Divergence of variant antibodies following SARS-CoV-2 booster vaccines in myeloma and impact of hybrid immunity.

Hematological malignancies are associated with an increased risk of complications during SARS-CoV-2 infections. Primary series or monovalent booster vaccines reduce disease severity, hospitalization, and death among multiple myeloma patients. We characterized virus-neutralizing and spike-binding antibody profiles following monovalent (WA1) or bivalent (WA1/BA.

How to rescue a DreaMM deferred ….

The recently published DreaMM-7 and -8 trials demonstrate the benefit of triplet combination regimens including the anti-BCMA antibody drug conjugate belantamab mafodotin. Here, we describe the findings of these trials including efficacy and safety data and provide commentary on the implications for future use of belantamab in the relapsed myeloma space.

Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients.

Lenalidomide, bortezomib, and dexamethasone (RVd) have previously been established as standard-of-care induction therapy for newly diagnosed multiple myeloma (NDMM). More recently, randomized phase 3 data have demonstrated the benefit of the addition of daratumumab (Dara-RVd) to the RVd backbone in terms of improved both depth of response and long-term survival benefit as measured by progression-free survival (PFS). Our group has previously published on a historical cohort of 1000 NDMM patients uniformly treated with RVd induction with impressive both PFS and overall survival.

Divergence of variant binding/neutralizing antibodies following SARS-CoV-2 booster vaccines in myeloma: Impact of hybrid immunity.

We characterized virus-neutralization and spike-binding antibody profiles in myeloma patients following monovalent or bivalent-SARS-CoV-2 booster vaccination. Vaccination improves the breadth of binding antibodies but not neutralization activity against current variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.

Divergence of variant binding/neutralizing antibodies following SARS-CoV-2 booster vaccines in myeloma: Impact of hybrid immunity.

We characterized virus-neutralization and spike-binding antibody profiles in myeloma patients following monovalent or bivalent-SARS-CoV-2 booster vaccination. Vaccination improves the breadth of binding antibodies but not neutralization activity against current variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.

Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy.

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models.

Impact of Black Race on Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma Receiving Bortezomib Induction.

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.

Impaired SARS-CoV-2 Variant Neutralization and CD8+ T-cell Responses Following 3 Doses of mRNA Vaccines in Myeloma: Correlation with Breakthrough Infections.

Unlabelled: Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.

Determinants of Neutralizing Antibody Response After SARS CoV-2 Vaccination in Patients With Myeloma.

Purpose: Vaccine-induced neutralizing antibodies (nAbs) play a critical role in protection from SARS CoV-2. Patients with B-cell malignancies including myeloma are at increased risk of COVID-19-related mortality and exhibit variable serologic response to the vaccine. The capacity of vaccine-induced antibodies in these patients to neutralize SARS CoV-2 or its variants is not known.

Impact of concurrent gabapentin or pregabalin with high-dose melphalan in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplant.

Background: Melphalan is an alkylating agent used in both autologous (ASCT) and allogeneic stem cell transplantation. It is a substrate of L-type amino acid transporter-1 (LAT-1) and LAT-2, which are involved in its tissue penetration and elimination. Gabapentin and pregabalin, common concomitant medications in patients with multiple myeloma undergoing ASCT, are also substrates of LAT transporters, raising concern for potential competitive inhibition of melphalan transport.

Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia.

Unlabelled: Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion.

Benefits of Autologous Stem Cell Transplantation for Elderly Myeloma Patients in the Last Quarter of Life.

Although survival outcomes have improved dramatically over the last few decades in newly diagnosed myeloma patients, elderly patients have not yielded the same magnitude of benefit as evidenced by higher rates of reported myeloma-related deaths in patients over the age of 75. This is of particular importance given this cohort comprises a large proportion of myeloma patients with the median age of diagnosis being 70 years. One contributor to this discrepancy is reduced use of high-dose therapy and autologous stem cell transplantation (HDT/ASCT) in this population because of concerns for increased toxicity and safety.

Maintenance Strategies for Myeloma: Is Bigger Always Better?

Over the last decade, several very important prospective randomized controlled trials have confirmed the significant survival benefit conferred by maintenance therapies. Owing to these developments, the role of continued maintenance in the optimal management strategies of newly diagnosed myeloma patients (both transplant-eligible and transplant-ineligible) has been strongly cemented. In dealing with an incurable disease such as myeloma, whether to offer maintenance is no longer as relevant a question as it was before, but which antimyeloma agent or agents to use, as maintenance remains more pertinent today.

Novel Approaches to Treating Relapsed and Refractory Multiple Myeloma with a Focus on Recent Approvals of Belantamab Mafodotin and Selinexor.

Though survival outcomes in multiple myeloma patients have improved drastically over the past few decades, there still remains an ongoing need for effective and tolerable treatment options in the relapsed and refractory space. Encouragingly, there have been three recent FDA approvals for triple-class refractory multiple myeloma, and there is promising ongoing development of additional agents with varying novel mechanisms of action. Here, we will review the most recent data on both belantamab mafodotin, an antibody drug conjugate (ADC) targeting BCMA, and selinexor, a first-in-class selective inhibitor of XPO1, as well as touch on some of the recently published data for other immunotherapies in development, namely bispecific T cell engagers, ADCs, and CAR-T cell therapies.

"I took the road less traveled, and that has made all the difference": Making a case for high-dose therapy and autologous stem cell transplantation in elderly patients with newly diagnosed multiple myeloma.

Elderly patients with myeloma derive benefits from transplantation similar to those for younger patients. Age should not be the sole criterion for determining transplant eligibility. Performance status assessment and other tools for assessing comorbidities such as the Charlson comorbidity score may potentially help in determining transplant eligibility and will allow us to move away from our heavy reliance on numerical age.

Venetoclax sensitivity in multiple myeloma is associated with B-cell gene expression.

Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent on BCL2 for survival. Most myeloma is MCL1-dependent; however, a subset of myeloma enriched for translocation t(11;14) is codependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood.

Game of Bones: How Myeloma Manipulates Its Microenvironment.

Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin's Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease.

Current developments in the combination therapy of relapsed/refractory multiple myeloma.

Introduction: Therapy for patients with multiple myeloma has improved dramatically over the past decade following the introduction of novel agents and combinations across the disease spectrum. When relapse or refractory disease develops, non-cross-resistant drugs, most often used in multidrug regimens, have provided significant improvements in patient outcomes. Despite these advances, myeloma remains incurable and additional therapeutic approaches, based on emerging molecular and cellular biology, are moving rapidly through development phases.

Practical approach to the management of smoldering myeloma.

Purpose Of Review: The aim of this article is to review the diagnosis and risk stratification of smoldering myeloma (SMM), describe recently published data regarding the early treatment of SMM, and to provide practical strategies on how to manage patients with SMM in the clinic.

Recent Findings: Recently published data from the ECOG E3A06 and GEM-CESAR studies supporting early intervention for certain subsets of high-risk SMM patients will be presented, and the relevance of these findings in relation to real-life application will be explored.

Summary: Accurate risk-stratification and standard of care for SMM is evolving, and here we summarize the pertinent clinical data and provide recommendations for clinical management of SMM patients.

Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma.

Purpose: The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is a highly effective and convenient induction regimen for both transplantation-eligible and -ineligible patients with myeloma. Here, we present the largest cohort of patients consecutively treated with RVD induction therapy followed by risk-adapted maintenance therapy with the longest follow-up and important information on long-term outcomes.

Patients And Methods: We describe 1,000 consecutive patients with newly diagnosed myeloma treated with RVD induction therapy from January 2007 until August 2016.