Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders

The proliferative rate of malignant plasma cells, as measured by the plasma cell labelling index (PCLI), is an important prognostic factor in multiple myeloma (MM); however, the PCLI alone is probably Inadequate to describe tumour growth because it ignores the idea that myeloma cells may have a reduced rate of apoptosis. The aims of this study were to develop a flow cytometric method to measure the apoptosis index of fresh marrow plasma cells and develop a plasma cell growth index (PCGI) that related both proliferation and apoptosis to disease activity. Marrow aspirates were obtained from 91 patients with plasma cell disorders and the plasma cells in apoptosis were identified by either 7-amino actinomycin-D (7-AAD) or annexin V-FITC three-colour flow cytometry. The median plasma cell apoptotic index (PCAI) for patients with monoclonal gammopathy of undetermined significance (MGUS), smouldering or indolent myeloma (SMM/IMM), and new multiple myeloma (MM) was 5.2, 3.4 and 2.4, respectively (P=0.03, MGUS v MM). The median PCLI for these same patient groups was 0.0, 0.2 and 0.6, respectively (P<0.001, MGUS v MM). The paired PCLI and PCAI for each sample were used to derive the PCGI=2 + [PCLI-(O.1)(PCAI)]. The median PCGI for patients with inactive disease (MGUS, SMM/IMM or amyloidosis) was 1.8 compared to 2.4 for those with active disease (new or relapsed MM) (P<0.001). These results suggest that a decrease in the PCAI may be a factor in the progression from MGUS to SMM to overt MM.     

Smoldering multiple myeloma: natural history and recognition of an evolving type

Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M-protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M-protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non-evolving SMM (n = 26) with stable M-protein that abruptly increases when symptomatic MM develops. Thirty-four patients developed symptomatic MM. The median time to progression in the overall series was 3.2 years and the only feature associated with a shorter time to progression was the evolving versus non-evolving type (1.3 vs. 3.9 years respectively, P = 0.007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty-seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8.2 and 3.5 years respectively.     

Kappa/lambda ratio on peripheral blood lymphocytes and bone marrow plasma cell labeling index in monoclonal gammopathies

Bone marrow plasma cell labeling index (L.I.), kappa/lambda ratio, CD4+ and CD8+ subpopulations were studied in patients with smoldering multiple myeloma (SMM), active myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). The loss of the light chain isotype suppression (LCIS) and a high labeling index (L.I.) allowed us to distinguish all MM patients from SMM patients. On the contrary, a low L.I. and a normal kappa/lambda ratio were found in most kappa and lambda MGUS. A significant difference in the kappa/lambda ratio was noted between MGUS and K-SMM. A significant decrease in CD4+ and a significant increase in CD8+ were not observed in patients with LCIS. The kappa/lambda ratio together with the plasma cell L.I. could be useful parameters for distinguishing active MM from SMM, especially in the cases with a border line L.I.     

Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma

The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45- CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).     

Clinical, morphological, and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma

We reviewed the clinical and morphological findings in 43 cases of monoclonal gammopathy of undetermined significance (MGUS), 9 of smoldering multiple myeloma (SMM), and 23 of overt multiple myeloma (MM). In all cases, the patients' physicians had requested a bone marrow examination because of the possibility of MM. In all 75 cases, 3H-thymidine labeling indices were performed. The plasma cell labeling index correctly classified 62 of the 75 cases (83%). A linear discriminant function combining the labeling index and percentage of plasma cells improved the accuracy to 92% (69/75), or to 95% (71/75) if patients in whom MM developed within 6 mo were considered to have MM. The labeling index was most critical for the differential diagnosis of MM from SMM (p less than 0.001). Serum or urine M-protein level, percentage of plasma cells or lymphocytes in the bone marrow, and plasma cell grade, asynchrony, and nucleolar size failed to discriminate the group with SMM from the group with MM. In patients with MGUS or SMM, a plasma cell labeling index greater than 0.4% warned of impending MM. The plasma cell labeling index is a reliable diagnostic test when applied in cases of monoclonal gammopathy, especially when differentiation from MM is difficult using standard clinical criteria.     

Asymptomatic immunoglobulin light chain amyloidosis (AL) at the time of diagnostic bone marrow biopsy in newly diagnosed patients with multiple myeloma and smoldering myeloma. A series of 144 cases and a review of the literature

The rate of asymptomatic amyloidosis (AL) among patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. We evaluated number and clinical significance of asymptomatic AL in consecutive MM and SMM patients, not having recognition of symptomatic AL at the time of their diagnostic bone marrow biopsy. Bone marrow biopsies were stained with Congo red and considered diagnostic for AL in case of positive Congo red staining with apple-green birefringence. Biopsies from 144 patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26?C84) years; the median follow-up was 76?months (range 0?C216). Immunoglobulin isotypes were 96/144 (67%), IgG; 23/144 (16%), IgA; 12/144 (8%), light chain only; 1/77 (1%), IgD; and biclonal or indeterminate, 12/144 (8%). Fifty-eight percent (84/144) were ?? restricted. The presence of amyloid was found in two cases (1%, 95% CI ?0.6 to 3.2), one in MM, and one in SMM group, and none had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, one (0.7%, 95% CI ?0.6 to 2.0) developed symptomatic AL after 119?months.     

Myelomagenesis: capturing early microenvironment changes

Plasma cell neoplasms result from the clonal expansion of terminally differentiated, immunoglobulin heavy-chain class switched B cells that typically secrete a monoclonal immunoglobulin. The 2008 World Health Organization (WHO) classification of plasma cell neoplasms encompasses a broad spectrum of disorders, from the precursor disorder monoclonal gammopathy of undetermined significance (MGUS) to plasma cell leukemia. The classification includes, in addition to precursor lesion MGUS, plasma cell myeloma, plasmacytoma, immunoglobulin deposition diseases, and osteosclerotic myeloma. Plasma cell myeloma is further divided into symptomatic plasma cell myeloma or multiple myeloma (MM), asymptomatic smoldering myeloma (SMM), non-secretory myeloma, and plasma cell leukemia. Although histopathologic cut-off criteria are incorporated into the classification schema, distinction between MGUS, SMM, and MM depends primarily on the presence or absence of end-organ damage, as defined by "CRAB" criteria (hypercalcemia, renal insufficiency, anemia, lytic bone lesions, or a combination of these). Systematic evaluation of pathogenetic differences between MGUS and MM should offer invaluable insights into early myelomagenesis. Given the complex, intertwined nature of the malignant plasma cell and its surroundings, multiple pathogenetic mechanisms play a critical role in interactions between neoplastic cells and their microenvironment. Understanding the events leading to end-organ damage, like anemia and bone remodeling, is a critical part of investigating early myelomagenesis and should provide us with better tools for early identification and treatment of these patients.     

Clinical characteristics and outcomes in biclonal gammopathies

A single monoclonal protein typically characterizes monoclonal gammopathies, but a small proportion may have more than one M protein identifiable. In the setting of symptomatic multiple myeloma (MM), the development of a new monoclonal protein following therapy is associated with better outcomes. As for the precursor conditions, monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM), there is limited information on the impact of a second monoclonal protein on the disease course, including progression and response to treatment. The outcomes of patients with MGUS and SMM with more than one monoclonal protein, after identifying 539 patients with biclonal proteins on electrophoresis and/or immunofixation, were reported. About 22 of 393 patients with MGUS/biclonal gammopathy of undetermined significance (BGUS) progressed to SMM (6), MM (11), AL (3), or WM (2), and 5 of 16 patients with biclonal SMM progressed to MM. The rate of progression for BGUS was approximately 1% per year, which is similar to MGUS with one monoclonal protein. The median estimated time of progression of biclonal SMM was 2.6 years; similar to monoclonal SMM. For patients with biclonal MM, both M spikes responded to treatment and, upon relapse, the original dominant M protein remained dominant as the disease progressed. In conclusion, the presence of a second monoclonal protein does not appear to affect the progression of precursor states and suggests multiple monoclonal proteins do not clinically impact one another in the course of the disease. Am. J. Hematol. 91:473–475, 2016. © 2016 Wiley Periodicals, Inc.     

Long‐term results of single‐agent thalidomide as initial therapy for asymptomatic (smoldering or indolent) myeloma

We report the long‐term follow‐up results of a phase II trial of thalidomide for early‐stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent MM without the need for immediate therapy. Thalidomide was initiated at a dose of 200 mg/day and adjusted as tolerated. Disease progression was defined using modified American Society of Hematology/Food and Drug Administration consensus panel criteria for SMM. Thirty‐one patients were enrolled; 29 (19 SMM and 10 indolent MM) were eligible. The median age was 61 years. Median follow‐up of living patients was 10.2 years (range, 7.5‐11.0 years). Ten patients (34%) had a partial response (PR) and nine had minimal response (MR) for an MR plus PR rate of 66%. The median time to progression (TTP) to symptomatic myeloma was 35 months. Median TTP was 61 months in those achieving PR, 39 months with MR, and 9 months among those failing to achieve either MR or PR, P = 0.005. Median overall survival from diagnosis was 86 months; median survival from onset of symptomatic myeloma was 49 months. Grade 3‐4 nonhematologic adverse events were noted in 55% of patients. Randomized trials are needed to determine the role of early therapy in SMM. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 microM (2.0 mg/dL; range, 79.56-327.08 microM [0.9-3.7 mg/dL]) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process.     

A high bone marrow plasma cell labeling index in stable plateau-phase multiple myeloma is a marker for early disease progression and death

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.     

Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders

A third of patients with multiple myeloma (MM) have a preceding diagnosis of plasma cell proliferative disorder (PCPD), mostly monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) or plasmacytoma. While autologous stem cell transplantation (SCT) improves survival in MM, it is not clear if patients with preceding PCPD have a different outcome. We identified 151 patients with preceding PCPD from among 804 patients undergoing SCT, and their outcomes were compared. The response rates, including complete responses, were similar between the groups. Patients with a preceding diagnosis of MGUS had longer time to progression (TTP; 27·5 months vs. 17·2 months, P  = 0·01), and longer overall survival (OS) from transplant (80·2 months vs. 48·3 months, P  = 0·03) compared to those with de novo myeloma. However no differences were seen among those with a preceding diagnosis of SMM or plasmacytoma in terms of TTP or OS from transplant when compared to those with de novo myeloma. Multivariate analysis indicated that the presence of MGUS prior to myeloma was prognostic for post-transplant relapse independent of other known risk factors. Patients with pre-existing MGUS prior to myeloma diagnosis have a better outcome following HDT, reflecting more indolent disease and a favourable biology than those presenting with de novo myeloma.     

A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS

Two major genetic categories of multiple myeloma (MM) exist. Hyperdiploid MM (48 to 74 chromosomes, median 53 chromosomes) is associated with trisomies especially of chromosomes 3, 7, 9, 11, 15, and 19, whereas the nonhyperdiploid (< 48 chromosomes or more than 74 chromosomes) MM is associated with primary translocations such as t(11;14), t(4;14), and t(14;16). Whether this dichotomy exists in monoclonal gammopathy of undetermined significance (MGUS) is uncertain due to limitations of current methods in the study of ploidy. This is especially true in MGUS where the number of clonal plasma cells is small. In this study, we derived a fluorescent in situ hybridization (FISH)-based trisomy index from pooled cytogenetic data (karyotype analysis) from 2 large cohorts of patients with MM with abnormal karyotype, and then validated it in 2 independent cohorts of patients who had known ploidy status either by karyotyping or DNA content measurement using flow cytometry. Using the criteria of 2 or more trisomies from a 3-chromosome combination, hyperdiploid myeloma can be detected with high specificity. Applying this index on 28 patients with smoldering multiple myeloma (SMM) or MGUS (11 SMM, 17 MGUS) who had normal karyotype, 11 cases of hyperdiploid SMM/MGUS were detected. This percentage (40%) is remarkably similar to the percentage of hyperdiploid MM reported in the literature, suggesting that hyperdiploid MM may originate early during disease evolution.     

Tumour necrosis factor-α and interleukin 4 promote the differentiation of myeloma cell precursors in multiple myeloma

Summary. The effects of tumour necrosis factor-α (TNF-α) and interleukin 4 (IL-4) on peripheral blood mononuclear cells (PBMC) from 36 patients with multiple myeloma (MM), 12 with monoclonal gammopathy of undetermined significance (MGUS) and 21 normal controls, were investigated. In 16/36 patients with MM, monoclonal plasma cells appeared after 4d in cultures containing TNF-α and IL-4. These changes were not observed in PBMC from patients with MGUS or from normal controls. These findings suggest that myeloma cell precursors do exist in the peripheral blood of MM patients and differentiate into plasma cells in the presence of TNF-α and IL-4. Based on these observations, we think that the variation in the number of myeloma cell precursors in peripheral blood could be used as a prognostic parameter of response to chemotherapy in myeloma patients. In addition, this assay may be useful to distinguish early-stage MM from MGUS.     

Two subsets of peripheral blood plasma cells defined by differential expression of CD45 antigen

The purpose of this study was to optimize the flow cytometric determination of circulating normal and malignant plasma cells (PC). We investigated peripheral blood (PB) samples of 65 patients with multiple myeloma or monoclonal gammopathy of unknown significance and 47 control subjects using CD38, CD45, B-B4, CD56, VLA-4, VLA-5 and CD19 monoclonal antibodies (MoAbs). Mono- or polyclonality was determined by staining of intracellular kappa and lambda light chains. Two subpopulations of PBPC were distinguished by differential expression of CD45. CD45 positive (CD45⁺) PC showed a more immature morphology and were detected in all groups. They were polyclonal in the control subjects and either poly- or monoclonal in the myeloma patients. In contrast, CD45 negative (CD45⁻) PBPC only occurred in myeloma patients and were consistently monoclonal, their presence being significantly associated with high disease activity ( P <0.001). Although detection of CD45⁻ PBPC using CD38 or B-B4 MoAbs lead to similar results, CD45⁺ PBPC often were recognized to a lesser extent by B-B4 than by CD38 MoAbs.
In conclusion, normal and malignant circulating PC can reliably be identified using CD38 and CD45 MoAbs. CD45 expression separates PBPC into two subsets of which the CD45⁻ one only occurs in myeloma patients.     

Differentiation of monoclonal gammopathy of undetermined significance and multiple myeloma using flow cytometric characteristics of plasma cells

BACKGROUND AND OBJECTIVES: The differential diagnosis between multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) may be uncertain in some cases; this problem is reflected by discrepancies between different classification systems with an accordance in only 2/3 of cases. We studied whether flow-cytometric characteristics of plasma cells (PC) can be used for the differentiation between MGUS and MM. DESIGN AND METHODS: Patients were divided into 3 groups: Group A included 13 myeloma patients with a plasma cell infiltration of the bone marrow of 10-30%, serum M-protein < or = 3.5 g/dL (IgG) or < or = 2 g/dl (IgA) and without bone lesions in conventional radiography. Group B consisted of 53 patients who fulfilled the Durie and Salmon diagnostic criteria including at least one major criterion, and group C individuals with MGUS (n=17). The ratio of immunophenotypically normal (i.e. CD19(+)/CD56(-)) to all bone marrow plasma cells (BMPC), the number of peripheral blood PC (PBPC), the percentage of BMPC in S-phase and the DNA content of BMPC were analyzed. RESULTS: All individuals with MGUS and no patient with MM in group A or group B had a ratio of phenotypically normal to all BMPC > or = 20%. The median of monoclonal PBPC was 0/microL (range 0-2/ microL) in MGUS, 1/microL (range 0-30/microL) in MM group A and 2.4/microL (range 0-211/microL) in MM group B. The median percentage of BMPC in S-phase was 1.6% both in MGUS and in group A and 3% in group B. Aneuploidy was found in 12%, 11% and 41% in MGUS, group A and group B, respectively. INTERPRETATION AND CONCLUSIONS: The ratio of immunophenotypically normal to all BMPC was the only flow-cytometric parameter for the differentiation of MGUS and MM group A (p<0.0005). The other parameters were significantly different between MGUS and MM group B, but not group A.     

A contribution to examination of propidium iodide and annexin V plasma cells indices in multiple myeloma

The aim of this study was a contemporaneous measurement and a mutual comparison of plasma cells proliferative activity and grade of apoptosis in patients with monoclonal gammopathy of undetermined significance (MGUS) and various phases of MM i.e. smoldering (SMM), stable/plateau and active (progression/relapse) forms of this disease. The analyzed group of 197 patients consisted of 30 MGUS, 21 SMM, 82 patients examined at the time of MM diagnosis and 64 patients analyzed during various phases of the disease after previous chemotherapy. Plasma cell proliferative activity was measured by means of a propidium iodide index (PC-PI) examined by flow cytometry using a DNA/CD138 double staining technique. For detection of plasma cells entering apoptosis (PC-AI) flow cytometry method with annexin V FITC and MoAb CD138 was used. The individuals with MGUS, SMM and stable/plateau form of MM had overall low levels of PC-PI (M-1.8, 1.7% and 2.1%) and relatively high levels of PC-AI (M-9.1, 10.8 and 9.0%). The correlation between PC-PI and PC-AI was in all the groups mutually highly statistically significant (p=0.000). Analysis of plasma cells proliferative activity (PC-PI) was statistically significant in comparison of MGUS or SMM and versus: patients examined at the time of MM diagnosis (p=0.018 or 0.016); patients evaluated during various phases of MM after previous chemotherapy (p=0.021 or 0.019); stable/plateau MM phase in the cohort of all patients (p=0.017 or 0.040); in the plateau phase after chemotherapy (p=0.008 or 0.024) but insignificant in comparison of MGUS and SMM and with the stable group examined at the time of MM diagnosis. Analysis of the apoptotic process revealed significant differences when comparing PC-AI of SMM but not MGUS group versus all cohort of stable/plateau MM patients (p=0.045); there were also insignificant differences in comparison of MGUS and SMM groupsand versus the stable form of MM measured at the time of MM diagnosis or plateau phase after chemotherapy. There was observed a statistically significant difference in the PC-AI in comparison of SMM group versus group of all patients examined at the time of MM diagnosis (p=0.001) or in various phases of this disease (p=0.015) and the group of MGUS patients compared with patients evaluated at the time of MM diagnosis (p=0.03). Very significant statistical differences of plasma cell proliferative (PC-PI) and apoptotic (PC-AI) activity were found when comparing the levels of both the indices of MGUS, SMM and stable/plateau MM group versus the active (progression/relapse) form of MM marked by a higher level of PC-PI (3.2%, p=0.000) and PC-AI (4.8%, p=0.000) in the whole cohort of MM patients, but also in comparison with both the active forms at the time of MM diagnosis or active forms evaluated during various phases of the disease after chemotherapy. Highly significant inverse relationship between PC-PI versus PC-AI was also revealed in the group of patients in the active (progression/relapse) phase of MM (p=0.000). These results revealed importance of measurement not only of proliferative but also of apoptotic plasma cells indices for a complex evaluation of the cells kinetics of plasma cells compartments in patients with MGUS or MM. This study confirmed the initial hypothesis of a common 'inverse relationship between the proliferative (PC-PI) and the apoptosis activity (PC-AI) in plasma cells compartments in patients with MGUS, smoldering, stable/plateau and active (progression/ relapse) forms of MM'.     

Reduction in C‐reactive protein indicates successful targeting of the IL‐1/IL‐6 axis resulting in improved survival in early stage multiple myeloma

We report the long‐term follow‐up results of a phase II trial of IL‐1 receptor antagonist and low‐dose dexamethasone for early stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent multiple myeloma (IMM) without the need for immediate therapy. Forty seven patients were enrolled and subsequently treated with IL‐1Ra; in 25/47 low‐dose dexamethasone (20 mg weekly) was added. The primary endpoint was progression‐free survival (PFS). In the clinical trial, three patients achieved a minor response (MR) to IL‐1Ra alone; five patients a partial response (PR) and four patients an MR after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index (PCLI) which paralleled a decrease in the high sensitivity C‐reactive protein (hs‐CRP). The median PFS for the 47 patients was 1116 days (37.2 months). The median PFS for patients without (n = 22) and with (n = 25) a decrease in their baseline hs‐CRP was 326 days (11 months) vs. 3139 days (104 months) respectively (P <0.0001). The median overall survival (OS) for the 47 patients was 3482 days (9.5 years). The median OS for patients without and with a decrease in their baseline hs‐CRP was 2885 days (7.9 years) vs. median not reached, respectively (P = 0.001). In SMM/IMM patients at risk for progression to active myeloma, reduction in the hs‐CRP indicates successful targeting of the IL‐1/IL‐6 axis resulting in improved PFS and OS. (Clinical Trials.gov Identifier: NCT00635154) Am. J. Hematol. 91:571–574, 2016. © 2016 Wiley Periodicals, Inc.     

Development of early treatment strategies for high-risk myeloma precursor disease in the future

Smoldering myeloma (SMM) is a precursor state of multiple myeloma. It is defined by an M-protein concentration ≥3 g/dL and/or ≥10% clonal bone marrow plasma cells, in the absence of end-organ damage. Based on clinical observations, the natural history of SMM varies greatly, from stable, monoclonal gammopathy of undetermined significance (MGUS)-like disease to highly progressive disease. Using conventional clinical markers, SMM patients can be stratified into clinical risk groups. However, due to considerable molecular heterogeneity, we currently lack reliable markers to predict prognosis for individual SMM patients. Based on the International Myeloma Working Group 2010 guidelines, patients diagnosed with MGUS and SMM should not be treated outside of clinical trials. Overall, treatment trials for MGUS patients are complicated, as these individuals are relatively healthy and the majority has a low life-time risk of progression, especially when other causes of death are taken into account. In contrast to MGUS, early treatment strategies for SMM are particularly attractive, as the rate of progression to multiple myeloma is substantially higher. Until recently, potent drugs with reasonable toxicity profiles have not been available for the development of early multiple myeloma treatment strategies. This review discusses how the integration of novel biological markers and clinical monitoring of SMM could facilitate the development of early treatment strategies for high-risk SMM patients in the future.