Anthropometric traits and risk of multiple myeloma: differences by race, sex and diagnostic clinical features.

BACKGROUND: Obesity is an established modifiable risk factor for multiple myeloma (MM). However, associations of obesity and MM risk in Black populations, for whom obesity and MM are more common, is less clear. METHODS: Using participants enrolled in the Integrative Molecular And Genetic Epidemiology study, we evaluated the association of anthropometric traits with MM risk overall, stratified by race and sex. Among cases, we assessed the association of BMI with the presence of myeloma-defining events. RESULTS: We observed an 18% increase in MM risk for every 5 kg/m2 increase in usual adult BMI. Participants with severe obesity (BMI ≥ 40 kg/m2) had the highest risk compared to those with a normal usual adult BMI (18.5-24.9 kg/m2; OR = 1.87, 95% CI 1.25-2.80), particularly among Black men (OR = 3.94, 95% CI 0.90-17.36). Furthermore, MM cases with overweight/obesity (BMI ≥ 25 kg/m2) were more likely to present at diagnosis with low renal function (OR = 1.62, 95% CI 1.09-2.40), deletion 13q (OR = 1.73, 95% CI 1.08-2.76) and lytic lesions or compression fractures (OR = 2.39, 95% CI 0.82-7.01) and less likely to present with severe diffuse osteopenia (OR = 0.51, 95% CI 0.31-0.81). CONCLUSIONS: Findings underscore the importance of obesity as a modifiable risk factor for MM, particularly in high-risk populations, and for the clinical presentation of disease.

Bridging treatment prior to chimeric antigen receptor T-cell therapy in multiple myeloma.

Autologous patient-derived adoptive T-cell therapies have revolutionized the management of relapsed multiple myeloma (MM). However, the current manufacturing and quality control processes result in lengthy vein-to-vein time, making bridging therapy necessary for most patients. Yet the decision and choice of optimal bridging therapy are complex in the heavily pretreated relapsed MM patient. In this perspective piece, the authors provide their approach and considerations while selecting an optimal bridging regimen before autologous chimeric antigen receptor T-cell therapy.

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations.

The combination of anti-CD38 monoclonal antibodies to a proteasome inhibitor, an immunomodulatory agent and dexamethasone (quadruplet-QUAD) in sequence with autologous stem cell transplantation (ASCT) leads to deep and durable responses in newly diagnosed multiple myeloma (NDMM). Disease progression in the first year post-QUADs is uncommon. We analysed 274 consecutive NDMM patients treated with QUADs + ASCT. After a median follow-up of 21.3 months, 20 patients had disease progression <18 months and 21 had progression ≥18 months after the onset of a QUAD regimen. All patients received subsequent anti-MM therapy, and 38 were evaluated for response. Nine (22.0%) received T-cell redirecting therapy as the next treatment, and 21 (51.2%) at some point in the treatment course. Response to next therapy was 26.3% for patients with progression <18 months and 52.6% for those with progression ≥18 months after the onset of a QUAD regimen. Median PFS on the next therapy was 2.5 months (95% CI 1.5-3.4) for those with progression <18 months and 7.0 months (95% CI 3.6-10.5) for those with progression ≥18 months. Efforts should focus on the early deployment of therapies with new mechanism of action for patients experiencing treatment failure after QUADs.

Recommendations on prevention of infections during chimeric antigen receptor T-cell and bispecific antibody therapy in multiple myeloma.

Chimeric antigen receptor T (CAR T) cell and bispecific antibody therapies have shown unprecedented efficacy in heavily pretreated patients with multiple myeloma (MM). However, their use is associated with a significant risk of severe infections, which can be attributed to various factors such as hypogammaglobulinemia, neutropenia, lymphopenia, T-cell exhaustion, cytokine-release syndrome and immune-effector cell-associated neurotoxicity syndrome. As these therapies have been recently approved by regulatory agencies, it is crucial to establish practical guidelines for infection monitoring and prevention until robust data from prospective clinical trials become available. To address this issue, a panel of experienced investigators from the Academic Consortium to Overcome Multiple Myeloma through Innovative Trials (COMMIT) developed consensus recommendations for mitigating infections associated with CAR T-cell and bispecific antibody therapies in MM patients.

Teclistamab in patients with multiple myeloma and impaired renal function.

Robust anti-myeloma activity with teclistamab in patients with severe renal impairment.

Revisiting the impact of immunoglobulin isotypes in multiple myeloma.

Association of immunoglobulin isotypes with survival in the context of modern prognostic factors has not been determined. We utilized the Flatiron Health Electronic Health Record database and identified 8468 MM patients. Compared to IgG MM, patients with IgA MM were more likely to have ISS-III, anemia, and t(4;14), and light chain (LC) MM had higher renal dysfunction and t(11;14). IgA and LC MM patients have an inferior OS. The adverse prognostic impact of IgA and LC isotypes on OS persisted even after adjustment for variables impacting outcomes and likely suggests their unique biology beyond the presence of adverse prognostic factors.

Impact of autologous hematopoietic cell transplantation on disease burden quantified by next-generation sequencing in multiple myeloma treated with quadruplet therapy.

The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next-generation sequencing (NGS) for patients enrolled in a clinical trial utilizing quadruplet induction, AHCT, followed by MRD-adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty percent achieved MRD < 10-5 post-induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range, -1.26 to 3.41). Patients with high-risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (p = .02) after AHCT. Median relative reduction was 0.91 log10 (range, -0.75 to 2.14), 1.26 log10 (range, -0.21 to 3.26) and 1.34 log10 (range, -1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high-risk MM.

New regimens and directions in the management of newly diagnosed multiple myeloma.

The introduction of novel agents over the last decade has rapidly expanded the therapeutic landscape of multiple myeloma (MM) for both transplant-eligible and transplant-ineligible patients. The assessment of minimal residual disease (MRD) by next-generation flow cytometry or next-generation sequencing is established as a powerful predictor of long-term outcomes. The use of MRD in response-adapted clinical trials may provide opportunities to identify candidates for treatment escalation and de-escalation. Agents with proven activity in the relapsed and refractory setting are being studied in the management of high-risk newly diagnosed MM (NDMM). Here, we summarize the most recent clinical trials that have led to the current paradigms in the management of NDMM. We also discuss how novel agents could be incorporated in the newly diagnosed setting and potential clinical trial designs that could leverage MRD information with the goal of treatment optimization.

Stem Cell Mobilization and Autograft Minimal Residual Disease Negativity with Novel Induction Regimens in Multiple Myeloma.

Autologous stem cell transplantation (ASCT) remains the standard of care for transplantation-eligible patients with multiple myeloma (MM). Bortezomib with lenalidomide and dexamethasone (VRD) is the most common triplet regimen for newly diagnosed MM in the United States. Carfilzomib with lenalidomide and dexamethasone (KRD) has shown promising efficacy and may supplant VRD. We compared stem cell yields and autograft minimal residual disease (MRD)-negativity after VRD and KRD induction. Deeper responses (ie, very good partial response or better) were more common with KRD. Precollection bone marrow (BM) cellularity, interval from the end of induction therapy to start of stem cell collection, and method of stem cell mobilization were similar for the 2 cohorts. Days to complete collection was greater with KRD (2.2 days, versus 1.81 days with VRD), which more often required ≥3 days of apheresis. Precollection viable CD34+ cell content was greater with VRD, as was collection yield (11.11 × 106, versus 9.19 × 106 with KRD). Collection failure (defined as <2 × 106 CD34+ cells/kg) was more frequent with KRD (5.4% versus .7% with VRD). The difference in stem cell yield between VRD and KRD is associated with the degree of lenalidomide exposure. Age ≥70 years predicted poorer collection for both cohorts. Stem cell autograft purity/MRD-negativity was higher with KRD (81.4%, versus 57.1% with VRD). For both cohorts, MRD-negativity was attained in a larger fraction of autografts than in precollection BM. For patients proceeding to ASCT, the time to neutrophil/platelet engraftment was comparable in the 2 study arms. In summary, our data demonstrate that KRD induces deeper clinical responses and greater autograft purity than VRD without compromising stem cell yield or post-transplantation engraftment kinetics.

Best practices for the assessment of measurable residual disease (MRD) in multiple myeloma.

Therapeutic advances in multiple myeloma have led to durable, deep remissions in a subset of patients. However, outcomes of patients achieving a complete response are not homogeneous. In recent years, measurable residual disease (MRD) has emerged as a prognostic biomarker. While several technologies have been evaluated to detect MRD, two assessment technologies are most frequently utilized in patients with multiple myeloma. Next-generation flow (NGF) uses flow cytometry to identify malignant plasma cells through the presence of immunologic markers located on the cell surface. Next-generation sequencing (NGS) analyzes for the presence of sequences in immunoglobulin genes that were previously identified as markers of that specific patient's plasma cell malignant clone. Both methods are included in criteria for MRD by the International Myeloma Working Group, which defines MRD negativity as less than 10-5. Recently, the NGS-based clonoSEQ® Assay obtained clearance from the US Food and Drug Administration, with a limit of detection of less than 10-6 given proper sample input. Based on available evidence correlating attainment of MRD negativity with outcomes, MRD assessment has been incorporated into ongoing clinical trials. Analyses will provide additional insight into the correlation between MRD and outcome. This monograph examines the available trial data and provides recommendations on how to incorporate MRD assessment into clinical management.

Challenges and opportunities in the assessment of measurable residual disease in multiple myeloma.

Treatment response assessment in multiple myeloma (MM) relies on the detection of paraprotein in serum and/or urine, bone marrow morphology and immunohistochemistry. With remarkable advances in therapy, particularly in the newly diagnosed setting, achievement of complete remission became frequent, creating the need to identify smaller amounts of residual disease and understand their prognostic and therapeutic implications. Measurable residual disease (MRD) can be assessed primarily by flow cytometry and next generation sequencing and state-of-the-art assays have sensitivity approaching 1 in 106 cells. This review discusses the existing challenges in utilizing MRD to inform management of MM and highlights open research questions and opportunities as MRD is more routinely incorporated into clinical practice for patients with MM.

The impending financial healthcare burden and ethical dilemma of systemic therapy in metastatic cancer.

Metastatic cancer remains a devastating disease that threatens to disrupt entire family structures creating economic and psychosocial stress. Fortunately, great strides have resulted in improved therapies over the years but at a huge social-economic cost. The economic burden has risen greatly and carries with it new ethical concerns when deciding treatment. Here, we discuss the financial and ethical challenges that oncologists and their patients face in the era of novel treatment strategies. J. Surg. Oncol. 2016;114:323-328. © 2016 Wiley Periodicals, Inc.

Myocardial perfusion imaging determination using an appropriate use smartphone application.

BACKGROUND: Inappropriate cardiac imaging has been a significant cost concern and cause of radiation burden to patients. OBJECTIVE: To assess if a smartphone application (app) based on 2009 Appropriate Use Criteria (AUC) for Cardiac Radionuclide Imaging published by American College of Cardiology would be feasible at the point of order. METHODS: We evaluated stress myocardial perfusion imaging (MPI) (N = 403) (mean age = 62.23 years; 47.89% males) over a 4 month period using a smartphone app to determine whether the study ordered was Appropriate, Inappropriate, or Uncertain per 2009 AUC. We also monitored the time needed to use the app to determine the level of appropriateness of each stress MPI. The results of the stress MPI were noted. RESULTS: Of the 403 stress MPIs evaluated, 267 (66.25%) were noted to be Appropriate, 118 (29.28%) were Inappropriate, and 13 (3.23%) were Uncertain, per AUC; 5 (1.25%) remained unclassified. Average time needed to use the app to assess each stress MPI for appropriateness was noted to be 44 (±9) seconds. Non-teaching physicians ordered 70 (38.89%) inappropriate stress MPIs as compared to 20 (23.53%) ordered by physicians on resident teaching service, and 28 (23.33%) by cardiologists (P = .0045). Among inappropriately ordered stress MPIs, 87 (42.65%) were ordered in females as compared to 31 (17.13%) in males (P < .0001). 70 (26.22%) stress MPIs among appropriately ordered were abnormal (reversible ischemia or fixed perfusion defect) as compared to 15 (12.17%) among inappropriately ordered stress MPIs (P = .0032). CONCLUSION: A free and convenient smartphone app provides an easy-to-use tool to assist physicians in determining the level of appropriateness of stress MPI in a time- and cost-effective manner at the point of order. The smartphone app may have potential to promote the usage of the AUC and possibly aid reduction of healthcare cost and ionizing radiation burden.