Research Spotlight

Kar, S., Mack, M.J., Lindenfeld, J., Abraham, W.T., Asch, F.M., Weissman, N.J., Enriquez-Sarano, M., Lim, D.S., Mishell, J.M., Whisenant, B.K., Rogers, J.H., Arnold, S.V., Cohen, D.J., Grayburn, P.A. and Stone, G.W. (2021). “Relationship Between Residual Mitral Regurgitation and Clinical and Quality-of-Life Outcomes After Transcatheter and Medical Treatments in Heart Failure: The COAPT Trial.” Circulation May 27. [Epub ahead of print].

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Background: In the randomized COAPT trial, among 614 heart failure (HF) patients with 3+ or 4+ secondary mitral regurgitation (MR), transcatheter mitral valve repair (TMVr) with the MitraClip reduced MR, HF hospitalizations (HFH), and mortality and improved quality of life compared with guideline-directed medical therapy (GDMT) alone. We sought to examine the prognostic relationship between MR reduction and outcomes after TMVr and GDMT alone. Methods: Outcomes in COAPT between 30 days and 2 years were examined based on the severity of residual MR at 30 days. Results: TMVr-treated patients had less severe residual MR at 30 days than GDMT-treated patients (0/1+, 2+, and 3+/4+: 72.9%, 19.9%, and 7.2% versus 8.2%, 26.1%, and 65.8%, respectively, P<0.0001). The rate of composite death or HFH between 30 days and 2 years was lower in patients with 30-day residual MR of 0/1+ and 2+ compared with 3+/4+ (37.7% versus 49.5% versus 72.2%, respectively, P<0.0001). This relationship was consistent in the TMVr and GDMT arms (P(interaction)=0.92). The improvement in KCCQ score from baseline to 30 days was maintained between 30 days and 2 years in patients with 30-day MR ≤2+ but deteriorated in those with 30-day MR 3+/4+ (-0.3±1.7 versus -9.4±4.6, P=0.0008) consistently in both groups (P(interaction)=0.95). Conclusions: In the COAPT trial, reduced MR at 30 days was associated with greater freedom from death or HFH and improved quality of life through 2-year follow-up whether the MR reduction was achieved by TMVr or GDMT. Clinical Trial Registration: https://www.clinicaltrials.gov Unique Identifier: NCT01626079.

Généreux, P., Piazza, N., Alu, M.C., Nazif, T., Hahn, R.T., Pibarot, P., Bax, J.J., Leipsic, J.A., Blanke, P., Blackstone, E.H., Finn, M.T., Kapadia, S., Linke, A., Mack, M.J., Makkar, R., Mehran, R., Popma, J.J., Reardon, M., Rodes-Cabau, J., Van Mieghem, N.M., Webb, J.G., Cohen, D.J. and Leon, M.B. (2021). “Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research.” Eur Heart J 42(19): 1825-1857.

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AIMS: The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research. METHODS AND RESULTS: Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs. CONCLUSIONS: Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

Wang, L., Leng, B. and Liu, L. (2021). “Angiomyolipoma of the Nasal Cavity: A Distinct Entity. A Case Report and Literature Review.” Head Neck Pathol 15(2): 709-714.

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Angiomyolipoma (AML) is a mesenchymal tumor commonly found in the kidneys. Extra-renal AML is uncommon and especially rare in the nasal cavity. To our knowledge, fewer than five cases of nasal AML are reported in the United States. We present a case of nasal AML in a 65-year-old man with a history of rhinosinusitis and obstruction of the left nasal cavity. The lesion comprised of admixed spindled smooth muscle cells, mature adipose tissue, and thick-walled blood vessels. Smooth muscle differentiation of the spindled cells was confirmed by expression of smooth muscle actin. Surprisingly, melanocytic markers, such as HMB45, were negative. The histologic features and immunoprofile suggest that nasal AML is pathologically distinct from neoplastic AMLs/perivascular epithelioid cell tumors (PEComas) that typically occur in the kidney. We propose that nasal AML is a hamartomatous lesion rather than neoplastic. Although AML is rare in the nasal cavity, it should be considered in the differential diagnosis of clinically benign nasal masses.

Richard, S., Chari, A., Delimpasi, S., Simonova, M., Spicka, I., Pour, L., Kriachok, I., Dimopoulos, M.A., Pylypenko, H., Auner, H.W., Leleu, X., Usenko, G., Hajek, R., Benjamin, R., Dolai, T.K., Sinha, D.K., Venner, C.P., Garg, M., Stevens, D.A., Quach, H., Jagannath, S., Moreau, P., Levy, M., Badros, A., Anderson, L.D., Jr., Bahlis, N.J., Facon, T., Mateos, M.V., Cavo, M., Chang, H., Landesman, Y., Chai, Y., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Grosicki, S. and Richardson, P.G. (2021). “Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk.” Am J Hematol June 1. [Epub ahead of print].

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In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n=70; Vd, n=71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n=125; Vd, n=136). Amongst patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p=0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p=0.0041). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p=0.0036), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p=0.0329). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562

Auner, H.W., Gavriatopoulou, M., Delimpasi, S., Simonova, M., Spicka, I., Pour, L., Dimopoulos, M.A., Kriachok, I., Pylypenko, H., Leleu, X., Doronin, V., Usenko, G., Hajek, R., Benjamin, R., Dolai, T.K., Sinha, D.K., Venner, C.P., Garg, M., Stevens, D.A., Quach, H., Jagannath, S., Moreau, P., Levy, M., Badros, A., Anderson, L.D., Jr., Bahlis, N.J., Facon, T., Mateos, M.V., Cavo, M., Chai, Y., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Richardson, P.G. and Grosicki, S. (2021). “Effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma.” Am J Hematol 96(6): 708-718.

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Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.