Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. OBJECTIVES: The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. STUDY DESIGN: This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. RESULTS: Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30-77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3-8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5-25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. CONCLUSION: This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance.

Clinical characteristics, treatment patterns, and outcomes among African American and White patients with multiple myeloma in the United States.

Multiple myeloma (MM) is more common among Black/African American (AA) patients than White patients, but survival rate improvements are less pronounced for AA patients. This study evaluated treatment patterns and survival among 1810 AA and 5904 White adults in the United States with ≥1 MM treatment and ≥3 months of follow-up. Median time from diagnosis to systemic treatment was longer (37 [0-3053] vs. 35 [0-3664] days) and median time to stem cell transplant (SCT) was longer for AA than White patients (255 [1-2352] vs. 225 [1-3094] days), and AA patients were less likely to receive SCT (odds ratio [OR]: 0.66; 95% confidence interval [CI]: 0.58-0.76). Despite disparities in treatment between AA and White patients, AA patients demonstrated lower risk of death (OR: 0.89; 95% CI: 0.81-0.96). These data highlight the value of equal access to care for the improvement of health outcomes in underserved populations.

Second primary malignancies in multiple myeloma: A review.

As survival times of multiple myeloma (MM) patients continue to improve, second primary malignancies (SPM) have become an increasingly relevant long-term risk among MM survivors. Population studies since the 1950s have consistently observed an increased incidence of hematologic SPMs, specifically acute leukemia, among MM survivors. Prolonged treatment with alkylators, especially melphalan, was associated with an increased hematologic SPM risk; likewise, autologous stem cell transplantation appeared to minimally increase SPM risk. Immunomodulatory drugs, specifically lenalidomide, was associated with an increased SPM incidence, although most studies concluded that the benefits of therapy outweighed any risks of SPM. Newer anti-myeloma therapy such as proteasome inhibitors and monoclonal antibodies did not appear to increase SPM risk although robust long-term follow-up is lacking. This review discusses current understanding regarding SPMs among survivors of MM, how different host-, disease- and treatment-related factors contribute to SPM incidence and highlights emerging screening guidelines and prognosis for SPMs.

Targeting MCL-1 in hematologic malignancies: Rationale and progress.

Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.

Investigation into the interference of the monoclonal antibody daratumumab on the free light chain assay.

OBJECTIVES: Recently monoclonal antibody therapy has been introduced in the treatment of multiple Myeloma (MM). One such efficacious therapy is the anti-CD38 monoclonal antibody, daratumumab (Dara). Since it is an Ig-G-kappa it can interfere with both the serum protein electrophoresis and immunofixation electrophoresis (IFE). The free light chain (FLC) assay is also useful in the diagnosis and therapeutic monitoring of MM. Hence we tested the effect of Dara on the FLC assay. METHODS: 30 serum samples from patients with known IgG-kappa (n=20) and non-IgG-kappa M -proteins (n=10) were spiked with Dara at a final concentration of 1.0mg/mL and the FLC performed on samples. On a further 20 samples we performed IFE to determine the migration of Dara. RESULTS: On IFE, Dara migrated in the same area of the gamma zone. In the 30 samples in which we assayed FLC there was no significant differences in levels of kappa, lambda and the ratio of kappa to lambda between untreated and Dara-spiked samples. CONCLUSION: Whilst Dara can interfere with the IFE to determine clinical responses the FLC assay can be useful in patients who have abnormal FLC ratios prior to Dara therapy to determine responses especially in IgG-kappa Myeloma.