Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations.

Chromosomal hyperdiploidy is the defining genetic signature in 40-50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P = 0.023), despite similar response to treatment. Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P = 0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients.

Ploidy status rarely changes in myeloma patients at disease progression.

Hyperdiploid and non-hyperdiploid multiple myeloma represents distinct biological entities characterized by different patterns of genetic changes. We sought to determine whether ploidy category (non-hyperdiploid versus hyperdiploid) remains stable over time from diagnosis to progression. Of the 43 patients studied (39 by flow cytometry DNA index and 4 by a FISH-based index), only five (12%) altered their ploidy status at progression. In three of these patients, the change may possibly be attributable to technical artifacts because of the low absolute change in DNA index. For those who retain their ploidy subtypes, the DNA index change minimally (3.75+/-4.87%). It would appear that the initiating genetic events underlying hyperdiploid and non-hyperdiploid MM that marks them out as distinct entities continue to dominate and persist during disease evolution and progression.

Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients.

Bone involvement is a central feature of multiple myeloma (MM). We investigated whether serum markers of osteoblastic and osteoclastic activity correlate with the presence of bone disease and survival in 313 MM patients enrolled in a phase III trial (E9486). Five markers were measured, including osteocalcin (OC), carboxy-terminal propeptide of type I collagen (PICP), bone alkaline phosphatase (BAP), carboxy-terminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). We analysed the relationship between serum levels of these markers and the presence of bone manifestations, and survival. Serum levels of ICTP and BAP correlated significantly with bone pain, lesions and fractures. Serum level of ICTP was also higher in stage II-III compared with stage I disease. The serum level of ICTP was significantly associated with shortened survival in the univariate analysis. The median survival times were 4.1 and 3.5 years for low and high ICTP respectively (P = 0.02). There was a strong relationship between ICTP and beta-2-micrgolobulin (B2M). ICTP stands out as a significant marker of bone disease. Incorporation of these markers into clinical trials assessing the use of bisphosphonates in MM is needed to determine whether they might serve as indicators of effectiveness of these agents.

Is flow cytometric DNA content hypodiploidy prognostic in multiple myeloma?

Hypodiploid multiple myeloma is uncommon when assessed by DNA content flow cytometry, having been reported in less than 6% of patients with newly diagnosed multiple myeloma. Previous studies have shown these patients to be unresponsive to therapy and to have short survival. To address this further, we studied 349 of 504 patients eligible for Eastern Cooperative Oncology Group (ECOG) treatment trial E9486 and laboratory correlative study E9487 who had marrow mononuclear cells available for ploidy analysis. Marrow samples were studied by dual channel flow cytometry, using propidium iodide to measure the DNA content and kappa and lambda light chain antisera to identify the clonal cells. A DNA index < 0.95 was considered hypodiploid. Five patients (1.4%) were found to have hypodiploid DNA content in their marrow plasma cells. Three of the 5 patients with hypodiploid myeloma had a partial objective response to chemotherapy, which is not different from the overall objective response rate for all patients enrolled on E9486. All five patients with hypodiploid multiple myeloma died within 4 years from diagnosis, but these patients had a similar overall median survival (2.6 years) compared to the patients with diploid DNA content. Our studies confirm the poorer survival of patients with diploid versus hyperdiploid myeloma; we cannot confirm, however, the previously reported very poor outcome associated with hypodiploid myeloma using DNA content flow cytometry. Hypodiploid DNA content of plasma cells by flow cytometry may not be as ominous a factor as previously reported.

Prognostic significance of the S-phase fraction of light-chain-restricted cytoplasmic immunoglobulin (cIg) positive plasma cells in patients with newly diagnosed multiple myeloma enrolled on Eastern Cooperative Oncology Group treatment trial E9486.

The bone marrow plasma cell labeling index (PCLI) as measured by bromodeoxyuridine uptake is a well-established independent prognostic factor for patients with newly diagnosed multiple myeloma, but the test is not easily done in most laboratories. The purpose of this study was to determine if the proliferative activity (% S-phase) as determined by two-color flow cytometry for cytoplasmic immunoglobulin (cIg) light chain and DNA content also had prognostic significance. As part of Eastern Cooperative Oncology Group clinical trial E9486, 500 patients had successful performance of the bone marrow PCLI. Of 349 patients who had flow cIg and DNA content cytometry, 210 had adequate data to reliably calculate S-phase %. Patients with low % S-phase fraction (<2%) had a significant overall survival advantage over patients high % S-phase fraction (>/=2%), median survivals 4.1 vs. 2.9 years (P = 0.032). Measurement of the S-phase % by flow cytometry gives significant prognostic information in patients with newly diagnosed myeloma. However, in multivariate analysis, S-phase % did not add prognostic information when PCLI was in the model. S-phase % added prognostic information only when all cases with flow measurement of S-phase % were included, and when PCLI was excluded from the model. Discriminating a population of only cIg positive cells proved difficult in patients with a low percentage of bone marrow plasma cells. Methodology to measure S-phase % in patients with a low percent plasma cells is needed before this technique can be used for diagnosis and prognosis in myeloma.

Incidence and morbidity of cholelithiasis in patients receiving chronic octreotide for metastatic carcinoid and malignant islet cell tumors.

BACKGROUND: Octreotide, a long-acting somatostatin analogue, has demonstrated clinical utility in patients with carcinoid syndrome and malignant islet cell tumors of the pancreas. Prior studies have reported a greater than expected incidence of cholelithiasis in patients treated with octreotide for acromegaly. This study attempted to determine the incidence and morbidity of cholelithiasis in a group of patients with metastatic carcinoid or malignant pancreatic islet cell tumors who were receiving chronic therapy with octreotide. METHODS: Forty-four of 55 patients on investigational protocols with octreotide were eligible for chart review; 10 patients were excluded due to prior cholecystectomy and 1 patient due to asymptomatic cholelithiasis at presentation. Patients fell into three treatment groups. The low dose (LD) group was comprised of 17 patients receiving 150 microg of subcutaneous octreotide 3 times a day. Twenty-one patients received high dose (HD) therapy comprised of 500 microg given 3 times a day. The low dose-high dose (LD-HD) group was comprised of 6 patients who had their dose escalated from 150 microg to 225-500 microg of octreotide 3 times a day. RESULTS: The overall incidence of cholelithiasis and/or gallbladder sludge was found to be 52.3% in all 3 treatment groups. Three of the 44 patients (6.8%) had symptomatic disease requiring emergency cholecystectomy. Five other patients underwent elective or incidental gallbladder surgery. The incidence of cholelithiasis in the LD, LD-HD, and HD groups was 35.3%, 66.6%, and 61.9%, respectively. The incidence of acute cholecystitis in the three groups was 11.8%, 0%, and 4.8%, respectively. CONCLUSIONS: Although greater than 50% of patients receiving octreotide developed cholelithiasis, a much smaller percentage of patients had symptomatic gallbladder disease. Patients receiving chronic octreotide treatment require monitoring for the development of gallstones. However, prophylactic cholecystectomy is not indicated, unless it is performed in conjunction with bowel resection or cytoreductive hepatic surgery.