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Summary: Background: The real-world impact of bivalent vaccines for wild type (WA.1) and Omicron variant (BA.5) is largely unknown in immunocompromised patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster, including neutralizing assays to identify patterns associated with continuing vulnerability to current variants (XBB1.16, EG5) in the current post-pandemic era. Methods: We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48 MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assays to assess inhibition of live virus. We measured spike specific T-cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow-cytometry based T-cell. In a subset of 38 patients, high-dimensional flow cytometry was performed to identify immune cell subsets associated with lack of humoral antibodies. Findings: We find that bivalent vaccination provides significant boost in protection to the omicron variant in our MM patients, in a treatment specific manner. MM patients remain vulnerable to newer variants with mutations in the spike portion. Anti-CD38 and anti-BCMA therapies affect the immune machinery needed to produce antibodies. Interpretation: Our study highlights varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairment in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate humoral and cellular responses to vaccination. Funding: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), NCI Serological Sciences Network for COVID-19 (SeroNet) and The Icahn School of Medicine at Mount Sinai.

Resistance to immunomodulatory drugs (IMiDs®) is a major cause of treatment failure, disease relapse and ultimately poorer outcomes in multiple myeloma (MM). In order to optimally deploy IMiDs and their newer derivates CRBN E3 ligase modulators (CELMoDs®) into future myeloma therapeutic regimens, it is imperative to understand the mechanisms behind the inevitable emergence of IMiD resistance. IMiDs bind and modulate Cereblon (CRBN), the substrate receptor of the CUL4CRBN E3 ubiquitin ligase, to target novel substrate proteins for ubiquitination and degradation. Most important of these are IKZF1 and IKZF3, key MM survival transcription factors which sustain the expression of myeloma oncogenes IRF4 and MYC. IMiDs directly target MM cell proliferation, but also stimulate T/NK cell activation by their CRBN-mediated effects, and therefore enhance anti-MM immunity. Thus, their benefits in myeloma are directed against tumor and immune microenvironment – and in considering the mechanisms by which IMiD resistance emerges, both these effects must be appraised. CRBN-dependent mechanisms of IMiD resistance, including CRBN genetic aberrations, CRBN protein loss and CRBN-substrate binding defects, are beginning to be understood. However, only a proportion of IMiD-resistant cases are related to CRBN and therefore additional mechanisms, which are currently less well described, need to be sought. These include resistance within the immune microenvironment. Here we review the existing evidence on both tumor and immune microenvironment mechanisms of resistance to IMiDs, pose important questions for future study, and consider how knowledge regarding resistance mechanism may be utilized to guide treatment decision making in the clinic.

Monoclonal gammopathy (MG) is a frequently detected clonal B-cell or plasma-cell disorder. Importantly, every multiple myeloma (MM) case is preceded by MG. Although clinical algorithms now allow earlier treatment of patients with biomarkers of malignancy before MM-induced tissue damage (CRAB) occurs, most patients are still diagnosed late. It is important to revisit how MG should be managed in clinical practice and whether screening is required. As the prevalence of MG and other medical co-morbidities both rise with increasing age, the degree of contribution of MG to disease states other than malignant progression is often unclear. This can lead to monitoring lapses and under recognition of the organ dysfunction that can occur with monoclonal gammopathy of clinical significance (MGCS). Therefore, models of progression to MM and/or MGCS require further refinement. While MG is currently detected incidentally, a case for screening has been made with ongoing studies in this area. Screening has the potential benefit of earlier detection and prevention of both MGCS and delayed MM presentations, but important drawbacks include the psychosocial impact on individuals and resource burden on healthcare services. MG terminology should transition alongside our increasing understanding of the condition and genomic characterization that have already begun to revise the MG nomenclature. The biology of MG has been poorly understood and is often inferred from the biology of MM, which is unhelpful. We review the literature and case for MG screening in this paper. In particular, we highlight areas that require focus to establish screening for MG.

ABSTRACT Large‐scale studies have not addressed the knowledge level of US resident physicians regarding osteoporosis management. We gauged the knowledge level of family medicine, internal medicine, and obstetrics and gynecology resident physicians regarding osteoporosis management. In 2019, we sent an anonymous survey via e‐mail to all program directors of Accreditation Council for Graduate Medical Education–accredited residency programs in family medicine, internal medicine, and obstetrics and gynecology for distribution to resident physicians. Knowledge items assessed osteoporosis screening, diagnosis, and treatment. We received responses from 182 family medicine, 275 internal medicine, and 122 obstetrics and gynecology programs. Of 582 resident physician respondents, 31% were family medicine residents, 47% were internal medicine residents, and 21% were obstetrics and gynecology residents. Although 77% of respondents correctly selected the T‐score threshold for the diagnosis of osteoporosis among persons aged 50 years and older (−2.5), only 20% of respondents correctly identified minimal‐trauma hip fracture as being diagnostic of osteoporosis. One‐third of respondents correctly identified which medications were demonstrated in clinical trials to decrease hip fracture risk. Fifteen percent of respondents correctly identified that denosumab and alendronate are associated with osteonecrosis of the jaw; and 40% of respondents correctly identified that decline in bone density is more rapid after discontinuation of denosumab than after discontinuation of bisphosphonates. Less than half of resident physicians knew that bisphosphonate‐associated atypical femoral fractures are duration‐dependent. One‐quarter of respondents felt not at all prepared to manage osteoporosis. In this nationwide survey of resident physicians, knowledge regarding osteoporosis diagnosis and treatment was poor, with a striking lack of knowledge regarding the two most serious adverse effects of osteoporosis pharmacotherapy (osteonecrosis of the jaw and atypical femoral fractures). The undertreatment of osteoporosis is unlikely to improve without increased education of resident physicians. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.