Isatuximab, carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed, transplantation-eligible multiple myeloma (SKylaRk): a single-arm, phase 2 trial.

BACKGROUND: Isatuximab is a CD38 monoclonal antibody approved for relapsed or refractory multiple myeloma. We aimed to evaluate the addition of isatuximab to weekly carfilzomib (K), lenalidomide (R), and dexamethasone (d; Isa-KRd) in transplant-eligible patients with newly diagnosed multiple myeloma and stratified maintenance by cytogenetic risk. METHODS: This single-arm phase 2 trial was done at three cancer centres (two hospitals and a cancer institute) in Boston (MA, USA). Eligible patients were aged at least 18 years and had transplant-eligible newly diagnosed multiple myeloma and an ECOG performance status of 2 or less. Patients received four 28-day cycles of Isa-KRd, including isatuximab 10 mg/kg intravenously weekly for 8 weeks, then every other week for 16 weeks, and every 4 weeks thereafter; carfilzomib 56 mg/m2 intravenously on days 1, 8, and 15 (20 mg/m2 for cycle 1 day 1); lenalidomide 25 mg orally on days 1-21; and dexamethasone 20 mg orally the day of and day after all doses of carfilzomib and isatuximab. Consolidation involved either upfront haematopoietic stem-cell transplantation (HSCT) with two additional cycles or deferred HSCT with four additional cycles of treatment. The primary endpoint was complete response after four cycles of treatment. Analyses were by intention-to-treat. All patients who received one dose of study drug were included in the safety analyses. This study was registered at ClinicalTrials.gov, NCT04430894, and has completed enrolment. FINDINGS: Between July 31, 2020 and Jan 31, 2022, 50 patients were enrolled. Median age was 59 years (range 40-70), 54% (27 of 50 patients) were male, and 44 (88%) were White. 46% (23 of 50) of patients had high-risk cytogenetics. Median follow-up was 26 months (IQR 20·7-30·1). 32% (16 of 50 patients) achieved a complete response after four cycles. The overall response rate (ORR) was 90% (45 patients) and 78% (39 patients) achieved a very good partial response (VGPR) or better. After completion of consolidation, 58% (29 patients) achieved a complete response; the ORR was 90% (45 patients) and 86% (43 patients) achieved a VGPR or better. The most common grade 3 or 4 side-effects (≥two patients) included neutropenia (13 [26%] of 50 patients), elevated alanine aminotransferase (six [12%] patients), fatigue (three [6%] patients), thrombocytopenia (three [6%] patients), acute kidney injury (two [4%] patients), anaemia (two [4%] patients), and febrile neutropenia (two [4%] patients). Grade 1-2 infusion-related reactions were seen in 20% (ten patients), with none grade 3. Grade 1-2 hypertension was seen in 14% (seven patients) with one grade 3 (one [2%] patient). There were two deaths assessed as unrelated to treatment. INTERPRETATION: Although the study did not achieve the prespecified complete response threshold, Isa-KRd induced deep and durable responses in transplant-eligible patients with newly diagnosed multiple myeloma. The treatment proved safe and consistent with similar regimens in this setting. FUNDING: Amgen, Sanofi, and Adaptive.

Mezigdomide-A Novel Cereblon E3 Ligase Modulator under Investigation in Relapsed/Refractory Multiple Myeloma.

Mezigomide is an oral cereblon E3 ligase modulator (CELMoD) that is under clinical investigation in patients with relapsed/refractory (RR) multiple myeloma (MM). Like other CELMoD compounds, mezigdomide acts by altering the conformation of cereblon within the cullin 4A ring ligase-cereblon (CRL4CRBN) E3 ubiquitin ligase complex, thereby recruiting novel protein substrates for selective proteasomal degradation. These include two critical lymphoid transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), also known as Ikaros and Aiolos, which have important roles in the development and differentiation of hematopoietic cells, in MM pathobiology, and in suppressing the expression of interferon-stimulating genes and T-cell stimulation. Among the CELMoDs, mezigdomide has the greatest cereblon-binding potency, plus the greatest potency for the degradation of Ikaros and Aiolos and subsequent downstream antimyeloma effects. Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM.

Idecabtagene vicleucel chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma with renal impairment.

We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.

Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy.

The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. These regimens are resulting in improved outcomes and increasingly high rates of minimal residual disease (MRD)-negative responses without HDM-ASCT as part of the upfront therapy. Furthermore, recent randomized studies have shown that, while transplant-based approaches as a frontline therapy result in significantly longer progression-free survival compared to non-transplant approaches, this has not translated into an overall survival benefit. Given these developments, and in the context of the treatment burden of undergoing HDM-ASCT, in addition to the acute toxicities and long-term sequelae of HDM, which are associated with the genotoxicity of melphalan, there is an increasing rationale for considering deferring upfront HDM-ASCT in select transplant-eligible patients and saving it as a treatment option for later salvage therapy. Here, we review the latest clinical trial data on upfront or deferred HDM-ASCT and on the activity of quadruplet induction regimens, including rates of MRD-negative responses, and summarize emerging treatment approaches in the upfront setting such as the use of MRD-directed therapy and alternatives to HDM-ASCT.

Clinical Outcomes of Monoclonal Gammopathy of Renal Significance Without Detectable Clones.

Introduction: Monoclonal gammopathy of renal significance (MGRS) is characterized by monoclonal immunoglobulin deposition in kidneys. However, monoclonal immunoglobulin and responsible clone(s) are not always detectable. Treatment response and kidney outcome of MGRS without detectable clones remain unclear. Methods: In this single-center, retrospective cohort study, we identified MGRS without detectable clones from our biopsy repository between 2010 and 2022. We investigated the correlations between treatment regimens and kidney outcomes defined by proteinuria and estimated glomerular filtration rate (eGFR), and the impact of repeat kidney biopsy. Results: Our study cohort included 29 cases (27 native kidney and 2 transplant allograft biopsies) of MGRS without detectable clones. At diagnosis, median serum creatinine was 1.8 mg/dl (interquartile range [IQR] 1.3-2.7), with proteinuria 4.6 g/gCr (IQR 2.3-7.9). Treatment regimens were variable: 6 (21%) received conservative therapy, 13 (45%) received plasma cell clone-directed therapy, 8 (28%) received lymphocytic clone-directed therapy, and 2 (7%) received nonclone-directed immunosuppressive therapy. Of 24 patients with proteinuria >0.5 g/gCr at diagnosis, 9 (38%) and 6 (25%) achieved complete response (CR) and partial response (PR), respectively. If interstitial fibrosis and tubular atrophy (IFTA) was >50% at the initial biopsy, less proportion of patients achieved CR. Six of 7 repeat biopsies showed progression of chronic changes (e.g., IFTA) but provided limited information on treatment response. Conclusion: Treatment regimens and outcomes of MGRS without detectable clones were extremely variable. Repeat biopsy provided limited information to assess disease activity or the need for additional treatment. More sensitive tools are needed to detect clones and to assess treatment response.

A safety review of recently approved and emerging drugs for patients with relapsed or refractory multiple myeloma.

INTRODUCTION: Multiple new drugs have been approved over the past 5 years for the treatment of relapsed/refractory multiple myeloma (RRMM), and these are being increasingly widely used. Clinicians need to familiarize themselves with common toxicities associated with these drugs and with novel toxicities requiring specific management and supportive care. AREAS COVERED: We review common toxicities associated with agents approved for RRMM in the past 5 years, including the anti-CD38 monoclonal antibody isatuximab, the antibody-drug conjugate belantamab mafodotin, the bispecific antibody teclistamab, the chimeric antigen receptor (CAR) T cell products idecabtagene vicleucel and ciltacabtagene autoleucel, the selective inhibitor of nuclear export compound selinexor, and the drug-peptide conjugate melflufen, as well as toxicities associated with emerging agents for RRMM including additional bispecific antibodies, the BCL-2 inhibitor venetoclax, and the cereblon E3 ligase modulators iberdomide and mezigdomide. We searched the published literature using PubMed, plus congress abstracts, for the above list of drug names or classes and 'myeloma.' EXPERT OPINION: Optimal management of toxicities associated with these recently approved and emerging therapies will be critical in maximizing clinical benefit and aiding widespread adoption in routine clinical practice. We summarize current recommendations and guidelines and provide expert insights into supportive care requirements.

Selinexor: Targeting a novel pathway in multiple myeloma.

Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin-1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor-based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor-dexamethasone approved in the later-relapse setting for penta-refractory patients and selinexor-bortezomib-dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor-based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis.

Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.

Can we lower the platelet threshold of ≥ 50 × 109/L for performing a lumbar puncture safely in patients with hematological malignancies?

Lumbar punctures (LP) are routinely used to administer intrathecal chemotherapy for children and adults with hematologic malignancies. The current guidelines suggest a platelet threshold of ≥ 50 × 109/L prior to LP for intrathecal chemotherapy (ITC). This can be challenging in patients with hematological malignancies who are thrombocytopenic. We conducted a retrospective chart review of 900 LPs for ITC and compared adverse events in patients with a platelet count of ≥ 50 × 109/L and < 50 × 109/L. Cohort 1 included 682 LPs (75.8%) with a pre-procedure platelet count ≥ 50 × 109/L, and cohort 2 included 218 LPs (24.2%) with a pre-procedure platelet count < 50 × 109/L. Cohort 2 was further subdivided into pre-procedure platelet counts of 41 × 109/L-49 × 109/L (n = 43), 31 × 109/L-40 × 109/L (n = 77), 21 × 109/L-30 × 109/L (n = 84), and 11 × 109/L-20 × 109/L (n = 14). Among 900 LP procedures, a pre-procedure platelet count < 50 × 109/L did not demonstrate a higher rate of post-procedure adverse events (6.5% vs 6.8%, p = 0.8237). When cohort 2 was further stratified, the cohort with a pre-procedure platelet count of 21 × 109/L-30 × 109/L had the highest percentage of complications from LP (9.5%) and the highest rates of traumatic taps with observed LP RBC count > 200 (35.7%, p = 0.0015). The rate of red blood cells (RBC) in the CSF was significantly higher in the group with platelets < 50 × 109/L with observed LP RBC count ≥ 200 (31.2% vs 20.5%, p = 0.0016), ≥ 500 (27.1% vs 14.6%, p < 0.0001), and ≥ 1000 (23% vs 11.6%, p < 0.0001). No instances of epidural hematomas were seen. We found no significant difference in bleeding complications between patients undergoing LPs for ITC with a platelet count above or below 50 × 109/L.

Forming the Hematology-Oncology Collaborative Videoconferencing (CO-VID) Learning Initiative: Experiential Lessons Learned From a Novel Trainee-Led Multidisciplinary Virtual Learning Platform.

PURPOSE: COVID-19 challenged medical practice and graduate medical education. Building on previous initiatives, we describe and reflect on the formative process and goals of the Hematology-Oncology Collaborative Videoconferencing Learning Initiative, a trainee-led multi-institutional virtual COVID-19 learning model. METHODS: Clinical fellows and faculty from 13 US training institutions developed consensus needs, goals, and objectives, recruited presenters, and generated a multidisciplinary COVID-19 curriculum. Weekly Zoom conferences consisted of two trainee-led instructional segments and a trainee-moderated faculty Q&A panel. Hematology-oncology training program faculty and trainees were the targeted audience. Leadership evaluations consisted of anonymized baseline and concluding mixed methods surveys. Presenter evaluations consisted of session debriefs and two structured focus groups. Conference evaluations consisted of attendance, demographics, and pre- or postmultiple-choice questions on topic learning objectives. RESULTS: In 6 weeks, the initiative produced five conferences: antivirals, anticoagulation, pulmonology, provider resilience, and resource scarcity ethics. The average attendance was 100 (range 57-185). Among attendees providing both pre- and postconference data, group-level knowledge appeared to increase: antiviral (n = 46) pre-/postcorrect 82.6%/97.8% and incorrect 10.9%/2.2%, anticoagulation (n = 60) pre-/postcorrect 75%/93.3% and incorrect 15%/6.7%, and pulmonary (n = 21) pre-/postcorrect 66.7%/95.2% and incorrect 33.3%/4.8%. Although pulmonary management comfort appeared to increase, comfort managing of antivirals and anticoagulation was unchanged. At the conclusion of the pilot, leadership trainees reported improved self-confidence organizing multi-institutional collaborations, median (interquartile range) 58.5 (50-64) compared with baseline 34 (26-39), but did not report improved confidence in other educational or leadership skills. CONCLUSION: During crisis, trainees built a multi-institutional virtual education platform for the purposes of sharing pandemic experiences and knowledge. Accomplishment of initiative goals was mixed. Lessons learned from the process and goals may improve future disaster educational initiatives.

Updates in Plasma Cell Dyscrasias and Related Monoclonal Immunoglobulin-Mediated Renal Disease.

Pathogenic roles of monoclonal immunoglobulins in kidney disease have been attributed previously to malignant plasma cell and lymphoproliferative disorders such as multiple myeloma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, or amyloid light chain amyloidosis. Improved technology, advancements in molecular diagnostics, and highly sensitive imaging techniques have established the need to redefine monoclonal gammopathies and the kidney disorders that are associated with monoclonal immunoglobulins regardless of tumor burden. This has led to the establishment of monoclonal gammopathy with renal significance (MGRS). MGRS was defined by the International Kidney and Monoclonal Gammopathy Research Group in 2012 as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined hematological criteria for treatment of a specific malignancy. MGRS encompasses a wide array of pathologies with knowledge surrounding its incidence, prognosis, and management continuously increasing. This review examines the current evidence on the diagnosis, prognosis, pathogenesis, and therapy of plasma cell dyscrasias and related MGRS.

Alcohol regulates gene expression in neurons via activation of heat shock factor 1.

Drinking alcohol causes widespread alterations in gene expression that can result in long-term physiological changes. Although many alcohol-responsive genes (ARGs) have been identified, the mechanisms by which alcohol alters transcription are not well understood. To elucidate these mechanisms, we investigated Gabra4, a neuron-specific gene that is rapidly and robustly activated by alcohol (10-60 mM), both in vitro and in vivo. Here we show that alcohol can activate elements of the heat shock pathway in mouse cortical neurons to enhance the expression of Gabra4 and other ARGs. The activation of Gabra4 by alcohol or high temperature is dependent on the binding of heat shock factor 1 (HSF1) to a short downstream DNA sequence, the alcohol response element (ARE). Alcohol and heat stimulate the translocation of HSF1 from the cytoplasm to the nucleus and the induction of HSF1-dependent genes, Hsp70 and Hsp90, in cultured neurons and in the mouse cerebral cortex in vivo. The reduction of HSF1 levels using small interfering RNA prevented the stimulation of Gabra4 and Hsp70 by alcohol and heat shock. Microarray analysis showed that many ARGs contain ARE-like sequences and that some of these genes are also activated by heat shock. We suggest that alcohol activates phylogenetically conserved pathways that involve intermediates in the heat shock cascade and that sequence elements similar to the ARE may mediate some of the changes in gene expression triggered by alcohol intake, which could be important in a variety of pathophysiological responses to alcohol.