Incidence and Management of Carfilzomib-induced Cardiovascular Toxicity; A Systematic Review and Meta-analysis.

BACKGROUND: The ASPIRE and ENDEAVOUR trials have shown cardiovascular adverse effects in patients treated with carfilzomib-based regimens. Therefore, we conducted this meta- analysis of published clinical trials to identify the cumulative incidence and risk of cardiovascular adverse effects due to carfilzomib. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed, and we identified 45 prospective trials of carfilzomib with data on 5583 patients. Among all patients being treated with carfilzomib (N=5,583), 8.9% sustained all grade cardiotoxicity, while 4.4% sustained high-grade cardiotoxicity. All-grade hypertension was present in 13.2%, while the incidence of high-grade hypertension was 5.3%. RESULTS: The observed incidences of all-grade heart failure, edema, and ischemia were 5.1%, 20.7%, and 4.6%, respectively. Likewise, for high-grade heart failure and edema observed incidence was 3.2%, and 2.7%, respectively. There was no difference in the event rate of all and highgrade cardiotoxicity between newly diagnosed multiple myeloma and relapsed/refractory (p-value 0.42 and 0.86, respectively). Likewise, we did not observe any difference in the event rate of all and high-grade cardiotoxicity when carfilzomib was used as a single agent versus when used in combination therapy with other agents (p-value 0.43 and 0.73, respectively). CONCLUSION: Carfilzomib is associated with a significant risk of cardiovascular toxicity and hypertension. With the increasing utilization of carfilzomib, it is critical for primary care physicians, oncologists and cardiologists to be aware of the risk of cardiotoxicity associated with the use of carfilzomib to recognize and treat baseline cardiovascular risk factors in such patients.

Characterisation and prognostic impact of immunoparesis in relapsed multiple myeloma.

Characterisation and prognostic impact of immunoparesis in relapsed multiple myeloma (MM) is lacking in the current literature. We evaluated 258 patients with relapsed MM, diagnosed from 2008 to 2015, to investigate the prognostic impact of deep immunoparesis on post-relapse survival. On qualitative immunoparesis assessment, no, partial and full immunoparesis was present in 9%, 30% and 61% of patients, respectively. Quantitative immunoparesis was assessed by computing the average relative difference (ARD) between polyclonal immunoglobulin(s) and corresponding lower normal limit(s), with greater negative values indicating deeper immunoparesis. The median ARD was -39%, with an optimal cut-off of -50% for overall survival (OS) by recursive partitioning analysis. Deep immunoparesis (ARD ≤-50%) was associated with a higher tumour burden at first relapse compared to none/shallow [ARD >-50%] immunoparesis. The OS (P = 0·007) and progression-free survival (PFS; P < 0·001) differed significantly between the deep and none/shallow immunoparesis groups. Kaplan-Meier estimates for 3-year OS were 36% and 46%, and for 2-year PFS were 17% and 27%, respectively. On multivariable analysis (MVA) for PFS, both qualitative and quantitative immunoparesis retained negative prognostic impact independently. However, only quantitative immunoparesis was independently prognostic for OS on MVA. Depth of immunoparesis in relapsed MM is an important prognostic factor for post-relapse survival in the era of novel agents and continuous therapy.

Real-world data on safety and efficacy of venetoclax-based regimens in relapsed/refractory t(11;14) multiple myeloma.

The treatment for relapsed/refractory multiple myeloma (RRMM) continues to be challenging despite recent therapeutic advancements. Venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, is a promising agent, especially in patients harbouring t(11;14). Our objective was to review our experience with venetoclax-based regimens at our institution. All ten RRMM patients treated with venetoclax were included and had a median of six prior lines of therapy. The overall response rate was 78% and one patient with cardiac amyloidosis and MM achieved a cardiac organ response. Haematologic toxicities requiring red blood cell and platelet transfusion and non-haematologic toxicities, most commonly gastrointestinal upset, were observed.

Treatment of relapsed multiple myeloma: Evidence-based recommendations.

The practice of choosing the next best therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) is becoming increasingly complex. There is no clear consensus regarding the best treatment sequence for RRMM. With the approval of novel proteasome inhibitors (ixazomib and carfilzomib), immunomodulatory agents (pomalidomide), monoclonal antibodies (daratumumab and elotuzumab), and other targeted therapies, multiple combination regimens utilizing these agents are being studied with the goal of enhancing disease control, prolonging progression-free survival, and improving overall survival. We, herein, describe a review of FDA-approved regimens for RRMM patients and offer a paradigm in selecting subsequent treatment regimens, focusing on patient specific morbidity, treatment toxicity, and disease-specific characteristics.

Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development.

BACKGROUND: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. CONCLUSIONS: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.