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This multicenter, open-label, randomized phase 2 study assessed the efficacy and safety of pomalidomide (POM) with/without low-dose dexamethasone (LoDEX) in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior therapies (including lenalidomide [LEN] and bortezomib [BORT]) and had progressed within 60 days of their last therapy were randomized to POM (4 mg/day on days 1-21 of each 28-day cycle) with/without LoDEX (40 mg/week). The primary end point was progression-free survival (PFS). In total, 221 patients (median 5 prior therapies, range 1-13) received POM+LoDEX (n = 113) or POM (n = 108). With a median follow-up of 14.2 months, median PFS was 4.2 and 2.7 months (hazard ratio = 0.68, P = .003), overall response rates (ORRs) were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median overall survival (OS) was 16.5 and 13.6 months, respectively. Refractoriness to LEN, or resistance to both LEN and BORT, did not affect outcomes with POM+LoDEX (median PFS 3.8 months for both; ORRs 30% and 31%; and median OS 16 and 13.4 months). Grade 3-4 neutropenia occurred in 41% (POM+LoDEX) and 48% (POM); no grade 3-4 peripheral neuropathy was reported. POM+LoDEX was effective and generally well tolerated and provides an important new treatment option for RRMM patients who have received multiple prior therapies. This trial was registered at www.clinicaltrials.gov as #NCT00833833.

We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

While studying the unique Nramp1 (Slc11a1)-independent susceptibility to Mycobacterium bovis (BCG) infection of BXH-2 mice, we noted that these mice develop important splenomegaly and enlargement of lymph nodes. Segregation analyses in several F2 crosses showed that splenomegaly segregates as a single recessive trait caused by a novel mutation in BXH-2, independent of the infection. Histologic and fluorescence-activated cell sorter (FACS) analyses indicated that splenomegaly is associated with a large increase in Mac1+/GR1+ (macrophage antigen-1+/granulocyte differentiation antigen 1+) granulocyte precursors in spleen, lymph nodes, and bone marrow, resembling a myeloproliferative syndrome. This is concomitant to extramedullary erythropoiesis in the spleen, as measured by proportion of Ter119+ erythroid cells. The locus controlling this myeloproliferative syndrome and splenomegaly was designated Myls and maps to an 18 centimorgan (cM) region of chromosome 8, which also contains an integrated copy of an N-ecotropic murine leukemia virus (MuLV) provirus (Emv2). The relationship between Myls, expansion of Mac1+/GR1+ cells, and Emv2 was investigated. Homozygosity at Myls is necessary but not sufficient for B-ecotropic virus replication in splenocytes, the extent of which appears to be under separate genetic control. Our results suggest a model in which Myls-dependent myeloproliferation in BXH-2 acts as a predisposing factor for the subsequent development of virally induced myeloid leukemia characteristic of this strain.

By depletion of effector-target conjugates and cloning, a variant of the human leukemic line K562 that is partially resistant to lysis by natural killer (NK) cells when tested under conditions of culture and assay identical to that of the parent has been derived. Its karyotype shows markers similar to the original K562. The resistant phenotype remains stable after over 1 year of continuous passage and persists in multiple replicate subclones. However, it can be killed to a degree equal to the parent by antibody-activated complement, antibody-dependent cellular mechanisms, and by effector cells activated by staphylococcal protein A. These observations and experiments on cold target competition suggest that on its surface there is a significantly decreased, absent, or blocked effective target structure for a major population of unstimulated peripheral blood NK cells.

The activity of natural killer (NK) cells can be augmented by incubation with interferons, or with other compounds, such as staphylococcal protein A, which stimulate interferon production. In the experiments described here we compared the patterns of lytic activity of human lymphoid effector cells, before (NK-B) and after (NK-A) short-term activation. Target cells used were K562, Clone I (a partially NK-resistant K562 variant), and those that had been preincubated with neuraminidase or trypsin. The results obtained include the following: proteases, but not neuraminidase, decreased lysis by NK-B, but not by NK-A, of both K562 and Clone I in the standard Cr-release assay. In the single cell assay, trypsin minimally decreased conjugate formation and the fraction of bound cells that were killed by NK-B, but did not reverse the increased lytic efficiency of NK-A. In the cold-target competition assay, Clone I, which does not compete as well with K562 for NK-B, did so equally well for NK-A. Trypsinized targets, regardless of their equal sensitivity to lysis by NK-A, were not as active competitors for NK-A. We conclude that the most reasonable interpretation is that K562 cells bear surface structures which can induce release of lytic mediators from NK-A under conditions that are not sufficient to stimulate NK-B. Although it appears that NK-A may respond to a smaller number of the same target molecules recognized by NK-B, the process must be better defined at the molecular level to exclude the possibility that there are qualitative differences between the proposed recognition structures for these two states of NK activity.

Ninety-seven patients with light chain disease (LCD) were studied. The median survival from diagnosis was 30 mo for 52 patients with kappa-LCD and 10 mo for 45 patients with lambda-LCD (p less than 0.0007). A lower proportion of kappa-LCD patients (15.7%) than lambda-LCD patients (42.2%) died within the first 6 mo after diagnosis. The survival of the remaining patients with kappa-LCD was still much longer than of those with lambda-LCD (p = 0.022). The shorter survival of lambda-LCD patients could not be ascribed to an increased incidence of recognized manifestations indicating a poor prognosis (e.g., anemia, hypercalcemia, azotemia, low albumin, the extent of osteolytic lesions, or proteinuria), the incidence of amyloidosis, the clinical stage of the disease at diagnosis, or the response to treatment, and remains unexplained. A comparison of the clinical manifestations of LCD with those of other myelomas revealed some differences. LCD patients were slightly younger than IgA and IgG patients but older than IgD patients. A 1:1 ratio of males to females was similar to the ratios in IgA and IgG myeloma, but differed from the 3:1 ratio reported for IgD myeloma. Plasma-cell leukemia developed in 7/97 LCD patients, an incidence that was higher than has been reported in other myelomas. The initial BUN was more than or equal to 30 mg/100 ml in 54 of 95 LCD patients, an incidence that was higher than has been reported for IgA and IgG myeloma, but lower than the incidence in IgD myeloma. The incidence of amyloidosis in LCD (23 of 97 patients) was similar to that reported for IgA and IgG myeloma, but less than the incidence in IgD myeloma.