Hwa, Yi L.

Abstract We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and transthoracic echocardiogram (TTE) in diagnosing cardiac involvement in patients with biopsy-proven systemic immunoglobulin light chain amyloidosis seen at the Mayo Clinic between 1 January 2006 and 30 December 2015. We analyzed 2 cohorts: patients undergoing endomyocardial biopsy for suspicion of cardiac involvement (cohort 1) and patients who had serum NT-proBNP and comprehensive echocardiographic evaluation at diagnosis (cohort 2). Of 179 patients undergoing endomyocardial biopsy (cohort 1), 173 (97%) had evidence of amyloid deposition, with 159 having NT-proBNP performed at the time of the procedure. The NT-proBNP was elevated (>300 pg/mL) in all 159 patients (sensitivity, 100%; median NT-proBNP, 4917 pg/mL; range, 355-69 541). The left ventricular ejection fraction, interventricular septal thickness, and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%), respectively. Among cohort 2 (n = 342), 259 (76%) had an elevated NT-proBNP, of whom 237 (92%) had an abnormality detected on TTE. Of 83 patients with normal NT-proBNP <300 pg/mL, 27 (33%) had an abnormality on TTE (all with borderline strain rate −18% to −15%). Only 5/27 patients were considered to have possible early cardiac involvement and none had any other diagnostic or classical features of amyloidosis on TTE. The combination of NT-proBNP and comprehensive echocardiographic evaluation can diagnose cardiac amyloidosis negating the need for endomyocardial biopsy. A negative NT-proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis.

AbstractAchievement of a complete response has been associated with improved outcomes in patients with multiple myeloma. Recently, increasing application of minimal residual disease (MRD) assessment has shown that MRD negativity is a powerful prognostic factor for survival outcomes. We wanted to examine the impact of the polyclonal plasma cell (pPC) compartment among patients in complete response (CR) but are MRD positive. This is a retrospective cohort study where 460 myeloma patients were identified who met criteria for CR and had multicolor flow cytometry performed on the bone marrow (BM). Monoclonal and pPCs were estimated during MRD testing. Final outcomes including overall survival (OS) and time to next treatment (TTNT) were compared among the groups. The median OS for the entire cohort was not reached (95% CI; 63 mos, NR) and the median TTNT was 31 months (95% CI; 27,36). Among the MRDneg group, median TTNT was 37.6 months vs 23 months for MRDpos patients (P < .001); the median OS was not reached for either group, but there was a trend toward better survival for MRDneg patients. Among the MRDpos group, median percentage of pPCs was 65% (2.5–98.5), and those with >95% pPCs had a significantly better TTNT (NR vs 23 months; P = .02) and a trend toward better OS. We conclude that achievement of MRD negativity predicts for better response durability and trend toward improved OS and an increased proportion of pPC predicts for better outcomes within those who have residual tumor cells highlighting the importance of marrow normalization.

Abstract We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and &lt;VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P &lt; .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

SummaryDespite the absence of high‐risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high‐risk phenotype among standard‐risk patients. Fifty‐six percent of all patients presented with standard‐risk disease. Among them, advanced age, extremes of body mass index, non‐hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard‐risk patients with 0–1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24–0·43, P < 0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41–0·72, P < 0·001) experienced better OS than high‐risk patients. Two or more adverse factors were present in 17% of standard‐risk patients and were associated with OS comparable to high‐risk patients (HR 0·91, 95% CI 0·67–1·24, P = 0·548). Predictive power among standard‐risk patients was improved using score groups compared to ISS stages. Patients with standard‐risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high‐risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.

Abstract Peripheral blood biomarkers of tumor microenvironment and immune surveillance are independent prognostic factors in multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma. We studied absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at the time of treatment initiation and 1 month thereafter in 771 newly diagnosed patients. Two hundred and thirty‐four patients (31%) had evidence of immune dysregulation at baseline (abnormal biomarkers). Eighty‐seven of these patients (37%) recovered normal biomarkers at 1 month (early immune reconstitution). The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61‐0.97, P = 0.025, n = 771). The absence of immune dysregulation at 1 month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50‐0.80, P < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43‐0.92, P = 0.016, n = 771). Cytogenetic high‐risk disease was negatively, and treatment with immunomodulators positively, associated with early immune reconstitution. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests immune dysregulation to be a potentially modifiable risk factor that may be exploited for therapeutic benefit.

Abstract The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry, detects cells in the S phase of the cell cycle and is a useful prognostic tool in patients with plasma cell disorders such as multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic effect of PCPI in 306 patients with smoldering multiple myeloma (SMM). Seventy-nine (26%) patients had an elevated PCPI (&gt;0.5). An elevated PCPI predicted an inferior time to progression (median, 3.0 vs 7.1 years for those with a low PCPI; P = .0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI (49% vs. 20%; P &lt; .0001). PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow-up and consideration of early intervention trials.

AbstractPositron emission tomography‐computed tomography (PET‐CT) can identify bony lesions, assess disease burden, and detect extramedullary disease (EMD) in patients with multiple myeloma. We retrospectively reviewed records of patients who underwent PET‐CT within 60 days of a new diagnosis (before therapy commenced) to identify the nature and prognostic impact of PET‐CT abnormalities. Patients (N = 313) were seen from April 2005 through June 2017. Of the 234 patients (75%) with focal lesions (FLs), 182 (58%) had at least 3 FLs, 38 (12%) had EMD, and 204 (65%) had documented myelomatous lytic lesions. The median maximum standardized uptake value (SUVmax) for the entire cohort was 5.9 (range 1.5‐48.3). Presence of at least 3 FLs and EMD predicted inferior overall survival (OS); median OS was 57.8 months for patients with 3 or more FLs and 103.6 months for patients with fewer than 3 FLs (P = .003). The median OS was 45.5 and 71.8 months for patients with and without EMD, respectively (P = .004). No clear SUVmax cutoff was predictive of progression‐free survival or OS. PET‐CT is a valuable tool for assessing disease burden and could provide prognostic information about a contemporary cohort of patients with newly diagnosed myeloma who received treatment with novel agents.