Steven R. Schuster

Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis

Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is highly effective in multiple myeloma. We treated patients with light chain amyloidosis (AL) before stem cell transplantation (ASCT), instead of ASCT in ineligible patients or as salvage. Treatment was a combination of bortezomib (1.5 mg/m2 weekly), cyclophosphamide (300 mg/m2 orally weekly), and dexamethasone (40 mg weekly). Seventeen patients received 2 to 6 cycles of CyBorD. Ten (58%) had symptomatic cardiac involvement, and 14 (82%) had 2 or more organs involved. Response occurred in 16 (94%), with 71% achieving complete hematologic response and 24% a partial response. Time to response was 2 months. Three patients originally not eligible for ASCT became eligible. CyBorD produces rapid and complete hematologic responses in the majority of patients with AL regardless of previous treatment or ASCT candidacy. It is well tolerated with few side effects. CyBorD warrants continued investigation as treatment for AL.

IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia.

IgM multiple myeloma (MM) and Waldenstroms macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A priori, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by an IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions and/or translocation t(11;14). Twenty‐one patients met this definition of IgM MM. All 21 patients had lytic bone lesions. Of the 16 evaluated with FISH, 6 (38%) demonstrated t(11;14). Median overall survival was 30 months, which is similar to non‐IgM myeloma patients treated during this period and shorter than what would be expected for WM. In this, the largest series of patients with IgM MM, we describe the clinical features and prognosis of patient with IgM MM using a strict definition for the disease. The subset of patients without lytic lesions or t(11;14) but with immunophenotypic features suggestive of MM need further study. Am. J. Hematol., 2010.

The clinical significance of cereblon expression in multiple myeloma

Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p<0.001) and OS (9.1 vs. 27.2 months, p=0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.

An X-band hybrid MIC feedforward amplifier for low residual noise operation

A 10 GHz, 15 dB gain feedforward amplifier (FFA) is described whose design is primarily aimed at reducing residual phase noise. The two-module hybrid MIC construction incorporates GaAs MMICs and microstrip thin-film interconnects on alumina. For loop balance electronic gain control is achieved using dual gate distributed amplifiers, while phase control is accomplished with mechanical phase shifters and delay lines. Measurements of near carrier noise are made from 1 Hz to 6.4 MHz. In the flicker region the 1 Hz intercept is -110 dBc/Hz, with an approximate corner frequency around 30 KHz at -160 dBc/Hz.

The definition of IgM multiple myeloma

We read with interest the recent report of Schuster et al. [1], who described the clinical presentation and outcome of 21 patients diagnosed with immunoglobulin M (IgM) multiple myeloma (MM). In this report, the authors defined IgM MM according to the following criteria—IgM monoclonal gammopathy, equal or greater than 10% bone marrow plasma cells and the presence of lytic bone disease and/or translocation t(11;14). We believe that this definition is restrictive and will fail to capture a proportion of patients particularly those with asymptomatic disease and other cytogenetic abnormalities. Ideally IgM MM should be defined according to principles identical to those used in standard MM. We have previously reported the clinicopathological features of 10 patients with IgM MM [2] and in this current report detail the features of two additional patients (Table I) to further clarify the immunophenotypic and genotypic characteristics of IgM MM. The cytogenetic characteristics of IgM MM were first evaluated by AvetLoiseau et al. [3], who demonstrated the t(11;14) by fluorescence in situ hybridization in seven of eight cases (88%). Similarly, in our initial study, we demonstrated the translocation in 5/8 evaluable cases and have also demonstrated it in a further patient included in this current report (overall incidence 6/10, 60%). Schuster and coworkers demonstrated the translocation in a lower proportion of patients (38%), although a further report has failed to demonstrate it in two further cases [1,4]. It is clear, therefore, that although the t(11;14) appears to occur at a higher frequency in IgM MM, it cannot be regarded as a defining abnormality. Similarly, we reported a patient with the t(4;14) in our original cohort and also include a patient with a t(14;16) in this current report (overall incidence 10% in each instance). Both patients have been reported in detail elsewhere [5,6]. Myeloma plasma cells are characterized by distinct phenotypic differences, when compared to normal plasma cells, and these typically include loss of CD19, CD27, CD45 along with aberrant expression of CD56, CD20, CD117, and cyclin D1 [7]. In our original analysis, an aberrant plasma cell phenotype was demonstrable in 7/10 cases [2] and is also demonstrable in each of the additional cases included in this report confirming the applicability of extended plasma cell phenotyping by either flow cytometry or immunohistochemistry in the diagnosis of IgM MM. This is particularly useful in distinguishing IgM MM from Waldenstrom macroglobulinemia (WM). Our data would also suggest that the immunophenotypic profile of IgM MM differs from that of classswitched myeloma in that there appears to be a lower incidence of CD56 expression [2]. The presence of lytic bone disease was also included in the selection criteria used by Schuster et al. [1]. In our cohort of patients, bone disease was demonstrable in 5/8 (63%), whereas 2/10 (20%) showed neither the t(11;14) nor bone disease. It is interesting to note that the two patients, who lacked both bone disease and the t(11;14), were the patients with the t(4;14) and t(14;16). The inclusion of lytic bone disease and/or the t(11;14) as defining criteria will systematically exclude patients with asymptomatic disease as well as those with other distinct cytogenetic abnormalities. We would conclude that the immunophenotypic and genotypic characteristics of IgM MM are now better characterized and allow for more definitive diagnostic criteria. IgM MM should be defined by IgM monoclonal gammopathy and 10% bone marrow plasma cells. The plasma cells should express monotypic IgM and will frequently demonstrate aberrant expression of a range of antigens including CD19 and cyclin D1, although the incidence of CD56 expression appears lower than in standard MM. Similarly, IgM MM is characterized, in contrast to WM, by immunoglobulin heavy chain (IGH) translocations, and these include not only the t(11;14) but also the t(4;14) and t(14;16).

IgM Multiple Myeloma

IgM myeloma (IgM MM) is a unique, rare subtype of multiple myeloma (MM) comprising just 0.5 % of all cases of MM. Like other types of myeloma with monoclonal gammopathies of other immunoglobulins (e.g., IgG, IgA), patients with IgM MM often have classic symptoms including hypercalcemia, anemia, renal failure, and lytic bone lesions (“CRAB” symptoms). However, unlike the other types of MM, IgM MM shares the finding of an IgM monoclonal gammopathy with another hematologic process, Waldenstrom’s macroglobulinemia (WM). Clinicians are presented with a diagnostic dilemma when a patient presents with a variety of concerning symptoms and an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy and prognosis greatly differ [1, 2].

A surprising cause of masses in the chest

An 82-year-old male presented to the emergency department with an acute onset of chest pain and mild shortness of breath at rest. The pain in his left lower chest was pleuritic with intensity 9- on a 10-point scale. He had driven 2 h in his car that day, but had no other prolonged immobility. About 15 years previously, he was found to have increased hemoglobin (18.1 g/dL) and diagnosed with secondary erythrocytosis due to active smoking, chronic obstructive pulmonary disease (COPD), and residence in Payson, Arizona (altitude 4,999 ft). Polycythemia vera was entertained, but not pursued due to multiple secondary risks. He had been treated with daily aspirin and monthly phlebotomies to maintain a hematocrit below 45%. He also had a history of superficial thrombophlebitis, nephrolithiasis, hypertension and superficial transitional cell carcinoma of the bladder resected and in remission. There was also a deep venous thrombosis (DVT) and pulmonary embolism (PE) 13 years previously, believed to be provoked by prolonged immobility after a radical prostatectomy for prostate cancer now in remission. His medications were aspirin and lisinopril; he had no known drug allergies. He quit smoking 2 years prior after a 70 pack-year history. There was no other family history of thrombosis or bleeding disorder, autoimmune disorders, pulmonary disease or malignancy.

Clinical utility of gene expression profiling data for clinical decision-making regarding adjuvant therapy in early stage, node-negative breast cancer: A case report

Breast cancer is the most common malignancy among women in the United States with the second highest incidence of cancer-related death following lung cancer. The decision-making process regarding adjuvant therapy is a time intensive dialogue between the patient and her oncologist. There are multiple tools that help individualize the treatment options for a patient. Population-based analysis with Adjuvant! Online and genomic profiling with Oncotype DX are two commonly used tools in patients with early stage, node-negative breast cancer. This case report illustrates a situation in which the population-based prognostic and predictive information differed dramatically from that obtained from genomic profiling and affected the patient’s decision. In light of this case, we discuss the benefits and limitations of these tools.