International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies.

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.

Carfilzomib, daratumumab, and dexamethasone (KdD) vs. lenalidomide-sparing pomalidomide-containing triplet regimens for relapsed/refractory multiple myeloma: an indirect treatment comparison.

Nearly all patients with multiple myeloma eventually relapse or become refractory to treatment. Lenalidomide is increasingly administered in the frontline until disease progression or intolerance to therapy, resulting in the need for highly effective, lenalidomide-sparing options. In this study, carfilzomib plus daratumumab and dexamethasone were evaluated against lenalidomide-sparing, pomalidomide-containing triplets using matching-adjusted indirect comparison in the absence of head-to-head data. The analyses utilized long-term follow-up data from the CANDOR study (NCT03158688). Treatment with carfilzomib, daratumumab, and dexamethasone resulted in significantly longer progression-free survival (hazard ratio 0.60 [95% confidence interval: 0.37, 0.88])vs. pomalidomide plus bortezomib and dexamethasone, and numerically longer progression-free survival (hazard ratio 0.77 [95% confidence interval: 0.50, 1.08]) vs. daratumumab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma and previous lenalidomide exposure, the majority of whom were lenalidomide refractory. Carfilzomib plus daratumumab and dexamethasone offers a highly effective, lenalidomide-sparing treatment option for this population.

Overall Survival in Patients With Multiple Myeloma in the U.S.: A Systematic Literature Review of Racial Disparities.

Multiple myeloma (MM) accounts for 10% of hematologic cancers in the U.S.; however, incidence and mortality occur disproportionately between racial groups in real-world settings. Our study's objective was to systematically characterize the disparities in overall survival (OS) among Black and White patients with MM in the US using real-world evidence studies. A systematic literature review was undertaken by searching Embase and MEDLINE for observational studies conducted in the US, published between January 1, 2015 and October 25, 2021, and reporting OS for Black and White patients with MM. Records were reviewed by 2 independent researchers. OS data were extracted as hazard ratios (HR), median survival, or %, with methods of adjustment, as reported. Evidence quality was assessed by data source, population, and variables for which HRs for risk of death were adjusted. We included 33 US studies comprising 410,086 patients (21.5% Black; 78.5% White) with MM. Receipt of treatment varied; however, most studies reported that patients either underwent stem cell transplant and/or received systemic therapy. HRs from 9 studies were considered "high quality" by comparing nationally representative, generalizable cohorts and adjusting for key prognostic, treatment, and/or socioeconomic factors. After adjustment, these data suggested that Black patients exhibit similar or superior survival outcomes compared with their White counterparts. When data are adjusted for important confounders, Black patients exhibit better or equal survival to White patients, indicating that similarities in patient populations and equal access to treatment can bridge the disparity in patient outcomes between races.

Addressing the disparities: the approach to the African American patient with multiple myeloma.

There are significant disparities with regards to incidence, timely diagnosis, access to treatment, clinical trial participation and health care utilization that negatively impact outcomes for African American patients with multiple myeloma. Health care providers have a role in ameliorating these disparities with thoughtful consideration of historical, sociocultural, individual and disease characteristics that influence the care provided to African American patient population. This review by a group of experts committed to health disparity in multiple myeloma provides a snapshot of disparities at both biologic and non-biologic levels, barriers to clinical care, and best practices to ensure that African American patients receive the best care available.

Management of multiple myeloma-related renal impairment: recommendations from the International Myeloma Working Group.

Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment.

Culturally Responsive Care Delivery in Oncology: The Example of Multiple Myeloma.

Multiple myeloma (MM) represents ∼1% of all cancers and is the second most common hematologic malignancy worldwide. The incidence of MM is at least two times higher in Blacks/African Americans compared with their White counterparts, and Hispanics/Latinxs are among the youngest patients diagnosed with the disease. Recent advances in available treatments for MM have demonstrated significant improvement in survival outcomes; however, patients from non-White racial/ethnic groups clinically benefit less due to multiple factors including access to care, socioeconomic status, medical mistrust, underutilization of novel therapies, and exclusion from clinical trials. Health inequities in disease characteristics and risk factors based on race also contribute to inequities in outcomes. In this review, we highlight racial/ethnic factors as well as structural barriers attributed to variations in MM epidemiology and management. We focus on three populations-Black/African American, Hispanic/Latinx, and American Indian/Alaska Native-and review factors that healthcare professionals may consider when treating patients of color. We offer tangible advice for healthcare professionals on how to incorporate cultural humility into their practice by following the five key steps: establishing trust, respecting cultural diversity, undergoing cross-cultural training, counseling patients on appropriate available clinical trial options, and connecting patients to community resources. The outlined recommendations will help the medical community to better understand and apply the important concept of cultural humility into their practice to provide the best care for all their patients, regardless of race/ethnicity.

Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study.

Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 [95% CI: 25.8-44.0] vs 19.2 [95% CI: 15.8-25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285.

Heart Failure Among Patients with Multiple Myeloma Treated with Carfilzomib-Based Versus Non-Carfilzomib-Based Regimens in the United States by Race.

BACKGROUND: Carfilzomib treatment for multiple myeloma (MM) can increase heart failure risk. Whether this risk differs by race is unknown. PATIENTS AND METHODS: We sought to estimate the incidence rates (IRs) of heart failure hospitalization among mostly 65-years-and-older US patients with MM by race treated with carfilzomib- and non-carfilzomib-based regimens in the real-world using Centers for Medicare & Medicaid Services Medicare Fee-for-Service data, Optum Clinformatics Data Mart, and Humana Research Database. The risk of heart failure hospitalization associated with a carfilzomib-based regimen was evaluated using propensity score matching among Black and White patients receiving second or later lines of therapy. RESULTS: Most patient-episodes (88%) were in persons 65 years or older for the 3 cohorts combined. The IR (95% CI) of heart failure hospitalization was higher for patient-episodes treated with a carfilzomib-based regimen than those with a non-carfilzomib-based regimen for both White (14.5 [12.2-17.0] vs. 10.7 [10.3-11.2] events per person-years) and Black patients (15.8 [10.1-23.5] vs. 12.1 [10.9-13.4] events per person-years) in the Medicare cohort. After propensity score matching, the hazard ratio (95% CI) of increased heart failure hospitalization comparing carfilzomib-based to non-carfilzomib-based regimens for White patients (1.6 [1.3-2.0]) was similar to that of Black patients (1.7 [1.0-2.9]) in the Medicare Database, and in the Humana Database (1.4 [0.8-2.6] and 1.2 [0.4-3.5], respectively). CONCLUSION: Although the IR of heart failure among patients with MM treated with a carfilzomib-based regimen was slightly higher, no evidence suggested the relative risk was different between White and Black patients with MM.

Integrated analysis of next generation sequencing minimal residual disease (MRD) and PET scan in transplant eligible myeloma patients.

Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS-MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10-6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD had poor agreement, with high rates of PET-CT negativity in MRD-positive patients. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the ability to measure deeper and sustainable responses distinguishes patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

Multisite Quality Improvement Initiative to Identify and Address Racial Disparities and Deficiencies in Delivering Equitable, Patient-Centered Care for Multiple Myeloma-Exploring the Differences between Academic and Community Oncology Centers.

Treatment of multiple myeloma (MM) is complex; however, with equal access to care, clinical outcomes for Black patients match those in other patient groups. To reveal and begin to address clinical practice barriers to equitable, patient-centered MM care, this quality improvement (QI) initiative assessed patient electronic medical records (EMRs) and surveyed patients and providers at two large hospital systems and four community-based practices. For the educational intervention, providers participated in feedback-focused grand rounds sessions to reflect on system barriers and develop action plans to improve MM care. EMR reviews revealed infrequent documentation of cytogenetics and disease staging at community-based practices compared to large hospital systems. In surveys, providers from each care setting reported different challenges in MM care. Notably, the goals of treatment for patients and providers aligned at community clinics while providers and patients from large hospital systems had discordant perspectives. However, providers in community settings underreported race-associated barriers to care and identified different factors impacting treatment decision-making than Black patients. Relative to pre-session responses, providers were more likely to report high confidence after the educational sessions in aligning treatment decisions with guidelines and clinical evidence and shared decision-making (SDM). This QI study identified discordant perceptions among providers at large hospital systems and community-based practices in providing quality MM care. Provider education yielded increased confidence in and commitment to patient-centered care.

Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: IKEMA Subgroup Analysis by Prior Transplantation.

In the era of highly active novel agents for multiple myeloma (MM), the role, ideal timing, and impact of transplantation on further therapy after relapse remains a matter of debate. The impact of prior transplantation on treatment benefit from monoclonal antibodies in patients with relapsed/refractory MM (RRMM) is largely unknown. Few Phase 3 studies of monoclonal antibody combinations with proteasome inhibitors or immunomodulatory agents have reported outcomes according to transplantation status. This subgroup analysis examined efficacy and safety in patients from the Phase 3 IKEMA study with and without previous transplantation. IKEMA (NCT03275285) was a randomized, open-label, multinational, parallel-group Phase 3 study that investigated isatuximab (Isa), an anti-CD38 monoclonal antibody, combined with carfilzomib and dexamethasone (Isa-Kd; experimental group) versus Kd (control group) in 302 patients with RRMM and 1 to 3 prior lines of therapy. Patients were randomized in a 3:2 ratio to either Isa-Kd or Kd, with stratification by number of prior lines (1 versus more than 1) and Revised International Staging System (R-ISS) stage (I or II versus III versus not classified). Treatment was given until progressive disease, unacceptable adverse events, or patient choice. Of the 302 randomized patients in IKEMA, 185 (61.3%) had received a prior transplant, comprising 116 of 179 (64.8%) patients in the Isa-Kd arm and 69 of 123 (56.1%) patients in the Kd arm. After a median follow-up of 20.6 months, median progression-free survival (PFS) in patients with prior transplant was not reached with Isa-Kd versus 19.15 months with Kd (hazard ratio [HR] = 0.60; 99% confidence interval [CI], 0.31-1.16). After a median follow-up of 20.8 months, median PFS in patients without prior transplant was not reached with Isa-Kd versus 18.99 months with Kd (HR = 0.44; 99% CI, 0.18-1.05). The overall response rate in patients with prior transplant was 87.9% (Isa-Kd) versus 85.5% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (43.1% versus 29.0%). The overall response rate in patients without prior transplant was 84.1% (Isa-Kd) versus 79.6% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (33.3% versus 25.9%). The minimal residual disease negativity rate was higher with Isa-Kd versus Kd in patients with (31.9% versus 13.0%) and without prior transplantation (25.4% versus 13.0%). In patients with prior transplant, Grade 3 or higher treatment-emergent adverse events (TEAEs) were more common with Isa-Kd; however, no increases in serious TEAEs or definitive treatment discontinuations were seen versus Kd. Among patients without prior transplant, serious treatment-related TEAEs were similar, and there were fewer TEAEs leading to definitive discontinuation with Isa-Kd. The most common Grade 3 or higher TEAEs in patients with and without prior transplant were hypertension and pneumonia. For patients who underwent prior transplantation, Isa-Kd is an effective treatment option. Overall, these data demonstrate that Isa-Kd represents a standard of care for patients with RRMM, regardless of prior transplant status.

Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations.

Multiple myeloma is the second most common hematologic malignancy in the United States and the most common hematologic malignancy among Blacks/African Americans. Delay in diagnosis is common and has been associated with inferior disease-free survival and increased rates of myeloma-related complications. Despite a roughly 2-times higher risk of multiple myeloma, diagnostic delay appears more common, and improvements in 5-year survival rates have been slower among Blacks/African Americans than their White counterparts. When patient symptoms and basic laboratory findings are suggestive of multiple myeloma, the primary care provider should initiate extended laboratory work-up that includes serum protein electrophoresis, serum immunoglobulin free light chain assay, and serum immunofixation. Heightened awareness within high-risk populations such as Blacks/African Americans may help to eliminate racial disparities in the diagnosis and treatment of multiple myeloma.

Chimeric Antigen Receptor T-Cell Therapies: Barriers and Solutions to Access.

Chimeric antigen receptor T-cell (CAR-T) therapies are relatively new treatments for patients with heavily pretreated hematologic malignancies. Although these innovative therapies can offer substantial benefit to patients with limited alternative treatment options, patient-access barriers exist. Conventional clinical trials are time-consuming and may be limited by strict patient eligibility criteria, resources, and availability of enrollment slots. Because of the complexity of the CAR-T administration process, treatment delivery can be associated with additional burden for the patient, including requiring patients to reside close to treatment centers and remain with a caregiver after infusion. Manufacturing of CAR-T cells is completed in specialized facilities and depends on the availability of reagents, manufacturing workforce, and timely transportation. CAR-T therapy is costly, and many US health plans restrict coverage of cell and gene therapies. Several of the existing challenges because of these barriers have been exacerbated during the COVID-19 pandemic. This review discusses these barriers and proposes some potential solutions to improving patient access, including innovation in clinical trial design and manufacturing, location of treatment delivery, and key stakeholder opinions regarding treatment and reimbursement. We propose a call to action for key stakeholder groups to address these barriers to CAR-T therapy to expand treatment access for patients. Future collaboration between key stakeholders, including payers, regulatory agencies, and industry/academia, will be critical to continue to address these barriers and enhance patient access to these therapies.