Citations

AbstractCurrent information on Waldenström macroglobulinemia (WM) is based on retrospective or single-institution studies of patients requiring therapy. Between 1992 and 1998, 231 patients with WM were enrolled in a prospective observational multicenter clinical trial. Of these, 182 patients with symptomatic or progressive disease were treated with 4 to 8 cycles of therapy with a purine nucleoside analogue, fludarabine (FAMP; 30 mg/m2 of body-surface area daily for 5 days every 28 days). A serum β2-microglobulin (β2M) level below 3 mg/L and a hemoglobin level of at least 120 g/L (12 g/dL) at presentation predicted a lower likelihood of requiring therapy. The overall rate of response to FAMP therapy was 36% (95% confidence interval, 29%-44%), with 2% complete remissions. Patients who were 70 years old or older had a substantially lower likelihood of response (odds ratio, 0.34; P = .004) than younger patients. On multivariate analysis, a serum β2M level of 3 mg/L or higher, hemoglobin level below 120 g/L, and serum IgM level below 40 g/L [4 g/dL] were significant adverse prognostic factors for survival. We developed a simple staging system for WM by using these variables and identified 4 distinct subsets of patients with estimated 5-year overall survival rates of 87%, 64%, 53%, and 22%, and 5-year progression-free survival rates of 83%, 55%, 33%, and 12%. Prognosis in WM is highly variable and serum β2M was the dominant predictor of a need for therapy and of survival. FAMP has activity against WM. Our staging system may provide guidance for a risk-based approach to the treatment of WM.

AbstractPreviously, it was reported that patients with multiple myeloma (MM) who have higher baseline levels of blood CD4+or CD19+ cells have longer survival. This article extends the analysis of immune cell levels and survival in a large cohort (N = 504) of patients with MM entered on Eastern Cooperative Oncology Group (ECOG) phase 3 trial (9486). Newly diagnosed patients with MM received 2 cycles of vincristine, bischloroethylnitrosourea, melphalan, cytoxan, prednisone (VBMCP) and were treated on one of 3 randomized arms: VBMCP with either interferon or high-dose cyclophosphamide, or VBMCP alone. Blood immune cell levels were studied at trial entry (baseline), after 2 cycles of chemotherapy, after 2 years of therapy, and at relapse. Baseline CD3+, CD4+, CD8+, CD19+, and CD4+ subset cell levels were all positively associated with survival (P = .0087 toP < .0001). A multivariate analysis incorporating CD4+ and CD19+ cell levels defined 3 separate groups of patients with MM to survival outcome. Higher CD19+ blood levels were positively associated with MM-patient survival at entry to the study, at year 2, and at relapse (P < .0001 at all 3 timepoints). Patients with MM had evidence of immune cell reconstitution after 2 years of therapy, but the rate and extent of recovery was greater for CD8+, which was greater than CD4+, which was greater than CD19+. This latter data affirms the positive relationship between the quantitative status of the blood immune system in MM and survival. In addition, the importance of the CD19+ blood cells to survival is evident throughout the course of MM. Therapeutic efforts to maintain an intact immune system may be crucial in maximizing chemotherapeutic and/or immunotherapy efforts in this disease.

Abstract The plasma cell labeling index (PCLI) is a measure of plasma cell proliferative activity and is an important prognostic factor in newly diagnosed multiple myeloma (MM). Occasionally patients have been observed with stable, plateau phase MM with minimal numbers of residual light-chain–restricted monoclonal plasma cells, but a high PCLI. No data are available on the outcomes for such patients. Data from 57 patients with plateau phase MM and a marrow PCLI of more than 1.0% were compared with 105 matched control patients with MM with a marrow PCLI of less than 1.0%. All patients had less than 10% total plasma cells on marrow aspirate and biopsy. The median time to progression and overall survival were 8 months and 20 months, respectively, in the high PCLI group versus 39 months and 56 months, respectively, in the low PCLI group (P < .0001). These findings suggest that a high PCLI in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death.

AbstractThe course of clonal evolution of 2 related clones in the blood of a patient with Waldenstrom macroglobulinemia (WM) indicates the functional importance for the expression of the B-cell receptor for the survival of these malignant cells. Protein and nucleotide sequencing of the paraproteins' variable regions revealed 2 predominant Vλ and 2 VH sequences, each set comprised in the ratio 1:1.5. The 2 VH sequences and 2 Vλ sequences shared the same VDJ and VJ junctional sequences, respectively, indicating that 2 malignant clones had evolved from a common ancestor. This is the first report on intraclonal heterogeneity in WM. Comparison of the Vλ and VH sequences with the closest matching known germline genes showed that they contained approximately 10 somatic mutations each. The distribution and type of mutations demonstrate that mutations have continued to accumulate in the malignant clones and that selection has been operating to preserve immunoglobulin structure.

Renal insufficiency, which is present initially in almost half of patients with multiple myeloma, usually results from myeloma kidney or hypercalcemia. Neither the class of light chain nor the isoelectric point plays an important role in kidney failure. Acute renal failure must be treated with appropriate fluids and with electrolytes and hemodialysis if necessary. Plasma exchange may be helpful, but has not been proven as such. The presence of a nephrotic syndrome and a monoclonal κ or λ light chain in the urine almost always indicates primary amyloidosis (AL) or light-chain deposition disease. Amyloid fibrils must be distinguished from the fibrils of immunotactoid glomerulopathy.