Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.

Multiple myeloma (MM), a malignant disorder of plasma cells affecting primarily elderly patients, is the second most commonly diagnosed hematologic neoplasm. With the recent influx of effective new agents available, including proteasome inhibitors, immunomodulators, targeted monoclonal antibodies, and now chimeric antigen receptor T cell (CAR-T) therapy, the treatment landscape is evolving rapidly. Although the role of consolidative autologous stem cell transplantation (ASCT) in first remission is well established, in the relapsed setting after upfront ASCT, the role of a second ASCT (SAT) following reinduction is less clear and understudied. Practice patterns vary significantly across institutions, and most of the literature available to guide clinical decisions consists of single-institution experiences, with only 1 randomized study evaluating the role of SAT compared with a nontransplantation approach. SAT is likely underused, because it has not been included in clinical trials examining novel regimens for relapsed disease. Furthermore, outcomes likely can be improved with approaches to intensify the preparative regimen and the use of standard post-transplantation maintenance. In this review, we examine the role of SAT in the current MM treatment landscape in the context of recent data on the efficacy of CAR-T therapy in this disease. We caution the abandonment of SAT, given that CAR-T therapy is in its infancy in MM treatment, and that real-world data in the relapsed setting are consistently inferior to clinical trial outcomes.

• Significant progress has been made on the treatment of MM during past two decades. • Acquired drug-resistance continues to drive early relapse in primary refractory MM. • XPO1 over-expression and cargo mislocalization are associated with drug-resistance. • XPO1 inhibitor selinexor restores drug sensitivity to subsets of RR-MM cells.

Objective: This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types.Methods: This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy.Results: A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 – 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 – 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 – 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 – 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 – 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 – 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia.Conclusion: Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.

Isatuximab is an immunoglobulin G1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multicenter, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered IV weekly during the first 28-day cycle, and then every other week during cycles 2 to 24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a very good partial response (VGPR) or better. The median time to partial response (PR) or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement, and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing N-terminal pro b-type natriuretic peptide (NT-proBNP) with cardiac involvement. The most common treatment-related grade ≥3 adverse events included lymphopenia (n = 3, 8.5%) and infection (n = 2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis, and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as #NCT03499808.