Role of Autologous Transplant in Newly Diagnosed Multiple Myeloma Patients Treated with Novel Triplets: A Systematic Review and Meta-Analysis.

INTRODUCTION: High-dose therapy with melphalan followed by autologous stem cell transplant at the upfront setting (upfront ASCT) has significantly improved clinical outcomes of myeloma patients and become the standard of care for the past 30 years. However, with the advent of modern induction therapy, the role of upfront ASCT approach has been called into question. Several prospective studies have examined whether continuing with triplet therapy as consolidation with optional ASCT at relapse (triplet-alone) could result in comparable outcomes. METHODS: This was a systematic review and meta-analysis of randomized controlled trials comparing upfront ASCT vs. triplet-alone approach among myeloma patients treated with triplet therapy as induction. Cochrane Library, PubMed, conference proceedings and references were searched until January 2023. Primary outcome was overall survival (OS). Secondary outcomes included progression free survival (PFS), safety, and SPM. Subgroup analysis was conducted for high risk cytogenetics (defined by the presence of either 17p deletion, t(4;14) or t(14;16)). RESULTS: Our search yielded three trials, conducted between 2010-2018, including 1,737 patients. Two trials evaluated bortezomib plus lenalidomide (VRd) induction and the third study tested carfilzomib plus lenalidomide (KRd) induction. Maintenance was given in all trials to both arms. There was no difference in OS between the arms, the pooled OS in all patients and in those with high-risk cytogenetics was HR 1.03 (95% CI, 0.85-1.26; I2 = 0%; 1,737 patients, 3 trials), and 0.85 (95% CI, 0.59-1.23; I2=0%; 222 patients, 2 trials), respectively. The pooled PFS for upfront ASCT vs. triplet-alone was significantly improved in all the patients and in the high-risk cytogenetics subgroup, HR 0.67 [95% CI 0.59-0.76; I2 = 0%; 1,737 patients, 3 trials] and HR 0.59 [95% CI 0.44-0.7; I2 = 0%; 306 patients, 3 trials], respectively. The risk of any grade 3-4 adverse events was higher in the upfront ASCT arm vs triplet-alone approach [RR=1.17 [95% CI, 1.12-1.23; 1,737 patients]. The risk of secondary malignancies was reported in all three trials and was comparable between both arms. Two trials reported on secondary myeloid neoplasms, which were significantly higher among upfront ASCT arm vs triplet-alone approach, OR 9.7 (1.8-52.25, I2=0%, 1422 patients). CONCLUSION: Although upfront ASCT approach in the era of triplet therapy resulted in significantly longer PFS among all patients, this did not translate into a survival benefit, regardless of cytogenetics risk. Upfront ASCT arm was associated with an increase rate of secondary myeloid neoplasms. In the current plethora of innovative therapies, the role of upfront ASCT is debatable.

Historical Perspective of High-Dose Therapy Followed by Autologous Stem Cell Transplantation in Multiple Myeloma.

BACKGROUND: High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) has become part of standard of care (SOC) in newly diagnosed multiple myeloma. In this review, we provide a historical perspective on ASCT since its introduction in the 1990s. SUMMARY: Overall survival (OS) benefit for HDT followed by ASCT was demonstrated in studies comparing HDT with ASCT to standard-dose therapy (SDT) before the era of novel agents. Conditioning is done with melphalan 200 mg/m2. Lower doses (MEL140, MEL150) for older patients with comorbidities are safe and have comparable results. The addition of busulfan to melphalan improves progression-free survival (PFS) but not OS. HDT with ASCT after induction with novel agents prolongs PFS but not OS compared to SDT alone. The benefit is more evident in patients with high-risk cytogenetics. Mobilization can be achieved with granulocyte colony-stimulating factor alone, but is improved with the addition of chemotherapy. Plerixafor reduces mobilization failure and enables sufficient stem cell collection after induction with novel agents. ASCT is safe with a low rate of mortality (1%), and selected patients can be managed as outpatients. KEY MESSAGES: HDT followed by ASCT remains part of SOC due to its PFS benefit and relatively low toxicity.

Immune Therapies in AL Amyloidosis-A Glimpse to the Future.

Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.

Lymphoplasmacytic lymphoma and multiple myeloma coexisting in the same patient: a case series and literature review.

The simultaneous occurrence of Waldenström macroglobulinemia and multiple myeloma in the same patient has been published as case reports. Patients with Waldenström macroglobulinemia often have a small clone of plasma cells. However, the concurrent occurrence of symptomatic myeloma with lytic bone lesions is rare. The diagnosis of this 'hybrid' entity is challenging, and there are no standard therapies. We present six patients from five centers (three in Israel and two in the United States). We describe these patients' unique clinical course and treatment approaches.

Smouldering multiple myeloma: To seek or not to seek? To treat or not to treat. That is the question.

In this issue, the British Society for Haematology presents guidelines for the diagnosis and management of patients with smouldering multiple myeloma (SMM). The authors provide a practical, evidence-based approach to managing these patients. Key questions remain yet unsolved. Commentary on: Hughes et al. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024;204:1193-1206.

Microvascular cardiac amyloidosis-Cardiac involvement of amyloidosis presenting as typical chest pain.

Coronary microvascular angina from cardiac amyloidosis.

Delivery of Therapeutic RNA to the Bone Marrow in Multiple Myeloma Using CD38-Targeted Lipid Nanoparticles.

Multiple myeloma (MM) is a cancer of differentiated plasma cells that occurs in the bone marrow (BM). Despite the recent advancements in drug development, most patients with MM eventually relapse and the disease remains incurable. RNA therapy delivered via lipid nanoparticles (LNPs) has the potential to be a promising cancer treatment, however, its clinical implementation is limited due to inefficient delivery to non-hepatic tissues. Here, targeted (t)LNPs designed for delivery of RNA payload to MM cells are presented. The tLNPs consist of a novel ionizable lipid and are coated with an anti-CD38 antibody (αCD38-tLNPs). To explore their therapeutic potential, it is demonstrated that LNPs encapsulating small interference RNA (siRNA) against cytoskeleton-associated protein 5 (CKAP5) lead to a ≈90% decrease in cell viability of MM cells in vitro. Next, a new xenograft MM mouse model is employed, which clinically resembles the human disease and demonstrates efficient homing of MM cells to the BM. Specific delivery of αCD38-tLNPs to BM-residing and disseminated MM cells and the improvement in therapeutic outcome of MM-bearing mice treated with αCD38-tLNPs-siRNA-CKAP5 are shown. These results underscore the potential of RNA therapeutics for treatment of MM and the importance of developing effective targeted delivery systems and reliable preclinical models.

Venetoclax in Relapse/Refractory AL Amyloidosis-A Multicenter International Retrospective Real-World Study.

Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results of a multi-center retrospective study on 26 R/R AL amyloidosis patients treated off-label with venetoclax. The median lines of therapy prior to venetoclax was 3.5 (range 1-7), and 88% of our cohort had t (11;14). Twenty-two patients (85%) were previously treated with daratumumab. The overall hematologic response rate was 88%, 35% achieved a CR, and 35% achieved VGPR. The median event-free survival was 25 months (m) (95% CI 9.7 m-not reached), and the median overall survival was 33 m (95% CI 25.9-39.2 m). Most of the patients in this cohort are in ongoing deep responses and continuing venetoclax therapy. The treatment was relatively safe. One patient died due to infection, and there were two grade 3 infections in our cohort. Tumor lysis syndrome (TLS) was not seen in any patient. Dose reductions were frequent but did not affect the efficacy. These promising results require confirmation in a randomized controlled trial.

The short and long-term characteristics and outcomes of patients with grade 1 myocardial uptake on cardiac scintigraphy.

AIMS: This study aimed to characterize the final diagnosis and prognosis of patients with grade 1 myocardial scintigraphy uptake, which is an unequivocal result for the diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) requiring further invasive investigation with tissue biopsy. METHODS AND RESULTS: We retrospectively compared the clinical and imaging parameters of patients suspected for ATTR-CA (based on clinical and echocardiographic parameters) with grade 1 vs. grades 2/3 technetium pyrophosphate uptake on cardiac scintigraphy. Prospectively, grade 1 patients underwent re-evaluation for ATTR-CA at long term. Of the 132 ATTR-CA suspected patients, 89 (67%) were diagnosed as grade 1 and 43 (33%) as grades 2/3 uptake. Grade 1 vs. grades 2/3 patients were younger and female predominant with lower biomarker levels and left ventricular mass. Based on available imaging and pathology findings, only 6 out of the 89 patients with grade 1 uptake (7%) were finally diagnosed with light-chain cardiac amyloidosis, whereas no patient was diagnosed with ATTR-CA. At 2 [interquartile range (IQR) 0.75, 3.25] years of follow-up, the survival of patients with grade 1 vs. grades 2/3 uptake was significantly better [hazard ratio 0.271 (95% confidence interval 0.130 to 0.563, P = 0.0005)]. Prospectively, 30 patients with grade 1 uptake were re-evaluated at a median follow-up of 3.2 (IQR 2.2, 3.9) years. Their New York Heart Association class, biomarker levels, and echocardiography findings remained stable. No patient (0/25) demonstrated grades 2/3 uptake at repeated long-term scintigraphy. CONCLUSIONS: Patients with suspected ATTR-CA and a grade 1 scintigraphy uptake demonstrate a stable clinical, laboratory, imaging, and scintigraphy phenotype along with a benign survival profile at long-term follow-up. Larger studies should define the optimal evaluation strategy in this population.

Clinical features, therapy patterns, outcomes and prognostic factors of solitary plasmacytomas: a report of the Israeli Myeloma Study Group.

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% - recurrent SP, 36.8% - active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy.

Prevalence and Clinical Characteristics of Paraproteinemia Associated with Chronic Myeloid Leukemia.

INTRODUCTION: Data regarding the prevalence of paraproteinemia in patients with chronic myeloid leukemia (CML) are lacking. METHODS: To evaluate for the prevalence of paraproteinemia, we undertook this cross-sectional study among consecutive chronic-phase CML patients. Complete blood count, chemistry, immunoglobulins, serum-free light chains, serum-protein electrophoresis and immunofixation were collected. Further analyses evaluated whether various patient-, disease-, and treatment-related variables are associated with paraproteinemia. RESULTS: One hundred patients, median age 63.5 (IQR 48.1-72) years were recruited. Median time from CML diagnosis to enrollment was 6.3 (IQR 2.3-11.3) years. Monoclonal protein was detected in 8 patients (8%), diagnosed with smoldering multiple myeloma (SMM, n = 2) and low-risk monoclonal gammopathy of undetermined significance (MGUS, n = 6). Six patients were on tyrosine kinase inhibitor treatment, 2 were in treatment-free remission. The only covariate associated with paraproteinemia was the presence of anemia, albeit with borderline statistical significance in univariate analysis (p = 0.053) and when adjusted for age (p = 0.056). CONCLUSIONS: In this largest study so far describing the prevalence of paraproteinemia among CML patients, we found MGUS prevalence to be higher than the 3.2% expected prevalence in the general population above 50 years and a non-negligible prevalence of SMM (2%). Screening for paraproteinemia in CML patients, especially in the presence of anemia, should be considered.

How I approach smoldering multiple myeloma.

The current standard of care in smoldering multiple myeloma (SMM) is close surveillance, outside of clinical trials. Efforts are being made to understand the pathobiologic process that leads to the progression of SMM to active MM. This review provides a critical description of available data, including risk factors and risk models of progression, as well as clinical trials investigating interventions for this patient population. We describe 2 cases in which patients were seen before the concept of a myeloma-defining event was established. Today, based on the International Myeloma Working Group criteria, both patients would have been identified as experiencing myeloma-defining events, and therapy would have been initiated. These cases show that occasionally, patients can undergo observation only, even when they exceed criteria for high-risk SMM.

Clinical and pathological predictors for FDG-PET/CT avidity in patients with marginal zone lymphoma-a retrospective cohort study.

BACKGROUND: The clinical value of FDG-PET/CT for staging and monitoring treatment response in patients with aggressive lymphoma is well established. Conversely, its role in the assessment and management of marginal zone lymphoma (MZL) is less conclusive. We aimed to assess clinical, laboratory, and pathological predictors for FDG uptake in these patients, in an attempt to identify MZL patients whose management will benefit from this imaging modality. METHODS: In this single-center, retrospective cohort study, we included all adult patients diagnosed with MZL at the Rabin Medical Center between January 2006 and December 2020 who underwent FDG-PET/CT at the time of diagnosis. Primary outcomes were FDG avidity (defined as a visual assessment of at least moderate intensity), SUVmax, and SUVliver. Variables such as advanced clinical stage, primary disease site, hemoglobin level (Hb), platelet count (Plt), serum albumin, LDH level, ß-2 microglobulin, and Ki 67 index were evaluated univariate and multivariate analysis using logistic and linear regression models. Association between FDG avidity and progression-free and overall survival was evaluated using Kaplan-Meier curves and Cox regression analysis. RESULTS: A total of 207 MZL patients were included in this study, 76 of whom (36.7%) had FDG-avid disease. Baseline patients' characteristics such as age, gender, and comorbid conditions were similar between patients with and without significant FDG uptake. In a multivariate logistic regression model, non-gastric MALT (OR 4.2, 95% CI 1.78-10), Ki 67 index ≥ 15% (OR 3.64, 95% CI 1.36-9.76), and elevated LDH level (OR 8.6, 95% CI 3.2-22.8) were all associated with positive FDG avidity. In a multivariate linear regression model, a combination of advanced clinical stage, specific disease subtypes, LDH level, and Ki 67 index predicted the value of SUVmax (P value < 0.001; adjusted R2 = 33.8%) and SUVmax/SUVliver (P value < 0.001; adjusted R2 = 27%). Baseline FDG avidity was associated to PFS and OS only in univariate analyses. CONCLUSIONS: In this retrospective cohort study, we present prediction models for positive FDG uptake and SUVmax in MZL patients. These models aim to help clinicians choose patients suitable for incorporation of FDG-PET/CT for staging and monitoring disease and reduce the costs of redundant tests.

Foot drop in patients treated with bortezomib - a case series and review of the literature.

Bortezomib-induced peripheral neuropathy (BIPN) has a profound impact on quality of life, which is an important issue considering the growing number of survivors of multiple myeloma and amyloidosis. BIPN is typically symmetric, distal, "stocking and glove" distribution and predominantly consists of sensory rather than motor symptoms. In this case series, we report an acute neurotoxicity syndrome induced by bortezomib, which is clinically distinct from BIPN by not being peripheral and distal. We describe six patients that developed unilateral or bilateral foot drop attributed to bortezomib. With bortezomib discontinuation symptoms improved gradually over months to years.

Differences in the characteristics and contemporary cardiac outcomes of patients with light-chain versus transthyretin cardiac amyloidosis.

AIMS: To compare the baseline cardiovascular characteristics of immunoglobulin light-chain (AL) and amyloid transthyretin (ATTR) cardiac amyloidosis (CA) and to investigate patients' contemporary cardiac outcomes. METHODS: Single-center analysis of clinical, laboratory, echocardiographic and cardiac magnetic resonance imaging (CMRi) characteristics of AL and ATTR-CA patients' cohort (years 2013-2020). RESULTS: Included were 67 CA patients of whom 31 (46%) had AL-CA and 36 (54%) had ATTR-CA. Patients with ATTR-CA versus AL-CA were older (80 (IQR 70, 85) years versus 65 (IQR 60, 71) years, respectively, p<0.001) with male predominance (p = 0.038). Co-morbidities in ATTR-CA patients more frequently included diabetes mellitus (19% versus 3.0%, respectively, p = 0.060) and coronary artery disease (39% versus 10%, respectively, p = 0.010). By echocardiography, patients with ATTR-CA versus AL-CA had a trend to worse left ventricular (LV) ejection function (50 (IQR 40, 55)% versus 60 (IQR 45, 60)%, respectively, p = 0.051), yet comparable LV diastolic function. By CMRi, left atrial area (31 (IQR 27, 36)cm2 vs. 27 (IQR 23, 30)cm2, respectively, p = 0.015) and LV mass index (109 (IQR 96, 130)grams/m2 vs. 82 (IQR 72, 98)grams/m2, respectively, p = 0.011) were increased in patients with ATTR-CA versus AL-CA. Nevertheless, during follow-up (median 20 (IQR 10, 38) months), patients with AL-CA were more frequently admitted with heart failure exacerbations (HR 2.87 (95% CI 1.42, 5.81), p = 0.003) and demonstrated increased mortality (HR 2.51 (95%CI 1.19, 5.28), p = 0.015). CONCLUSION: Despite the various similarities of AL-CA and ATTR-CA, these diseases have distinct baseline cardiovascular profiles and different heart failure course, thus merit tailored-cardiac management.

The Role of Autologous Stem Cell Transplantation in Amyloidosis.

Autologous stem cell transplantation (ASCT) has been an essential part of the treatment armamentarium in light chain (AL) amyloidosis for several decades. Patients who achieve a complete hematologic response following ASCT have a long overall survival. However, only 1 randomized controlled trial compared ASCT with the standard of care used at the time, which was melphalan and dexamethasone, and the results did not support the use of ASCT in AL amyloidosis. These results are of limited significance due to the unexpected high transplant-related mortality (TRM) (24%). TRM is a major concern in AL amyloidosis, but its incidence can be lessened by better patient selection and by patients receiving ASCT in specialized centers. ASCT in AL amyloidosis is performed only in selected patients; approximately 20% of patients with AL amyloidosis are transplant eligible up front or after bortezomib (Velcade) based conditioning. The introduction of newer agents such as bortezomib and daratumumab (Darzalex), which lead to deep responses and have good safety profiles, encourage revisiting the benefit and timing of ASCT in the modern era. This review provides a comprehensive assessment of eligibility criteria for ASCT in AL amyloidosis, conditioning dosing, efficacy in terms of hematologic and organ response, and future areas of research.

The Efficacy and Safety of Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma Patients Who Are Poor Responders to Induction: The Mayo Clinic Experience.

We report the outcomes of 117 patients with newly diagnosed multiple myeloma who received novel agent induction, had a poor response to induction, and were mobilized using intravenous intermediate-dose cyclophosphamide (82%) or VD-PACE (18%) plus granulocyte colony-stimulating factor (G-CSF) and on-demand plerixafor. The median progression-free survival and overall survival of the chemo-mobilized cohort were 21 months (95% confidence interval [CI], 15-71) and 58 months (95% CI, 47-80), respectively. We compared our cohort to a 117-patient cohort matched by the level of response at pretransplant evaluation. The matched patients were mobilized with G-CSF and on-demand plerixafor without chemotherapy. Patients receiving chemo-mobilization had higher stem cell yields than the growth-factor-only cohort (median, 10.7 × 106 cells/kg vs. 8.77 × 106 cells/kg, respectively; P < .001). The safety profile of chemo-mobilization was favorable, and there was no difference between the two groups in length of hospitalization during autologous stem cell transplantation (P = .95), days to neutrophil engraftment (P = .22), days to platelet engraftment (P = .27), or risk of bacteremia (P = .52). Twenty-nine percent of the chemo-mobilized cohort and 65% of the matched cohort required plerixafor for adequate mobilization (P < .001). Chemo-mobilization enhances stem cell collection without adversely impacting the post-transplant clinical course.

Disease monitoring with quantitative serum IgA levels provides a more reliable response assessment in multiple myeloma patients.

Unlike IgG monoclonal proteins (MCPs), IgA MCP quantification is unreliable due to beta-migration of IgA MCPs on serum protein electrophoresis (SPEP). The utility of nephelometric quantitative IgA (qIgA) to monitor IgA multiple myeloma (MM) is unclear. We retrospectively studied disease response kinetics using qIgA versus MCPs by SPEP, and developed and validated novel qIgA disease assessment criteria in 491 IgA MM patients. The SPEP MCP nadir occurred a median of 41 (IQR 0-102) days before the qIgA. The median time to achieve a partial response (PR) was shorter using standard IMWG versus qIgA response criteria (32 vs 58 days, p < 0.001). Stratification by qIgA criteria, unlike IMWG criteria, led to clear separation of the progression-free survival curves of patients achieving a PR or very good PR. There was a consistent trend toward earlier detection of disease progression using qIgA versus IMWG progression criteria. In conclusion, monitoring IgA MM using MCP-based IMWG criteria may be falsely reassuring, given that MCP levels on SPEP decrease faster than qIgA levels. The qIgA response criteria more accurately stratify patients based on the progression risk and may detect disease progression earlier, which may lead to more consistent measurement of trial endpoints and improved patient outcomes.

Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.