Current Main Topics in Multiple Myeloma

Simple Summary In newly diagnosed multiple myeloma patients (NDMM) the introduction of three-drug, and recently, four-drug combinations allowed to reach response rates never seen before, leading to significantly improved PFS and OS. Long-term therapies play a key role in delaying or preventing relapses, but they are expensive and may cause significant toxicities. As a result, several ongoing trials are evaluating the possibility to intensify or de-intensify treatment based on minimal residual disease status, assessed by highly sensitive molecular or immunophenotypic methods. In relapsed/refractory patients (RRMM), especially those with advanced disease who become refractory to all available agents, new generation immunotherapies, such as conjugated monoclonal antibodies (mAbs), bispecific antibodies and CAR-T cells showed relevant results. In patients with high-risk cytogenetics, outcome remains poor and results from risk-adapted strategies are not yet available. Here we discuss the most recent issues regarding the management of MM, reporting the most up-to-date modalities of treatment and monitoring under evaluation. Multiple Myeloma (MM) remains a difficult to treat disease mainly due to its biological heterogeneity, of which we are more and more knowledgeable thanks to the development of increasingly sensitive molecular methods that allow us to build better prognostication models. The biological diversity translates into a wide range of clinical outcomes from long-lasting remission in some patients to very early relapse in others. In NDMM transplant eligible (TE) patients, the incorporation of mAb as daratumumab in the induction regimens, followed by autologous stem cell transplantation (ASCT) and consolidation/maintenance therapy, has led to a significant improvement of PFS and OS.; however, this outcome remains poor in ultra-high risk MM or in those who did not achieve a minimal residual disease (MRD) negativity. Several trials are exploring cytogenetic risk-adapted and MRD-driven therapies in these patients. Similarly, quadruplets-containing daratumumab, particularly when administered as continuous therapies, have improved outcome of patients not eligible for autologous transplant (NTE). Patients who become refractory to conventional therapies have noticeably poor outcomes, making their treatment a difficult challenge in need of novel strategies. In this review, we will focus on the main points regarding risk stratification, treatment and monitoring of MM, highlighting the most recent evidence that could modify the management of this still incurable disease

Real‐world assessment of treatment patterns and outcomes in patients with relapsed‐refractory multiple myeloma in an Italian haematological tertiary care centre

Despite significant improvements in therapeutic options, multiple myeloma (MM) patients experience a series of remissions and relapses requiring further lines of therapy (LOTs). We analysed treatment pathways, attrition rates (ARs) and refractoriness patterns across LOTs in 413 MM patients treated from 2011 and 2021. Across LOT-2 to LOT-5 ARs were 26%, 27%, 34% and 37.5%, being 50% for subsequent LOTs. In univariate analysis age over 65 years, international staging system (ISS) II/III, more than two comorbidities, no transplant and no maintenance therapy were significantly associated with AR but regression analysis selected only age over 65 years and more than 2 comorbidities. Median progression-free survival (PFS) was 40.5, 19.5, 10.3, 6 and 4.7 months from LOT-1 to LOT-5. Lenalidomide-refractory patients, among those relapsed after LOT-1, were 26% and 64.5% respectively, in patients starting therapy before 2019 versus in or after 2021. In the two cohorts, 57.5% and 85.5% of patients relapsed after LOT-2 were lenalidomide-refractory. Among patients not relapsed from LOT-1, 80% are receiving continuous lenalidomide and could become lenalidomide-refractory, whereas 91% and 51.5% of patients in LOT-2 could become potential lenalidomide- and daratumumab-refractory respectively. In our analysis the rate of patients reaching subsequent LOTs was higher than previously reported and the increase in early refractoriness would require faster and more efficient treatment licensing processes

Second Neoplasms in Italian Patients with Hairy Cell Leukemia after Treatment with Cladribine: A Multicenter Investigation and Literature Review

Simple Summary The prevalence of second neoplasms among patients with hairy cell leukemia (HCL) treated with cladribine is not negligible. Immunosuppression, high rate of cure, and aging may have a role in the pathogenesis of second cancers after HCL. We aimed to compare the risk of cancer between patients with HCL treated with cladribine and the general population.Abstract Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2-169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4-409.2 months), while the median OS from second cancer was 27.6 months (range: 1-117.8 months). The SIR was 0.86 (95% CI: 0.54-1.30) for males and 1.13 (95% CI: 0.36-2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm

Predictors of Unsustained Minimal Residual Disease Negativity in Multiple Myeloma (MM) Patients

: The prognostic impact of achieving and in particular maintaining MRD negativity in multiple myeloma is now established, therefore identifying among MRD-negative patients the ones at higher risk of losing MRD negativity is of importance. We analyzed predictors of unsustained MRD-negativity in patients enrolled in the FORTE trial (NCT02203643). MRD was performed by multiparameter flow-cytometry (sensitivity of 10-5) at premaintenance and every 6 months thereafter. The cumulative incidence (CI) of MRD resurgence and/or progression was analyzed in MRD-negative patients. 306/474 (65%) MRD-negative patients were analyzed. After a median follow-up of 50.4 months from MRD-negativity, 185/306 (60%) patients were still MRD-negative and progression-free, 118 (39%) lost their MRD-negative status and 3 patients (1%) died without progression. Amp1q vs. normal (4-years CI 63% vs 34), ≥2 concomitant high-risk cytogenetic abnormalities vs. 0 (4-years CI 59% vs 33%), Circulating tumor cells at baseline (high vs. low 4-years CI 62% vs. 32%) and time-to-reach MRD negativity post-consolidation vs. pre-consolidation (4-years CI 46% vs 35%) were associated with a higher risk of unsustained MRD-negativity in a multivariate Fine-Grey model. During the first 2 years of maintenance, patients receiving carfilzomib-lenalidomide vs. lenalidomide alone had a lower risk of unsustained MRD-negativity (4-years CI 20% vs 33%). CT# NCT02203643