MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative ...patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10(11) TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.
OBJECTIVE To examine whether the outcome of patients with primary systemic amyloidosis (AL) has improved over time and to identify predictors of early mortality in patients with AL. PATIENTS AND ...METHODS We studied 2 separate cohorts of patients. The first cohort, consisting of 1998 patients with AL seen at Mayo Clinic between January 1977 and August 2006, was used to examine the trends in overall survival (OS) from diagnosis during this 30-year period. The second cohort, consisting of 313 patients seen between September 2006 and August 2009, was used to validate a model for predicting early mortality. RESULTS The 4-year OS from diagnosis improved during each decade of follow-up: 21%, 24%, and 33%, respectively, for the periods 1977-1986, 1987-1996, and 1997-2006 ( P <.001). Within the last group (1997-2006), 4-year OS during 1997-1999, 2000-2002, and 2003-2006 was 28%, 30%, and 42%, respectively ( P =.02). However, the 1-year mortality remained high during the 30-year period. A risk stratification score using cardiac troponin T, N-terminal probrain natriuretic peptide, and uric acid identified patients at risk of early mortality. The 1-year mortality with 0, 1, 2, or 3 risk factors was 19%, 37%, 61%, and 80%, respectively, in this training cohort of 459 patients. This was confirmed in a validation cohort of 313 patients. CONCLUSION Survival in AL has improved over time, with maximum improvement occurring in the past decade. However, early mortality remains high, and prospective identification of patients at risk of early mortality may allow development of risk-adapted strategies.
To study the hematologic characteristics of proliferative glomerulonephritides (GNs) from nonorganized glomerular monoclonal immunoglobulin (MIg) deposition (MIPG).
The pathology database at Mayo ...Clinic (Rochester, Minnesota) was used to find patients with MIPG who underwent a kidney biopsy between January 1, 2008, and December 31, 2013. Retrospective medical record review was conducted in the identified cohort (N=60).
The median patient age was 56 years (interquartile range, 47-62 years) and the estimated glomerular filtration rate was 36 mL/min/1.73 m(2) (interquartile range, 22-52 mL/min/1.73 m(2)). Most patients had IgG MIg deposits (90%; 54 of 60) and a membranoproliferative pattern (48%; 29 of 60). A circulating nephropathic MIg was detected by serum immunofixation (SIFE(+)) in 20% (12 of 59) and by abnormal serum free light chain ratio (sFLCR(+)) in 21% (12 of 56). The subsets of SIFE(+) and sFLCR(+) incompletely overlapped. The nephropathic clone was found by bone marrow testing (BM(+)) in 25% (10 of 40; 6 plasma cell clones 5 IgG; 1 IgA, 3 chronic lymphocytic leukemia all IgG, and 1 lymphoplasmacytic clone IgM). The clone detection rate was significantly higher in patients with SIFE(+) (P<.001) and in those with SIFE(+) and/or sFLCR(+) (P<.001). Patients with SIFE(+) and BM(+) frequently had IgG1-restricted MIg deposits on renal biopsy immunofluorescence (P=.005). Most BM(+) patients required flow cytometry and immunohistochemical analysis of the marrow specimen for accurate diagnosis.
Undetectable circulating nephropathic MIg and pathologic clones characterize most MIPG. Immunoglobulin isotype may predict detectability of MIg and clone by currently available technology. Bone marrow evaluation, including flow cytometry and immunohistochemical analysis, should be performed for SIFE(+) and/or sFLCR(+). More sensitive clone-identifying techniques in the marrow and extramedullary tissue are needed when SIFE and sFLCR test negative.
Multiple myeloma is a malignant plasma cell neoplasm that affects more than 20,000 people each year and is the second most common hematologic malignancy. It is part of a spectrum of monoclonal plasma ...cell disorders, many of which do not require active therapy. During the past decade, considerable progress has been made in our understanding of the disease process and factors that influence outcome, along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life. Identification of well-defined and reproducible prognostic factors and introduction of new therapies with unique modes of action and impact on disease outcome have for the first time opened up the opportunity to develop risk-adapted strategies for managing this disease. Although these risk-adapted strategies have not been prospectively validated, enough evidence can be gathered from existing randomized trials, subgroup analyses, and retrospective studies to develop a working framework. This set of recommendations represents such an effort—the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence.
OBJECTIVE To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent ...active myeloma. PATIENTS AND METHODS Stromal cells were cocultured with IL-1β-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). RESULTS In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively ( P =.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years. CONCLUSION In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS. Trial Registration clinicaltrials.gov identifier: NCT00635154
To characterize the natural history of immunoglobulin light chain amyloidosis-associated myopathy and to provide guidelines for recognition.
Fifty-one patients with systemic immunoglobulin light ...chain amyloidosis and biopsy-confirmed muscle amyloid deposition diagnosed between January 1, 1995, and December 31, 2015, were included in this study.
Common presenting symptoms were muscle weakness in 49 patients (96%), dysphagia in 23 (45%), myalgia in 17 (33%), macroglossia in 17 (33%), jaw claudication in 13 (25%), and hoarseness in 9 (18%). The median time from the onset of symptoms to diagnosis was almost 2 years. Less than two-thirds of the patients with an outside muscle biopsy (16 of 27) had an established pathologic confirmation of amyloidosis due to failure to routinely incorporate Congo red staining. Moreover, 12 patients were incorrectly treated before diagnosis of amyloid myopathy. More than half of the patients had normal creatine kinase levels at diagnosis. Cardiac troponin T levels were elevated above the reference range in 5 of 12 patients who lacked evidence of cardiac involvement. Median overall survival was 32 months. Factors associated with inferior survival were involvement of more than 2 organs (median survival, 13 months), cardiac involvement (median survival, 15 months), and absence of stem cell transplant (median survival, 18 months). With the exclusion of patients treated with stem cell transplant, no improvement in survival was seen over the 1995-2004 and 2005-2015 decades.
Immunoglobulin light chain amyloidosis-associated myopathy is rare. Delay in diagnosis is common, and there is a high rate of pathologic and clinical misdiagnosis. Awareness of elevation of cardiac troponin T levels in the absence of cardiac disease may be a clue to diagnosis.
Abstract Introduction Limited data exist with respect to the outcome and optimal management of patients with myelomatous involvement of their central nervous system (CNS). Methods Of 4060 patients ...with multiple myeloma (MM), evaluated at Mayo Clinic MN between 1998 and 2014, 29 patients (0.7%) had identifiable CNS involvement, established by the presence of atypical plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal/meningeal involvement on magnetic resonance imaging (MRI). A cohort of 87 MM patients without CNS disease served as a control group (1:3), matched by diagnosis date and gender. Results Plasma cells were detected in the CSF in 87% and MRI findings consistent with CNS involvement were noted in 82% of the patients. Bone marrow plasma-cell labeling index ≥ 3%, presence of disease at other extramedullary sites or peripheral-blood plasma cells > 800 per 150,000 events were associated with an odds ratio of 7.1, 10.3 and 14, respectively for the risk of CNS involvement. Overall survival (OS) from diagnosis of MM was significantly shorter in the CNS-MM group (median 40 months, 95% CI:24-56) compared to the control group (median 93 months, 95% CI:67-129). OS was 3.4 months from the time of detection of the CNS disease. Patients who underwent autologous stem-cell transplantation post CNS involvement (n=7) had a median OS of 19 months (95%CI:10-67) from the time of CNS involvement. Conclusion Myelomatous involvement of the CNS is a rare complication that portends poor survival. Current therapeutic approaches appear to be largely ineffective in this subset of myeloma patients.
OBJECTIVE To determine the long-term effects of a combined regimen of lenalidomide and dexamethasone (Rev-Dex) on time to progression, progression-free survival, and overall survival (OS) in patients ...with multiple myeloma. PATIENTS AND METHODS From March 2004 through October 2004, 34 patients were registered for the study. They were treated with 25 mg/d of lenalidomide on days 1 through 21 of a 28-day cycle and 40 mg/d of dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 of each cycle. After 4 cycles of therapy, patients were allowed to discontinue treatment to pursue autologous stem cell transplant (SCT). Treatment beyond 4 cycles was permitted at the physician s discretion. RESULTS Thirteen patients proceeded to SCT after initial therapy and were censored at that time point for purposes of calculation of response. Thirty-one patients achieved an objective response, defined as a partial response or better (91%; 95% confidence interval, 79%-98%), with a complete response plus very good partial response rate of 56%. The complete response plus very good partial response among the 21 patients who received Rev-Dex without SCT was 67%. The 2-year progression-free survival rates for patients proceeding to SCT and patients remaining on Rev-Dex were 83% and 59%, respectively; the OS rates were 92% and 90% at 2 years and 92% and 85% at 3 years, respectively. The 3-year OS rate for the whole cohort was 88%. CONCLUSION The Rev-Dex regimen is highly active in the treatment of newly diagnosed multiple myeloma. Responses are durable with a low progression rate at 2 years. Randomized trials that incorporate quality-of-life measures are needed to determine if this and other combination regimens are better used early in therapy or should be reserved for later interventions.
Multiple myeloma is a neoplastic plasma cell dyscrasia that on a yearly basis affects nearly 17,000 individuals and kills more than 11,000. Although no cure exists, many effective treatments are ...available that prolong survival and improve the quality of life of patients with this disease. The purpose of this consensus is to offer a simplified, evidence-based algorithm of decision making for patients with newly diagnosed myeloma. In cases in which evidence is lacking, our team of 18 Mayo Clinic myeloma experts reached a consensus on what therapy could generally be recommended. The focal point of our strategy revolves around risk stratification. Although a multitude of risk factors have been identified throughout the years, including age, tumor burden, renal function, lactate dehydrogenase, β2 -microglobulin, and serum albumin, our group has now recognized and endorsed a genetic stratification and patient functional status for treatment.
Historically, patients with AL amyloidosis and overt congestive heart failure have had an ominous prognosis with median survival of approximately 6 months.
Between 1994 and 2005, 11 patients ...underwent sequential orthotopic heart transplantation (HT) followed by autologous peripheral blood stem cell transplantation (SCT) for treatment of AL amyloidosis. Patients were accepted for this approach if they had heart-dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Conditioning chemotherapy consisted of melphalan 200 mg/m(2) (6 patients) or melphalan 140 mg/m(2) (5 patients).
Two patients died of complications from the SCT (18% transplant-related mortality). Nine patients survived both the HT and the SCT. Three patients subsequently died from progressive amyloidosis at 66, 56.7 and 55 months after SCT. The 1- and 5-year survival for HT was 82% and 65%. The median survival was 76 months from HT and 57 months from SCT.
These data suggest that aggressive treatment of the underlying plasma cell clone after HT may improve long-term outcomes in patients with cardiac amyloid. HT followed by SCT is feasible and offers the possibility of remission for carefully selected patients with cardiac amyloidosis.
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