Mortality in acquired thrombotic thrombocytopenic purpura in the pre-caplacizumab era.

Despite the effectiveness of plasma exchange (PEX) and immunosuppressants in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP), a number of patients still die as a result of the disease. Whether caplacizumab could rescue these patients remains still unsettled. The objective of this study was to characterise mortality patterns and prognostic factors in the first episode of aTTP.We queried the Spanish TTP Registry for patients with a diagnosis of aTTP in their presenting episode who fulfilled complete clinical and follow-up data (n = 102). The patients were diagnosed between 2004 and 2018, and all were treated with daily PEX and corticosteroids. Clinical and laboratory data were analysed at diagnosis and during the treatment course.Eight patients (7.7%) died between 12 h and 36 days after presentation, and could be classified into three patterns: death before treatment, early death driven by acute cardiac or neurologic events, and late death due to unremitted aTTP. Stupor or coma at diagnosis and platelet count < 20 × 109 /L by the 6th treatment day were independently associated with increased risk of death.Stupor or coma at diagnosis and lack of response to PEX by the 6th day in patients experiencing the first episode of aTTP are strong predictors of mortality. These patients could be rescued by novel agents aimed at halting the microvascular thrombosis until adequate immunosuppression is achieved.

Dose intensity and treatment duration of bortezomib in transplant-ineligible newly diagnosed multiple myeloma.

BACKGROUND: Bortezomib-related peripheral neuropathy (PN) affects a relevant proportion of multiple myeloma (MM) patients treated with melphalan, prednisone, and bortezomib (VMP). Empirical dose modifications have attempted to reduce toxicity without compromising efficacy. PATIENTS AND METHODS: We retrospectively evaluated the dose-response and dose-toxicity relationships in 114 unselected untreated MM patients intended for treatment with VMP with subcutaneous bortezomib. RESULTS: Sixty-two patients (54%) completed the 9 scheduled cycles. Median treatment duration was 48 weeks (range 1-57), cumulative bortezomib dose was 41.8 mg/m2 (2.6-67.6) and median dose intensity was 1.0 mg/m2 /wk (0.2-2.6). Median progression-free survival (PFS) and overall survival (OS) for the full cohort were 86 weeks (95%CI 77-104) and 209 weeks (95% CI 157-259) respectively. Patients who progressed <60 days after discontinuing bortezomib had received a significantly inferior mean cumulative dose, 34.6 mg/m2 than the remaining individuals, 45.5 (P = .023). PFS was significantly improved for patients achieving a very good partial response (VGPR) or better (P = .00007). Additional variables with a prognostic impact on PFS on univariate analysis included completion of the 9 scheduled cycles (P = .00002), patients with at least 50 weeks of treatment (P = .02) and patients receiving a cumulative dose of at least 49 mg/m2 (P = .05). Achievement of a VGPR (HR 0.23; 95%CI 0.12-0.46; P = .00002) and a cumulative dose of 49 mg/m2 (HR 0.46, 95%CI 0.27-0.78; P = .003) were statistically independent prognostic factors for PFS. Toxicity-related treatment dose reductions occurred in 75 individuals (66%). PN was observed in 50 individuals (44.6%), grade 3 in 9 (8%). The only prognostic factor for emergence of PN in multivariate analysis was the presence of baseline PN. CONCLUSIONS: Biweekly full-dose treatment in the first cycles has a major impact in depth of response. Depth of response, cumulative bortezomib dose, and treatment duration had an impact in prolongation of PFS.

First-line treatment of multiple myeloma in both transplant and non-transplant candidates.

INTRODUCTION: The last decade's progress in the treatment of newly diagnosed multiple myeloma has relied on the synergistic combination of agents with different mechanisms of action, basically proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, in order to achieve the deepest possible response early in the course of treatment. Following induction, several therapeutic strategies aim to improve and maintain response. AREAS COVERED: The manuscript reviews available data for the treatment of newly diagnosed multiple myeloma patients with a focus on most recent induction and maintenance combinations and the still important role of autologous stem transplantation. Future perspectives in the light of initial results from ongoing clinical trials are also addressed. EXPERT OPINION: Remarkable progress has been made in myeloma treatment due to the integration of immunomodulators, proteasome inhibitors, monoclonal antibodies, and high dose therapy in the frontline setting. Upfront therapy may be further improved intensifying induction combinations, adapting high dose therapy and consolidation strategies to the patient's profile, improving maintenance in high-risk individuals, or limiting maintenance duration in those with a better prognosis. Evidence needs to be reviewed, taking into account the therapeutic objectives at each treatment stage and patient specific risk factors.

The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma.

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody-drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

Limited treatment options in refractory multiple myeloma: promising therapeutic developments.

Introduction: Combinations of proteasome inhibitors, immunomodulators, and monoclonal antibodies are highly active against multiple myeloma. Consequently, several combinations have moved from the relapsed to the front-line setting. In the context of lenalidomide and bortezomib being used upfront, salvage options need to be evaluated.Areas covered: This manuscript reviews available data for the treatment of patients progressing on optimal frontline strategies, with a focus on the role of second-generation proteasome inhibitors and immunomodulators, monoclonal antibodies and immunotherapy.Expert opinion: Remarkable progress has been made in myeloma treatment due to the integration of immunomodulators, proteasome inhibitors and more recently monoclonal antibodies in the front-line setting. However, we work on the assumption that most individuals will eventually relapse. Optimized upfront therapy negatively selects more resistant patients among still relapsing individuals. Bortezomib and lenalidomide-exposed patients are under-represented in trials leading to currently approved combinations. Evidence needs to be reviewed taking into account how the improvement of frontline therapy has modified the characteristics of patients at the time of relapse. Second generation immunomodulatory agents and proteasome inhibitors, monoclonal antibodies and other agents have shown efficacy in this new landscape. Immunotherapeutic agents, including CAR-T cells are promising for patients failing standard combinations, despite current data are still immature.

Response to First Cycle Is the Major Predictor of Long-Term Response to Lenalidomide and Dexamethasone Therapy in Relapsed and Refractory Multiple Myeloma: Can We Spare Patients the Toxicity and Costs of Additional Agents?

BACKGROUND: Lenalidomide plus dexamethasone (Ld) is still considered an option of care for some selected patients with relapsed or refractory multiple myeloma (RRMM), despite the proven superiority of lenalidomide-based triplet therapy. Up to 20% of patients obtain long-term benefit from Ld alone. The aim of this multicenter retrospective study was to identify and characterize those with good response to Ld salvage therapy, defined as progression-free survival lasting more than 24 months. PATIENTS AND METHODS: Patients treated with Ld in a consortium of 3 tertiary-care hospitals (Institut Català d'Oncologia) between 2009 and 2016 were prospectively registered; 227 patients had evaluable data. RESULTS: In multivariate analysis, obtaining partial response after the first therapy cycle was the main independent factor associated with progression-free survival lasting more than 24 months. Together with standard risk cytogenetics, partial response after first cycle was also independently associated with a higher rate of complete response. Previous plasma-cell dyscrasia remained as the only baseline characteristic independently associated with long-lasting responses. High-risk cytogenetics and no history of monoclonal gammopathy of undetermined significance were the only statistically significant negative prognostic factors for overall survival. Patients who had received only one prior therapy showed a trend toward higher overall survival. CONCLUSION: If Ld is to be considered a treatment choice, at least a partial response should be obtained after the first therapy cycle to maintain double-agent therapy safely.