"Real-life" data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma-the Mayo Clinic experience.

Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively.

First report of clear cell renal carcinoma metastasizing to the ischiorectal fossa 17 years after radical nephrectomy: an additional reason for lifelong follow-up.

Renal cell carcinoma has a high propensity for metastatic spread. There are several case reports of metastatic renal cell carcinomas associated with rare metastatic sites, in many cases more than ten years after the initial diagnosis. We present a 60-year-old man with perianal pain and a mass in the ischiorectal space, revealed by computed tomography. The patient had a history of clear cell renal carcinoma operated on 17 years ago. A wire localization surgical excision of the ischiorectal fossa mass was performed. The pathological report revealed a metastatic clear cell renal carcinoma. To our knowledge, this is the first case of a clear cell renal carcinoma metastasizing to the ischiorectal fossa reported in the literature. We therefore recommend that any newly discovered mass in any site of a patient with a history of renal cell carcinoma should be carefully explored and biopsied.

Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation.

Post-transplant maintenance is widely used in multiple myeloma (MM); however, there is a lack of data on real-world outcomes. We have analyzed 577 patients with newly diagnosed MM undergoing early auto-transplantation between 2010 and 2015. A total of 341, 132 and 104 patients received no, lenalidomide (Len) or bortezomib (Bort) maintenance, respectively. Patients receiving Len or Bort maintenance had a higher incidence of high-risk cytogenetics by fluorescence in situ hybridization (31% (Len) vs 58% (Bort) vs 8% (No); P<0.001). Len maintenance led to a superior progression-free survival (PFS) compared with no maintenance (median, 37 vs 28 months, respectively; P=0.002; adjusted hazard ratio 0.48 (95% CI, 0.35-0.66)), including in subgroups with ISS stage III disease (median, 40 vs 24 months; P=0.008) and high-risk cytogenetics (median, 27 vs 16 months; P=0.032). Bort maintenance did not confer PFS benefit for the entire cohort, but improved PFS in the high-risk cytogenetic subgroup (median, 28 vs 16 months; P=0.035). Discontinuation due to toxicity was seen in 17 and 7% of patients receiving Len or Bort maintenance, respectively. Our results indicate that post-transplant maintenance with Len or Bort is well tolerated in clinical practice and improves PFS in high-risk subgroups of MM patients.

Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.

Natural history of t(11;14) multiple myeloma.

Translocation (11;14) on interphase fluorescent in situ hybridization in plasma cells is regarded as a standard risk prognostic marker in multiple myeloma based on studies conducted before introduction of current therapies. We identified 365 patients with t(11;14), and 730 matched controls:132 patients with non-(11;14) translocations and 598 patients with no chromosomal translocation. The median progression-free survival for the three groups were 23.0 (95% confidence interval (CI), 20.8-27.6), 19.0 (95% CI, 15.8-22.7) and 28.3 (95% CI, 25.7-30.6) months, respectively (P<0.01). The median overall survival (OS) for t(11;14), non-(11;14) translocation and no-translocation groups were 74.4 (95% CI, 64.8-89.3), 49.8 (95% CI, 40.0-60.6) and 103.6 (95% CI, 85.2-112.3) months, respectively (P<0.01). Excluding those with 17p abnormality, the median OS in the three groups were 81.7 (95% CI, 67.0-90.7), 58.2 (95% CI, 47.0-76.4) and 108.3 (95% CI, 92.4-140.1) months, respectively (P<0.01). The above relationship held true in patients with age <65 years, international staging system (ISS) I/II stage or those who received novel agent-based induction. Advanced age (hazard ratio (HR): 1.98), 17p abnormality (HR: 2.2) and ISS III stage (HR: 1.59) at diagnosis predicted reduced OS in patients with t(11;14). These results suggest that outcomes of t(11;14) MM are inferior to other standard risk patients.

Clinicopathologic idiosyncrasies of nasopharyngeal cancer in a moderate-risk Mediterranean region.

Cancer of the nasopharynx displays an unparalleled skewness of its epidemiologic, pathogenic and clinico-prognostic characteristics depending on the geographic location. Between the endemic and sporadic forms, which occur in Southeastern Asia and Northern America, respectively, intermediate incidence is noted around the Mediterranean. This study describes the patterns of the disease affecting the population of Western Greece. The records of 70 patients with nasopharyngeal cancer diagnosed in a single institution between 1994-2014 were retrospectively reviewed. Primary treatment involved irradiation with or without concurrent chemotherapy. Demographic data, patient risk factors, tumour parameters, clinical presentation and treatment outcomes were assessed for potential intercorrelations. Overall (OS) and disease-specific (DSS) 5-year survival rates were determined. Possible predictors of survival were tested on univariate and multivariate analysis. WHO-type 3 histopathology was diagnosed predominantly (74.3%) and associated significantly with nasal symptomatology upon presentation (p = 0.050), metastatic lymphadenopathy (p = 0.028), advanced clinical stage (p = 0.009) and complete response to initial treatment (p = 0.018). Univariate analysis revealed a negative prognostic significance for older age (OS, p = 0.029 DSS, p = 0.041), poor response to treatment (OS & DSS p < 0.001) and cancer recurrence (OS, p = 0.003 DSS, p = 0.001). On multivariate analysis, disease relapse maintained its adverse effect (HR 7.442, 95% CI 2.199-25.187, p = 0.001). In conclusion, among nasopharyngeal carcinomas arising in western Greece, lymphoepitheliomas manifest a distinct clinical behaviour, so that their latest grouping along with WHO-type 2 tumours into the "non-keratinising" category may not apply. Regardless of pathology, cancer recurrence after initial remission is a severe event.

Prevalence and predictors of thyroid functional abnormalities in newly diagnosed AL amyloidosis.

BACKGROUND: Data on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited. OBJECTIVE: To assess the prevalence of hypothyroidism in AL amyloidosis patients and determine its predictors. METHODS: 1142 newly diagnosed AL amyloidosis patients were grouped based on the thyroid-stimulating hormone (TSH) measurement at diagnosis: hypothyroid group (TSH above upper normal reference; >5 mIU L-1 ; n = 217, 19% of study participants) and euthyroid group (n = 925, 81%). Predictors for hypothyroidism were assessed in a binary multivariate model. Survival between groups was compared using the log-rank test and a multivariate analysis. RESULTS: Patients with hypothyroidism were older, more likely to present with renal and hepatic involvement and had a higher light chain burden compared to patients in the euthyroid group. Higher proteinuria in patients with renal involvement and lower albumin in patients with hepatic involvement were associated with hypothyroidism. In a binary logistic regression model, age ≥65 years, female sex, renal involvement, hepatic involvement, kappa light chain restriction and amiodarone use were independently associated with hypothyroidism. Ninety-three per cent of patients in the hypothyroid group with free thyroxine measurement had normal values, consistent with subclinical hypothyroidism. Patients in the hypothyroid group had a shorter survival compared to patients in the euthyroid group (4-year survival 36% vs 43%; P = 0.008), a difference that was maintained in a multivariate analysis. CONCLUSION: A significant proportion of patients with AL amyloidosis present with hypothyroidism, predominantly subclinical, which carries a survival disadvantage. Routine assessment of TSH in these patients is warranted.

Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.

Autologous stem cell transplantation (ASCT) is an important treatment modality in light chain (AL) amyloidosis. Use of reduced-dose melphalan conditioning is common, given the associated organ and functional decline. The impact of full-intensity melphalan conditioning (n=314) was compared to reduced-dose conditioning (n=143). Patients in the full-intensity group were younger, with better performance status, fewer involved organs, lower tumor burden and lower Mayo stage. Full-dose conditioning was associated with higher rate of very good partial response or better (79% vs 62%; P<0.001), complete response rate (53% vs 37%; P=0.003) and organ response rate (74% vs 59%; P=0.002) as compared to reduced-dose conditioning. PFS was superior in the full-intensity group compared to the reduced-dose group (4-year PFS 55% vs 31%; P<0.001) as well as a longer overall survival (OS) 4-year OS (86% vs 54%; P<0.001). In addition, the OS and PFS were significantly lower in the reduced-dose group compared to the full-intensity group in Mayo stage III/IV as well as stage I/II. A multivariate analysis confirmed an independent impact for conditioning dose on PFS/OS. This study calls for re-assessment of the use of reduced-dose conditioning in ASCT for AL amyloidosis.

Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.

The significance of interphase fluorescence in situ hybridization (iFISH) by regimen type was assessed in 692 immunoglobulin light-chain (AL) amyloidosis patients with iFISH at diagnosis. First-line treatment was categorized as stem cell transplant and three non-transplant regimens. The most common abnormality was t(11;14) (49% of patients) followed by monosomy 13/del(13q) (36%) and trisomies (26%). A lower rate of very good partial response (VGPR) or better was observed in patients with t(11;14) treated with bortezomib-based (52% vs 77%; P=0.004) and IMiD-based regimens (13% vs 54%; P=0.04) compared with those lacking t(11;14). This corresponded to an inferior overall survival (OS) in t(11;14)-positive bortezomib-treated (median 15 vs 27 months; P=0.05) and IMiD-treated patients (median 12 vs 32 months; P=0.05). The inferior OS associated with t(11;14) bortezomib-treated patients was restricted to patients with favorable disease. Trisomies were associated with a shorter OS (median 29 vs 69 months; P=0.001), reaching statistical significance only for melphalan (median 15 vs 32 months; P=0.02). Multivariate analysis confirmed an independent survival impact for trisomies in the entire cohort and for t(11;14) among bortezomib-treated patients. iFISH is prognostic in untreated AL amyloidosis and may influence treatment selection. Patients with t(11;14) should be considered for ASCT or standard-dose melphalan at diagnosis because the survival disadvantage may be abrogated.

Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression.

The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to MM. The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ⩾150 cPCs (N=9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ⩾150 cPCs was 9 months compared with not reached for patients with <150 cPCs (P<0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage.

Immunoparesis in newly diagnosed AL amyloidosis is a marker for response and survival.

Immunoparesis is an adverse prognostic marker in plasma cell proliferative disorders. Its impact in AL amyloidosis has not been explored in depth. Newly diagnosed AL amyloidosis patients (n=998) were evaluated for immunoparesis by two methods. The first method was qualitative, considering the number of suppressed uninvolved immunoglobulins below the lower limit of normal (LLN) (none, partial, all). The second method was quantitative, assessing the average relative difference (ARD) of the uninvolved immunoglobulins from the LLN. Patients with suppression of all the uninvolved immunoglobulins were less likely to achieve very good partial response (VGPR) or better to first-line treatment (44%) compared with patients with partial suppression (68%) or preserved uninvolved immunoglobulins (64%; P<0.0001). In addition, patients with suppression of all the uninvolved immunoglobulins had a shorter survival compared with the respective comparators (median 18 vs 54 vs 52 months; P<0.0001). In the quantitative method, patients with a negative ARD were less likely to achieve VGPR or better (48%) and had a shorter survival (median 24 months) compared with patients with a positive ARD (69%, 57 months, respectively; P<0.0001). In a multivariate analysis for survival, both assessment methods retained an independent impact. Significant immunoparesis has a negative impact on response and survival in newly diagnosed AL amyloidosis.

Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer.

UNLABELLED: Essentials Venous thromboembolism (VTE) prevention strategies require effective risk assessment models. We sought to validate the Khorana Risk Score (KRS) in patients with lung cancer. A high KRS was not predictive of VTE but was independently associated with all-cause mortality. Our findings stress the need for a lung cancer-specific VTE risk assessment model. SUMMARY: Objectives Lung cancer is strongly associated with venous thromboembolism (VTE), but primary prevention against VTE is not a validated management strategy. Risk assessment models will be necessary for efficient implementation of preventative strategies. Materials and methods Utilizing a prospectively collected lung cancer database, we aimed to validate the Khorana Risk Score (KRS) in the prediction of VTE among patients with lung cancer. VTE events were retrospectively identified by reviewers unaware of the clinical prediction score calculation. The association between KRS and the risk of VTE was examined using cumulative incidence function with competing risk models. Mortality prediction was evaluated as a secondary outcome. Results We included 719 patients in our review. The patients were predominantly older men with non-small cell lung cancer and 40% had metastatic disease at inception. The median follow-up was 15.2 months. There were 83 VTEs (11.5%) and 568 (78.8%) patients died. A high KRS (cumulative incidence, 12.4%; 95% confidence interval [CI], 6.4-20.5%) was not associated with VTE compared with an intermediate score (cumulative incidence, 12.1%; 95% confidence interval, 9.5-15.0%) in both univariate and multivariable analyses. However, a high KRS was a predictor of mortality (hazard ratio, 1.7; 95% CI, 1.4-2.2). Conclusions Among patients with lung cancer, the KRS did not stratify the patients at the highest risk of VTE. Improved risk stratification methods are needed for this group of patients prior to implementing a primary prevention strategy.

Risk factors for and outcomes of patients with POEMS syndrome who experience progression after first-line treatment.

Although clinical improvement is almost universal with therapy in patients with POEMS (an acronym for polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and a variety of skin changes) syndrome, outcomes and management of patients who relapse or progress (R/P) after first-line treatment have not been described. We retrospectively identified 262 patients with POEMS syndrome treated at the Mayo Clinic from 1974 to 2014 and who had follow-up information. The 5-year progression-free survival (PFS) and overall survival (OS) was 58% and 78%, respectively. Median time to R/P was 42 months. Seventy-nine patients (30%) had an R/P, with 52 (19%) experiencing a symptomatic R/P. Eighteen patients relapsed with symptoms or signs that were not documented at diagnosis. Median times to vascular endothelial growth factor, hematologic, radiographic and clinical R/P were 35 months (range, 4-327 months), 72 months (range, 4-327 months), 51 months (range, 4-327 months) and 48 months (range, 6-311 months), respectively. On multivariate analyses, low albumin at diagnosis and failure to achieve a complete hematologic response to first-line therapy were independent risk factors for PFS. Thirty patients had documentation of a second R/P at a median of 26 months from diagnosis of the first R/P. An early R/P was a risk factor for death, but most patients with an R/P had salvageable disease. A majority of patients are still without R/P at 5 years from diagnosis.

Abnormal expression of C3ORF9 gene in patients with myelodysplastic syndromes.

Myelodysplastic Syndrome (MDS) cells present genetic instability and dysregulation of the gene C3ORF9, which was isolated from an MDS cDNA library and codes for a putative protein. We studied the expression of C3ORF9 in MDS syndromes to contribute to the understanding of the pathophysiology of MDS. One hundred and thirty-one patients and 35 healthy controls were involved in our study. Bone marrow aspirates and isolated CD34+ cells were used. Gene expression was estimated by quantitative PCR. C3ORF9 was found to be down-regulated in patients with CMML compared to the controls (p<0.01). There was no difference between RARS and the controls (p=0.1), while increased expression was found in RA, RAEB and RAEB-T (p<0.01 for all). No mutations or polymorphism were detected in our population. CD34+ cells expressed higher levels of C3ORF9 (p<0.01) in patients. The gene expression was correlated to the percentage of +cells in RAEB and RAEB-T (r=0.64). The altered C3ORF9 expression was possibly due to different gene regulation in these patients and/or to the increased CD34+ cells.