Aaron Seth Rosenberg

Current treatment of newly diagnosed multiple myeloma involves lenalidomide maintenance therapy given until disease progression. The appropriate duration of maintenance therapy with lenalidomide has been unclear. In this phase 3 trial, we enrolled patients with standard-risk newly diagnosed multiple myeloma who were not undergoing up-front autologous stem-cell transplantation. After induction treatment with a proteasome inhibitor-lenalidomide combination, patients were randomly assigned to receive indefinite-duration (continuous) lenalidomide or fixed-duration lenalidomide (for 2 years). The primary end point was overall survival; the trial had 80% power to detect a 50% increase in median survival (from 5 years to 7.5 years), with a two-sided alpha level of 5%, 395 patients undergoing randomization, and 204 deaths occurring during 9 years of follow-up. At the end of induction, 516 patients were randomly assigned to the indefinite-duration group (260 patients) or the fixed-duration group (256 patients). At a median follow-up of 86 months, overall survival did not differ significantly between the groups. With 80 deaths in each group, overall survival at 7 years was 68.6% in the indefinite-duration group and 69.0% in the fixed-duration group (difference, -0.4 percentage points; 95 confidence interval [CI], -9.0 to 8.3; P = 0.93). Progression-free survival at 7 years was 36.1% in the indefinite-duration group and 29.7% in the fixed-duration group (difference, 6.4 percentage points; 95% CI, -2.6 to 15.4). The 5-year cumulative incidence of second primary cancers, excluding nonmelanoma skin cancer, was 11.2% with indefinite-duration lenalidomide and 8.3% with fixed-duration lenalidomide. More adverse events occurred with indefinite-duration lenalidomide; the incidence of nonhematologic events of grade 3 or higher was 48.2% with indefinite-duration therapy and 31.5% with fixed-duration therapy. In this phase 3 trial involving patients with standard-risk newly diagnosed multiple myeloma who were not undergoing up-front autologous stem-cell transplantation, indefinite-duration maintenance therapy after induction therapy did not result in significantly longer overall survival than fixed-duration maintenance therapy. (Funded by the National Cancer Institute of the National Institutes of Health and Amgen; ENDURANCE ClinicalTrials.gov number, NCT01863550.).

Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor of multiple myeloma (MM). Compared with non-Hispanic White (White) patients, African American individuals experience approximately twofold greater, and Asian American individuals 50% lower, occurrence of MGUS and MM. We examined determinants of MGUS among Japanese American, African American, Latino, Native Hawaiian, and White participants in a case-control study nested in the Multiethnic Cohort (MEC) study. Presumptive cases included MEC participants aged ≥65 years initially screened using the Medicare billing code for paraproteinemia along with those diagnosed with MM or another plasma cell neoplasm at least 1 year after blood draw. Presumptive controls had no Medicare paraproteinemia billing code or MM. Laboratory confirmation resulted in 426 confirmed MGUS cases (370 non-immunoglobulin M [non-IgM] and 56 IgM) and 863 MGUS-free controls. We used multivariable logistic regression to estimate associations with MGUS. The distribution of immunoglobulin isotypes differed by race/ethnicity (P = .005): Japanese American individuals had the lowest (11.0%) and Native Hawaiian individuals the highest (23.5%) proportion of IgA. Each unit increase in body mass index (BMI; kilogram per square meter) was associated with a 6% increase in non-IgM MGUS (95% confidence interval, 3-9) among all racial/ethnic groups combined. BMI was also significantly associated within most racial/ethnic groups, especially among Native Hawaiian individuals (13% increase per BMI unit), with IgA and IgG MGUS, and with high and low risk MGUS. BMI was the main determinant associated with MGUS. Isotype distribution differed between racial/ethnic groups.

Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.

For over half a century, dexamethasone has been a backbone of treatment regimens for plasma cell disorders such as multiple myeloma (MM) and light-chain (AL) amyloidosis. Dexamethasone doses of approximately 40 milligrams (mg) once weekly are often continued for months or years despite accumulating evidence that they can cause dose-dependent toxicities such as cataracts and infections. Acute dexamethasone-related toxicities such as insomnia or pedal edema, even if low-grade by clinical criteria, can significantly interfere with patient quality of life. In the past 5 years, several trials have demonstrated the efficacy and improved tolerability of corticosteroid-sparing regimens in MM. In this review, we discuss these and other studies to comprehensively assess the role of dexamethasone in the modern era. In newly diagnosed MM, robust data support planned dexamethasone discontinuation after one to two cycles in older and frailer patients. In the maintenance setting, the risk-benefit ratio of prolonged dexamethasone is unfavorable. While randomized trials have shown that once-weekly dexamethasone adds value within doublet regimens in relapsed/refractory MM, its contribution to triplet and quadruplet regimens is uncertain. Furthermore, data suggest that indefinite dexamethasone may actually limit the feasibility and efficacy of subsequent postprogression therapies. In AL amyloidosis, dexamethasone 40 mg once weekly for 6 months is excessive and may predispose patients to volume overload. In our review, we also discuss dexamethasone as a premedication for CD38-targeted monoclonal antibodies (where it is no longer required after one to two cycles) and for supportive care (where lower doses of 4-8 mg as needed can often suffice). Despite the historical inertia of corticosteroid-containing regimens in clinical trials and practice guidelines, corticosteroid-sparing regimens warrant prospective investigation across the gamut of plasma cell disorders.

Despite a recent increase in therapeutic options, patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) eventually require novel therapies. We conducted a phase 1 trial of blinatumomab and lenalidomide in R/R B-NHL. Three dose levels representing 2 schedules were explored. The primary end points were adverse events (AEs) and determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Thirty-five patients were enrolled, and 34 patients initiated treatment with a median number of prior regimens of 3 (range, 2-8). There were no dose-limiting toxicities (DLTs) in the first 2 dose levels. Dose level 3, 20 mg of lenalidomide daily on days 1 to 21 and days 29 to 49 of a 56-day induction cycle plus blinatumomab 9 μg/d continuous IV infusion (CIVI) on days 1 to 7, 28 μg/d CIVI on days 8 to 14, and 112 μg/d CIVI on days 15 to 56 was determined to be the MTD/RP2D. The most common grade ≥2 AE was neurotoxicity in 11 of 34 patients (32%), with 4 of 16 patients (25%) at the RP2D. At the RP2D, there was 1 DLT, a patient with grade 2 tremor and word-finding difficulty. For all patients completing induction, the overall response rate was 80% (95% confidence interval, 56-94) with a complete response rate of 70%, and 8 of 34 patients (24%) had durable remissions lasting >2 years. GranB+ CD56bright CD16dim CD11b+ natural killer cells and memory regulatory T cells in the peripheral blood at baseline were predictive of response. Concomitant administration of lenalidomide appeared to reduce blinatumomab-mediated T-cell exhaustion. In conclusion, encouraging activity was seen with blinatumomab and lenalidomide in heavily pretreated R/R B-NHL (NCI Protocol no. 9924).

Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

Background: We previously reported preliminary results of a phase I trial with blinatumomab/lenalidomide (blina/len) in relapsed/refractory B-cell non-Hodgkin l

Glucocorticoids, including dexamethasone, have been a mainstay of treatment for multiple myeloma (MM) for decades. In current treatment protocols and NCCN clinical practice guidelines, dexamethasone is included in all phases of MM treatment as a key adjunct to novel therapies within all preferred therapy regimen, augmenting clinical response rates to these agents. The inclusion of dexamethasone in MM treatment regimens, combined with novel agents, continues to deliver good response rates. Further understanding of drug combinations and dose modifications is anticipated to enhance clinical care, mitigate toxicities and optimize outcomes. New formulations are providing the opportunity for a reduction in pill burden and potential for medication errors, whereby improving treatment adherence. Here, we summarize and discuss the role of dexamethasone in the treatment of MM, its mechanism of action and doses used, and provide a critical appraisal current evidence and its clinical implications.