Go, Ronald S.

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.

Abstract Background Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. Materials and Methods We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. Results Out of 1,103 trials, 70 trials (6%) excluded patients &gt;75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. Conclusion Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. Implications for Practice The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

A 70-year-old female presented with a three-year history of evolving macroglossia causing dysphagia and dysarthria, with proximal muscle weakness. Given the classic physical finding of macroglossia, the patient underwent extensive evaluation for amyloidosis which proved to be negative apart from a bone marrow biopsy which stained positive for transthyretin without amino acid sequence abnormality, thus giving wild-type transthyretin amyloidosis. Since the wild-type transthyretin amyloidosis could not entirely explain her clinical presentation and evaluation, further studies were conducted in a sequential manner, thus leading to a diagnosis of Pompe disease explaining her presenting signs and symptoms including her macroglossia. Through this fascinating case, we attempt to highlight the approach for the diagnoses of two rare diseases in a patient by emphasizing the importance of having a broad differential diagnosis when presented with findings which may have been thought as pathognomonic for certain diseases.

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.