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Abstract Autologous transplantation remains the standard of care for eligible multiple myeloma (MM) patients, yet optimal CD34+ cell dose remains unclear. We conducted a retrospective study on MM patients undergoing upfront transplant between 2005 and 2021 and divided them into low (≤2.5 × 106 cells/kg) and high (>2.5 × 106 cells/kg) CD34+ dose groups. We included 2479 patients, 95 in the low CD34+ group and 2384 in the high CD34+ group. Patients in the low CD34+ group were older (63.2 vs 61.1 years, p = 0.013), more often had R-ISS III (19% vs 9%, p = 0.014), received plerixafor (60% vs 35%, p 2.5 × 106 cells/kg. Multivariable analysis affirmed that CD34+ >2.5 × 106 cells/kg was associated with better PFS (HR 0.71, p = 0.008) and OS (0.59, p 2.5 × 106 cells/kg remained a predictor of better OS (0.42, p 2.5 × 106 cells/kg was associated with improved survival, without any additional benefit at incrementally higher doses.

Abstract Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.

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Abstract Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p

Abstract The prognostic impact of additional copies of chromosome 1q (1q + ) on outcomes of newly-diagnosed multiple myeloma (NDMM) patients undergoing autologous transplantation (autoSCT) is unclear. We conducted a retrospective single-center analysis of NDMM patients with 1q21 gain/amplification (3 or ≥4 copies of 1q, respectively) that received autoSCT between 2008–2018. 213 patients were included (79% 1q gain; 21% 1q amplification). The most commonly used induction regimen was bortezomib, lenalidomide, and dexamethasone (41%). At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved ≥VGPR, and 38% and 50% achieved MRD-negative ≥VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative ≥VGPR before autoSCT (HR 0.52, p = 0.013) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03, p = 0.003). On multivariate analysis for OS, achieving MRD negative ≥VGPR at best post-transplant response was associated with superior survival (0.29, p

The incidence of secondary monoclonal gammopathy of undetermined significance is limited in patients with multiple myeloma post chimeric antigen receptor T-cell therapy. This is a case of secondary monoclonal gammopathy of undetermined significance with the appearance of distinct paraprotein peaks demonstrating isotype switching from IgA lambda to IgG lambda within 6 months post autologous chimeric antigen receptor T-cell therapy in a 66 year old multiple myeloma patient. Secondary monoclonal gammopathy of undetermined significance with or without isotype switching and/or new paraprotein bands may be a rare but important example of a benign and transient phenomenon representing pseudo-disease progression and potentially associated with longer progression-free survival and better overall outcomes. Although such association remains speculative given paucity of literature and an absence of high-quality data.

Abstract Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC− in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC− (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p

IntroductionThis study examined the role of echocardiographic and cardiac histomorphology parameters in predicting mortality in patients with cardiac AL amyloidosis.MethodsPatients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images and endomyocardial biopsy samples were processed for myocardial strain analysis and a detailed histomorphology characterization.ResultsOf 43 patients; 44% were women and 63% white. Median age was 65 years; 51% underwent stem cell transplantation (SCT). Thirty patients (70%) died during follow up (median follow up: 4.1 years). Lower LA strain (

Abstract Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the ‘efficacy’ of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual’s composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.

ABSTRACT Bone disease is common in patients with multiple myeloma (MM), which manifests as bone pain and skeletal‐related events (SREs) such as pathological fractures and spinal cord compression. Myeloma bone disease (MBD) can adversely affect the quality of life of patients and have negative effects on morbidity and mortality. The pathogenesis of MBD is complex, and several factors are involved in the dysregulation of bone metabolism and uncoupling of bone remodeling, which result in net bone loss and devastating SREs. Broadly speaking, elevated osteoclast activity, suppressed osteoblast activity, and an aberrant marrow microenvironment play a role in MBD. Interaction of MM cells with the main bone cell osteocytes also promote further bone destruction. This review focuses on the role of bone‐modifying agents in the prevention and treatment of MBD. The mainstay of MBD prevention are antiresorptive agents, bisphosphonates and denosumab. However, these agents do not play a direct role in bone formation and repair of existing MBD. Newer agents with anabolic effects such as anti‐sclerostin antibodies, parathyroid hormone, anti‐Dickkopf‐1 antibodies, and others have shown potential in repair of MBD lesions. With the development of several new agents, the treatment landscape of MBD is likely to evolve in the coming years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Introduction: Patients with systemic AL amyloidosis (AL) should be evaluated for cardiac amyloidosis (CA), as prognosis is strongly related to cardiac involvement. We assessed the characteristics of patients referred to cardiac magnetic resonance (CMR) with suspected CA from a cancer center and determine predictors of mortality/heart failure hospitalizations (HFH).Methods: Forty-four consecutive patients referred for CMR with suspected CA were retrospectively included. Variables collected included cardiac biomarkers, in addition to echocardiographic and CMR variables. Survival analyses were performed to determine which variables were more predictive of mortality and HFH.Results: Of the 44 patients included, 55% were females. 73% of patients were diagnosed with CA by CMR; 56% of them had an established diagnosis of AL. Patients with CA by CMR had higher native T1, higher extracellular volume (ECV) fraction, higher T2, less negative GLS by Echo, and higher troponin I and B-type natriuretic peptide (BNP). Kaplan-Meier survival analysis revealed that the following were predictive of mortality: an ECV ≥ 0.50 (p = 0.0098), CMR LVEF < 50% (p = 0.0010), T2/ECV ≤ 100 (p = 0.0001), and troponin I > 0.03 (p = 0.0025). In a stepwise conditional Cox logistic regression model, the only variable predictive of a composite of mortality and HFH was ECV (HR: 1.17, 95% CI = 1.02–1.34 p = 0.030).Conclusion: ECV seems to be an important biomarker that could be a predictor of outcomes in cardiac AL amyloidosis. In combination, CMR and serum cardiac biomarkers might help to establish prognosis in patients with CA.

Belantamab mafodotin (belamaf) is a first-in-class anti-B-cell maturation antigen (BCMA) antibody–drug conjugate (ADC) that recently gained regulatory approval for the treatment of relapsed and/or refractory multiple myeloma (RRMM) patients who have received at least four prior therapies including an anti-CD38 monoclonal antibody (mAb), a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD). As the first BCMA-targeted therapy to be approved in multiple myeloma along with its “off-the-shelf” outpatient administration, belamaf addresses a significant unmet need in RRMM that is refractory to IMiD, PI, and anti-CD38 mAb therapy, otherwise known as triple-class refractory myeloma. Belamaf is also associated with frequent corneal ocular adverse events, which represents a unique toxicity in multiple myeloma therapeutics, and its administration requires a multidisciplinary approach with oncologists and eye care specialists to safely and effectively manage patients on belamaf therapy. In this review, we discuss the preclinical and clinical data leading to the regulatory approval of belamaf, the monitoring and mitigation strategies of corneal ocular adverse events, and its current and future role in the RRMM treatment landscape.

The expanding therapeutic landscape of relapsed and/or refractory multiple myeloma (RRMM) has contributed to significant improvements in patient outcomes. These have included combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), histone deacetylase inhibitors, and/or alkylating agents. More recently, the approval of the first-in-class nuclear export inhibitor selinexor and the first-in-class B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin has helped address the current unmet need in patients refractory to PI, IMiD, and anti-CD38 mAb directed therapy, otherwise known as triple class refractory myeloma. With the growing number of treatment options in the RRMM therapeutic landscape, the choice and sequencing of drugs and combinations has become increasingly complex. In this review we discuss our approach and considerations in the treatment of both early and late RRRM based on best available data and our clinical experience.

In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure) were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma.