need for integrating the molecular selection of targets with cutting-edge bioengineering solutions as a key trend for raising the efficacy, stability, and safety of cellular therapy in the case of MM. Full article

Introduction: In the past decade, chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of relapsed refractory multiple myeloma (RRMM) and lymphoma, but it is associated with significant cardiovascular adverse effects. We aim to analyze the incidence, patterns, and outcomes of cardiac events in RRMM and lymphoma patients undergoing CAR-T therapy utilizing the FDA Adverse Event Reporting System (FAERS) database, paving the way for future research and being more vigilant in treating high-risk populations. Methods: We conducted a retrospective post-marketing pharmacovigilance inquiry using the FDA Adverse Event Reporting System (FAERS) database and the Medical Dictionary for Regulatory Activities (MEDRA). We examined the adverse effects associated with CAR-T and TCE since their FDA approval in US and non-US populations (accessed 5 January 2024), and we analyzed the incidence of cardiac events related to six CAR-T products: Idecabtagene vicleucel, Ciltacabtagene autoleucel, Axicabtagene ciloleucel, Tisagenlecleucel, Lisocabtagene maraleucel, and Brexucabtagene autoleucel since FDA approval. Cardiotoxicities were assessed, including coronary artery disease (CAD), myocardial infarction (MI), arrhythmia, heart failure, and hypotension. Results: Out of 12,949 adverse events, we identified 675 (5.2%) cardiac events irrespective of severity. Almost 440 (65%) cardiac events were associated with cytokine release syndrome (CRS). The most common cardiotoxic event was atrial fibrillation (122), followed by the development of heart failure (113), ventricular arrhythmia (108), hypotension (87), and bradyarrhythmia (41). The mortality rate was highest among Brexucabtagene autoleucel recipients (n = 26, 2.3%), followed by Tisagenlecleucel (n = 71, 2.1%) and Lisocabtagene maraleucel (n = 10, 2.1%). Conclusions: CAR-T therapy can result in fatal adverse events due to its cardiotoxic properties. Timely monitoring, such as screening echocardiography and electrocardiograms, can help identify the at-risk population and allow for early intervention—particularly in patients with high baseline cardiovascular risk or previous exposure to cardiotoxic agents—thereby improving outcomes by enabling risk stratification and supportive management. Full article

Background: The remarkable efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T) has had a significant impact on treatment strategies for relapsed/refractory multiple myeloma (RRMM). However, response durability remains a concern, necessitating the optimization of CAR-T procedures. Therapies preceding CAR-T therapy are crucial for disease control and preserving T-cell fitness. Methods: This review summarizes the evidence supporting the potential of selinexor-based regimens as holding or bridging therapy with preclinical research, demonstrating selinexor’s ability to foster an anti-inflammatory tumor microenvironment. Results: Selinexor enhances CD8+ T-lymphocyte and NK cell activation, re-polarizes macrophages, and inhibits immunosuppressive cells. Bone marrow samples from patients in clinical studies show that selinexor increases CD8 and granzyme B expression in T-cells. Selinexor also disrupts NK cell inhibition, enhances anti-tumor activity, and reduces pro-inflammatory cytokines. Selinexor may upregulate BCMA expression and increase myeloma cell immunogenicity. Real-world data suggests selinexor as bridging therapy does not compromise CAR-T outcomes and may even improve them. Conclusions: Overall, the evidence indicates selinexor’s potential to optimize CAR-T outcomes, warranting further investigation as a holding or bridging therapy for CAR-T. Full article

High-risk genetic multiple myeloma (HRMM) remains a major therapeutic challenge, as patients harboring adverse genetic abnormalities, such as del(17p), TP53 mutations, and biallelic del(1p32), continue to experience poor outcomes despite recent therapeutic advancements. This review explores the evolving definition and molecular features of HRMM, focusing on recent updates in risk stratification and treatment strategies. The new genetic classification proposed at the 2025 EMMA meeting offers improved prognostic accuracy and supports more effective, risk-adapted treatment planning. In transplant-eligible patients, intensified induction regimens, tandem autologous stem cell transplantation, and dual-agent maintenance have shown improved outcomes, particularly when sustained minimal residual disease negativity is achieved. Conversely, in the relapsed or refractory setting, novel agents have demonstrated encouraging activity, although their specific efficacy in HRMM is under investigation. Moreover, treatment paradigms are shifting toward earlier integration of immunotherapy, and therapeutic strategies are individualized based on refined molecular risk profiles and clone dynamics. Therefore, a correct definition of HRMM could help in significantly improving both clinical and therapeutic management of a subgroup of patients with an extremely aggressive disease. Full article

Multiple myeloma (MM) remains an incurable hematologic malignancy due to the inevitable development of drug resistance, particularly in relapsed or refractory cases. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, and glycosylation, play pivotal roles in regulating protein function, stability, and interactions, thereby influencing MM pathogenesis and therapeutic resistance. This review comprehensively explores the mechanisms by which dysregulated PTMs contribute to drug resistance in MM, focusing on their impact on key signaling pathways, metabolic reprogramming, and the tumor microenvironment. We highlight how PTMs modulate drug uptake, alter drug targets, and regulate cell survival signals, ultimately promoting resistance to PIs, IMiDs, and other therapeutic agents. Furthermore, we discuss emerging therapeutic strategies targeting PTM-related pathways, which offer promising avenues for overcoming resistance to treatment. By integrating preclinical and clinical insights, this review underscores the potential of PTM-targeted therapies to enhance treatment efficacy and improve patient outcomes in MM. Full article

Treatment for relapsed/refractory multiple myeloma (RRMM) is complex, with several classes of drugs that can be combined into doublet, triplet, or quadruplet regimens. Real-world studies can help to determine the optimal treatment sequences and dosing through observed usage of drugs outside of clinical trials. Previous clinical trials have demonstrated high rates of durable responses in the treatment of patients with triple-class-exposed RRMM with regimens containing selinexor, a first-in-class, orally available selective exportin 1 inhibitor. This study analyzed real-world treatment patterns and survival outcomes using a nationwide electronic health record-derived, deidentified database of patients with RRMM treated with an eligible selinexor-containing, triplet-based regimen, including combinations with dexamethasone and pomalidomide, bortezomib, carfilzomib, or daratumumab. Patients had a real-world overall survival (rwOS) of 14.7 months (95% CI: 10.6, 20.9) and a derived progression-free survival (dPFS) of 4.7 months (95% CI: 3.4, 6.7). Patients with previous exposure to anti-CD38 monoclonal antibodies (mAbs) in the most recent regimen prior to the selinexor treatment had numerically higher survival outcomes (rwOS, 20.9; dPFS, 8.7 months). These data suggest that, in the real-world setting, the use of selinexor triplet regimens is effective in patients with RRMM, especially those with prior exposure to an anti-CD38 mAb in the immediate prior line of therapy. Full article

Background: In the randomized, phase-3 IKEMA trial, the triplet isatuximab, carfilzomib, and dexamethasone (IsaKd) demonstrated superior clinical benefit compared to those of carfilzomib and dexamethasone alone in patients with relapsed/refractory multiple myeloma after 1–3 prior treatments. Methods: Our real-world, AENEID study aimed to evaluate the efficacy and safety of IsaKd in patients who relapsed after frontline lenalidomide treatment, poorly represented in the IKEMA trial. Specifically, in the present multicenter analysis, we enrolled eighty-two patients who received, between April 2022 and September 2024 and outside of clinical trials, at least one cycle of IsaKd as a second-line treatment at the first relapse after induction therapy, autologous stem cell transplantation (ASCT), and lenalidomide maintenance. Results: After a median follow-up time of 12.9 months (range, 1–77), the overall response rate, at least a very good partial response rate, and median progression-free survival time were 79.3%, 56.1%, and 24.4 months, respectively. This slightly lower performance compared to that in the IKEMA study may be attributed to the well-known poor prognostic impact of lenalidomide refractoriness (len-R), developed by all our patients during maintenance therapy, and to a higher proportion of patients with extramedullary disease present in our series, which was identified as the only factor significantly affecting the PFS in multivariable analysis. The median overall survival was not reached, as in the pivotal trial, while the 1-year survival probability was 85.1%. Regarding the safety profile, our findings were consistent with those of the IKEMA trial, with no new safety signals reported. Conclusions: These real-world data support the use of IsaKd as a valuable option for len-R MM patients relapsing after the first-line therapy, including ASCT and lenalidomide maintenance. Full article

In the past few years, a new promising therapy, called bispecific T-cell engager (TCE), has been developed and is now available in many countries for patients with relapsed or refractory multiple myeloma. T-cell engagers are associated with sustained efficacy and progression-free survival benefits in patients with heavily treated myeloma. However, complications such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections complicate their administration, particularly in remote centers. This review discusses the key requirements for delivering TCEs therapies, focusing on outpatient delivery. We also outline the primary acute and chronic complications of TCE therapy and their management. Full article

Background: Treatment of multiple myeloma has advanced tremendously with the approval of anti-CD38 antibodies. Their efficacy is impressive but still controversial in the 1q amplification subgroup (amp1q). This retrospective study aims to provide real-world data. Methods: This trial is analyzing 74 patients with relapsed/refractory multiple myeloma treated with CD38Abs at the Medical University of Innsbruck (2016–2023). High-risk (HR) cytogenetics according to R-ISS (t(4;14), t(14;16), t(14;20), del(17p)), the presence of amp(1q21), the frequency of two HR markers (double hit), and the high-risk criteria agreed at IMS 2024 (HR-IMS24) were considered. Results: The median age of the 74 patients (62.1% male) was 62 years, with a median follow-up of six years. Most patients received third-line therapy (37.8%). R-ISS HR was documented in 39.2% of patients, double hit in 13.5% of patients, and HR-IMS24 in 32.4% of patients, while amp1q was detected in 35.1% of patients. The median OS was 66 months (35–89), and the median PFS was 17 months (6.5–26.9). While neither R-ISS HR nor isolated amp1q had an impact on progression-free survival (e.g., amp1q 7.03: 1.95–22.44; p = 0.347), the occurrence of a double-hit pattern significantly impaired PFS and OS (6.2: 1.4–16.4 months; p = 0.044; OS, 42.8: 25.9–74.6 months; p = 0.035). Patients fulfilling the HR-IMS24 criteria (32.4%, 24 patients) also exhibited an impaired PFS and OS (7: 2.7–18.1 months, p = 0.023; 40.12: 21.1–74.5 months, p = 0.01). Conclusions: This retrospective study highlights the durable effect of daratumumab on cytogenetic abnormalities, particularly amp1q. However, patients who meet the criteria for double-hit myeloma or the high-risk IMS2024 criteria remain a difficult-to-treat patient population who require early access to new treatment approaches. Full article