High Plasma Cell Labeling Index Research Articles

Impact of Novel Agents on Young Patients with t(11;14) Multiple Myeloma

Background: Outcome studies for the unique cohort of young patients with multiple myeloma (MM) are sparse. In general, MM is a heterogenous disease with the genetic signature being one of the major determinants of prognosis. We have recently reported on improvement in overall survival (OS) of young patients with the use of novel agents, but the maximal survival gain has been achieved by integrating autologous stem cell transplant (SCT) to our current approach. Herein, we report on outcomes of patients with MM who were 50 years or younger at diagnosis and stratified by fluorescence in situ hybridization (FISH) results. Our study focuses on t(11;14) myeloma as its prognostic impact remains unclear with the use of novel agents upfront.Methods: Out of 1384 patients with MM, evaluated consecutively at Mayo Clinic, Rochester, MN between 1/1/2000 and 12/31/2011, 290 (21%) were 50 years or younger at diagnosis. Interphase FISH, performed within 100 days of diagnosis of MM, was utilized to stratify patients as high-risk [deletion 17p, t(14;16), t(14;20) or t(4;14)] or standard-risk [normal FISH, trisomies, t(11;14), t(6;14) or monosomy13/deletion 13q]. FISH results were available in 125 young patients that comprise the cohort of interest in the current study. OS from diagnosis was estimated by the Kaplan-Meier method.Results: Median age at diagnosis of MM was 47 years (range: 22 to 50 years) and 58% of the patients were male. At the time of data cut-off (7/31/2014), 45 (36%) patients had died with 90% of all known causes of deaths (n=39) being MM related. FISH abnormalities were noted in 114 (91%) patients. At diagnosis, 46%, 30% and 24% patients were categorized as International Staging System (ISS) stage I, II and III, respectively.The estimated median follow up was 60 months (95% CI: 54-67) and the 5-year OS rate was 69% [median 86 months (95% CI: 76-108)]. Standard (n=100; 80%) and high (n=25; 20%) risk patients had a median OS of 89 months (95% CI: 76-108) and 77.6 months (95% CI: 42-130), respectively (p=0.87). In order to further investigate the similar outcomes between these broad risk-groups with typically diverse disease course, we assessed the outcomes based on the common genetic abnormalities (Table 1) within each of the 2 categories. Presence of t(11;14) (n=37; 29%) was associated with a significantly shorter median OS (76 months) compared to patients with trisomic and normal FISH profile (n=46) (91 months, p=0.01; Figure 1). Patients with t(11;14) also had a significantly shorter median OS compared to those with other standard-risk FISH abnormalities (median OS 96 months, p=0.02). Presence of t(11;14) was not associated with higher plasma cell labeling index (PCLI, p=0.29) or worse ISS stage (p=0.99) compared to patients without t(11;14). OS survival of patients with t(11;14) was similar to those with high risk features (median 76.2 vs. 77.6 months, p=0.32).Of 24 (65%) patients with t(11;14) who underwent SCT, 79% had early SCT (within 12 months from diagnosis). Median OS was 79.4 months (95% CI: 36-108) vs. not reached (NR) (95% CI: 27-NR), respectively (p=0.79) in early versus late SCT. Twenty-one (57%) and 13 (35%) patients with t(11;14) received initial immunomodulatory drugs or bortezomib-based therapies, respectively. Those receiving frontline bortezomib had a higher median OS (76.2 months, 95% CI 76-79) compared to 64.8 months (95% CI 32-108) with other initial agents although it did not reach statistical significance (p=0.78).Conclusion: Presence of t(11;14) is associated with an inferior OS compared to patients with normal FISH, trisomies, or other standard risk abnormalities in young patients with MM. Given, the inherent biases associated with a retrospective study from a referral institution, our findings require external validation. However, our data suggest that our current therapeutic approaches in managing young patients with this unique genetic signature are inadequate. Table 1FISHn(%)Median OS in months (95% CI)t(11;14)37(29)76.2 (53.5-107.7)Trisomies35(28)91.3 (76.4-NR)13/del(13q)11(9)NR (32-NR)Normal11(9)95.5 (45.4-95.6)t(4;14)11(9)NR (40.1-NR)del(17p)/-1710(8)42 (19.2-129.6)t(14;16)4(3)77.6 (42.4-NR)Others6(5)NR (11.5-NR) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Second auto-SCT for treatment of relapsed multiple myeloma

High-dose therapy and auto-SCT remain integral in the initial treatment of multiple myeloma (MM), and are increasingly being applied for management of relapsed disease. We examined the outcomes in 98 patients undergoing salvage auto-SCT (auto-SCT2) for relapsed MM after receiving an initial transplant (auto-SCT1) between 1994 and 2009. The median age at auto-SCT2 was 60 years (range: 35-74). The median time between auto-SCT1 and auto-SCT2 was 46 months (range: 10-130). Treatment-related mortality was seen in 4%. The median PFS from auto-SCT2 was 10.3 (95% confidence interval (CI): 7-14) months and the median OS from auto-SCT2 was 33 months (95% CI: 28-51). In a multivariable analysis, shorter time to progression (TTP) after auto-SCT1, not achieving a CR after auto-SCT2, higher number of treatment regimens before auto-SCT2 and a higher plasma cell labeling index at auto-SCT2 predicted for shorter PFS. However, only a shorter TTP after auto-SCT1 predicted for a shorter OS post auto-SCT2. Hence, auto-SCT2 is an effective and feasible therapeutic option for MM patients relapsing after other treatments, especially in patients who had a TTP of at least 12 months after their auto-SCT1.

English

INTRODUCTION: Secondary PCL (Plasma Cell Leukemia), arising from multiple myeloma is aggressive and rare variant of multiple myeloma. It is known that AL (Amyloid Light Chain) type of Amyloidosis is primary amyloidosis occurring in multiple myeloma. Attempt to report this case of secondary PCL of light chain secretory type with primary amyloidosis. Emphasis given to this report is so as to highlight the helpful prognostic tools in this rare variety. CASE REPORT: 60 year old female presenting with Hepatosplenomegaly, severe anemia, bleeding manifestations and fever. She had pancytopenia with ESR of 170. Peripheral smear showed plenty of plasma cells >20% and bone marrow biopsy showed mature to immature plasma cells, plenty in number. Skull X ray showing multiple punched out lesions. Electrophoresis was normal, abdominal wall fat stained positive for Congo Red and Serum Free Light Chain Assay was positive. Diagnosed as PCL of light chain secretory type. CONCLUSION: PCL itself, high plasma cell labeling index, increased LDH, increased serum β2microglobulin,renal indices like increased serum creatinine, organomegaly, non secretory variety-all carry bad prognostic signs.

Efficacy of thalidomide- or lenalidomide-based therapy in proliferative multiple myeloma

The proliferative activity of neoplastic plasma cells (PCs) is an independent determinant of the clinical course of patients with multiple myeloma (MM). It can be measured by the plasma cell labeling index (PCLI), which denotes the percentage of bone marrow PCs in the S-phase of the cell cycle.1 Typically, MM is a slow-growing tumor with very few PCs synthesizing DNA at a given time. Proliferative myeloma, characterized by a high PCLI (1%), constitutes nearly a third of all MM cases, and has a poorer outcome.1 Although technical difficulties have limited its widespread application, the slide-based PCLI provides valuable insight into the tumor biology, with higher PCLI predictive of an aggressive course.1, 2, 3 There is a direct correlation between the cytogenetic abnormalities and the rate of PC division perhaps because these chromosomal abnormalities impart a distinct proliferative advantage to the myeloma cells.4 Conversely, it can be argued that rapid PC division leads to sufficient genetic instability to cause secondary chromosomal abnormalities, which adversely affect the prognosis of the patients.

Plasma cell labeling index correlates with deletion of 13q14 in multiple myeloma

Multiple myeloma (MM) is characterized by complex genetic and chromosomal abnormalities involving both numerical and structural aberrations, which have clinical prognostic value. The plasma cell labeling index (PCLI) is one of the most important prognostic factors in newly diagnosed MM, and indicates plasma cell proliferative capacity. In this study, we determined the PCLI and the deletion of 13q14, retinoblastoma-1 gene (RB-1), 1p13, and 17p13, 1q21 amplification, and IgH rearrangements in 42 newly diagnosed patients with MM. A high PCLI was observed in 18 patients (42.9%), and the del(13q14) was present in 25 patients (59.5%), del(RB-1) in 23 patients (54.8%), del(17p13) in eight patients (19.1%), amp(1q21) in 23 patients (54.7%), del(1p13) in 17 patients (40.5%), and IgH rearrangements in 28 patients (66.7%). We further detected the IgH translocation partners: t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in 19, 15, and five patients, respectively. The PCLI had a significant correlation with del(13q14) (p = 0.006), but no correlation with other chromosome abnormalities or clinical and laboratory features (p > 0.05). The PCLI was higher among patients with del(13q14), and patients with a high PCLI had a short time to disease progression. In conclusion, PCLI is a powerful and independent prognostic parameter in newly diagnosed MM, and correlates with del(13q14).

Elevated Serum Lactate Dehydrogenase (LDH) Should Be Included Among the Variables Which Define High Risk Multiple myeloma

AbstractAbstract 2969LDH is elevated in approximately 10% of patients with newly-diagnosed, symptomatic, multiple myeloma (MM). In patients treated with conventional chemotherapy, elevated LDH is associated with poor outcome (Dimopoulos et al, Ann Intern Med 1991). In selected patients treated with combinations of novel agents and tandem transplantation, LDH is an independent prognostic factor and is associated with short event free and overall survival even when cytogenetic abnormalities and gene expression signature are considered (Barlogie et al, J Clin Oncol 2010). An analysis from our group has also suggested that LDH improves the prognostic value of the International Scoring System (ISS) for MM (Terpos et al, Eur J Hematol 2010). However, there is limited data about the prognostic importance of elevated LDH in unselected MM patients who have been treated upfront with novel agent-based regimens. To address this issue, we analyzed 180 consecutive, unselected patients from a single center in Athens, Greece, who were treated upfront with novel agent (thalidomide, bortezomib or lenalidomide)-based therapies. Many of these patients had been included in clinical trials; however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also treated with novel agent-based regimens. Thus, these patients are more representative of the general myeloma population. Fifty-one per cent of our patients were older than 70 years of age. LDH was elevated (≥300 IU/L, upper limit of normal 225 IU/L) in 8% patients before initiation of treatment. Elevated LDH was associated with features of advanced disease such as ISS-3 stage (p=0.063) and impaired renal function (p=0.034). The objective response rate in patients with elevated LDH was 47% and in patients without elevated LDH was 79% (p=0.011). The median overall survival for all patients was 54 months. Elevated LDH was associated with poor outcome (median survival 21 months vs. 56 months for patients with LDH <300 IU/L, p=0.007). Other factors which were associated with inferior survival, in the univariate analysis were age >70 years (p<0.001), Hb <10 g/dl (p<0.001), platelet counts <130,000/ml (p<0.001), corrected serum calcium >11.5 g/dl (p=0.012), ISS-3 stage (p<0.001) and renal impairment (p=0.001). In the multivariate analysis, elevated serum LDH was an independent factor and had a major prognostic impact associated with a 5.4-fold increased risk for death (p<0.001). Furthermore, elevated serum LDH was more often associated with early death. We conclude that in unselected MM patients treated upfront with novel agents, serum LDH is a simple, inexpensive and readily available blood test, which identifies a subset of patients with poor outcome. Our data suggest that in future phase 3 trials, LDH should be taken into account for the stratification of patients. Furthermore, elevated baseline serum LDH should be included in the current criteria (i.e. poor risk cytogenetics, high plasma cell labeling index) which are being used to characterize high risk myeloma. Disclosures:No relevant conflicts of interest to declare.

Unraveling Early Mortality In Patients with AL Amyloidosis

AbstractAbstract 4990 Background:Although there have been improvements in 5-year overall survival (OS) rates among patients with AL amyloidosis over the past decades, OS is still poor, and death rates within the first 3–6 months after diagnosis have not changed significantly. This retrospective study was performed to identify risk factors for and causes of death during the first 90 days following diagnosis of AL amyloidosis. Method:From July 2002 to April 2009, 301 patients with a diagnosis of AL amyloidosis who were seen at Mayo Clinic within 30 days of diagnosis were identified from the dysproteinemia database. The 100 who died within 90 days were the focus of our study. The other 201 who were alive beyond 90 days were used as a comparator group. Outside physician offices were contacted to obtain further information pertaining to treatment and cause of death for our study group. Results:Of the 100 patients with early death, median age at diagnosis was 63.7 years (range: 34.7–89.4). 25 patients were diagnosed with concurrent multiple myeloma (MM) based on MM-specific end-organ damage. Overall, the number of patients with 2, 3 and 4 organs (cardiac, renal, nerve or liver) involved with amyloidosis was 37, 15 and 4, respectively. Using the cardiac biomarker staging system, 78% of 46 evaluable patients were stage III at diagnosis followed by 22% stage II and no stage I. Table 1 describes the characteristics of the studied population. Amyloid-related deaths were identified in 61 patients with the most common cause being cardiac arrest or sudden death (33%) followed by end-organ failure (24%). Treatment was started in 50% of patients; 34% received no treatment; and no treatment information was available for the remainder. OS was 54.5 days in patients who received treatment as compared to 7.5 days in those who received no treatment (p<0.0001); outcomes were similar in the group in whom no treatment information was available and those patients who were known to have received treatment. Melphalan with dexamethasone was the most common treatment (21%) and was associated with improved OS compared to other treatments including novel agents (57 vs. 26 days, p=0.003). Outcomes were no different if the patients had received novel therapies, but numbers were small. When compared to patients who lived for more than 90 days from their diagnosis, patients with early mortality had higher median intraventricular septum (IVS) (15 vs. 13 mm, p<0.0001), lower ejection fraction (EF) (50 vs. 64%, p<0.0001), and higher troponin-T (0.125 vs. 0.01 ng/ml, p<0.0001) and NT-proBNP (9020 vs. 1292 pg/ml, p<0.0001). We also found that patients who died within 90 days of their diagnosis had significantly higher plasma cell labeling index (PCLI), uric acid, beta-2 microglobulin, involved free light chain (FLC) and creatinine. Conclusion:This study highlights the characteristics of patients who died within 90 days of diagnosis of AL amyloidosis. The majority of patients died from arrhythmia and organ failure. This implies that other interventions aside from treatment of the underlying plasma cell (PC) disorder will likely be required to change the early outcomes of this disease. Disclosures:Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Autologous Stem Cell Transplantation Provides Additional Cytoreduction Following Induction Therapy in Multiple Myeloma.

Background: High dose therapy (HDT) and stem cell transplant has been shown to improve survival in patients with myeloma and remains the standard of care. However, the reported results of initial HDT in these patients reflect the combined effect of the initial therapy and the HDT. The contribution of HDT on its own is often difficult to analyze in this group of patients with varying degree of response to initial therapy. In this single institution retrospective study, we have analyzed the results of HDT in a group of patients with measurable disease at the time of HDT.Methods: We identified patients from our transplant database, who had measurable disease at the time of initiation of transplant as defined by a serum M protein of ≥ 1.0 g/dL, 24 hour urine M-protein ≥ 200 mg or a bone marrow plasma cell % of ≥ 30. Details regarding the clinical outcome were obtained from the database and from patient clinical records. Chi square test was used for comparison of nominal variables and t-test for continuous variables. Kaplan Meier analysis was used for comparing survival and Cox proportional hazards was employed to identify predictors of progression free and overall survival. Responses were defined by the EBMTR criteria, using the measurements at the time HDT and the lowest measurement obtained. VGPR required a 90% reduction in the serum M component with urine protein < 100 mg/24 hours.Results: A total of 440 patients were studied; 271 (61.5%) of whom had a transplant within one year of their diagnosis. Among the 271 patients, 140 (52%) were in the initial plateau, 99 (36%) failed to achieve a PR to initial therapy and 32 (12%) were in their first relapse. Given the known differences in the outcome between these groups of patients, those receiving an early transplant were analyzed separately. The response rates included CR (24%), VGPR (7%), PR (52%), MR or less (17%) and among the late transplants CR (23%), VGPR (8%), PR (61%) and MR or less (8%). The median progression free survival was 23.6 mos and the overall survival from HDT was 62 mos. In a multivariate analysis, presence of cytogenetic abnormalities (RR: 2.5) and high plasma cell labeling index (≥ 1%) (RR: 2.4) at HDT and failure to achieve a CR or VGPR (RR: 1.7) were prognostic for decreased progression free survival post HDT. In a similar model, only high PCLI (RR: 2.8) and abnormal cytogenetics (RR: 2.5) at HDT predicted for poor overall survival after transplant.Conclusion: This study provides a sense of the contribution of HDT, independent of the initial therapy, by determining responses based on the immediate pre-transplant disease measurements and the best values observed post transplant. In this group of patients with residual measurable disease after the initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a VGPR in another 7%, an outcome associated with better progressin free survival. While measurements at transplant do not correlate strictly with response to initial therapy, the aim of this study was to understand the individual contribution of HDT in these patients. Thus some of the patients who would have been classified as having a partial response to induction and HDT may be classified as non-responders in this analysis. These numbers will provide a historical comparison for trials evaluating novel consolidation therapies for myeloma.

Clinical and Biologic Studies in Smoldering/Indolent Multiple Myeloma (SMM/IMM) Suggest That Therapies That Specifically Inhibit IL-6 Production Are More Effective at Targeting the Proliferative Myeloma Component Than Apoptosis Inducing Agents.

Background: Myeloma remains incurable due to a stem cell/proliferative component that responds poorly to standard treatments. We have shown that aberrant IL-1beta stimulates the generation of paracrine IL-6, a central myeloma growth factor. A Phase II trial was completed using IL-1 receptor antagonist (IL-1Ra/Anakinra), which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with SMM/IMM. SMM/IMM patients are most likely to benefit from anti-cytokine therapy in order to delay/prevent the development of active myeloma.Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of IL-1Ra SQ qd for 6 months unless clinical progression occurred. Non-progressors were allowed to continue on therapy with IL-1Ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1Ra or for evidence of clinical progression; the dose was adjusted based on response/toxicity.Results: To investigate the effects of IL-1Ra and Dex alone and in combination in vitro, we co-cultured IL-1beta transduced +/− myeloma cells with stromal cells +/− dexamethasone, IL-1Ra, or both for 48 hours and quantitated the percent apoptotic cells by flow cytometry and IL-6 production by ELISA. The results showed that: 1) IL-1Ra was superior to Dex at inhibition of IL-6 but caused no myeloma apoptosis; 2) Dex induced apoptosis was inhibited by IL-6 3) Dex and IL-1Ra combined induced maximal IL-6 inhibition and apoptosis of myeloma cells. In the clinical trial, data were available on 47 patients; smoldering (79%) / indolent (21%). All patients received IL-1Ra initially and 20/47 subsequently received IL-1Ra/Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI), a marker of cell proliferation, on IL-1Ra alone which paralleled a decrease in the high sensitivity C-reactive protein (CRP). Interestingly, in one patient treated with Dex alone for 6 months, Dex induced a decrease in the M-protein and IL-1 levels, however, the PCLI and CRP values increased. The IL-1Ra/Dex combination has resulted in stability of disease in the majority of the 47 patients; 28 continue on therapy with a median overall progression-free survival (PFS) of 37.5 months. Four of the 47 pts achieved a minor response (MR) with IL-1Ra alone, and an additional 6 pts achieved a MR/PR after addition of dex. The continuous measure of % reduction in CRP was significantly associated with time to progression (p=0.02). Similarly, those patients who had a >5% decrease in serum M protein also had a longer PFS (p<0.001). Of note, 2 patients with high PCLI values of 6.4 and 3.0, characteristic of poor prognosis, responded with a reduction in the PCLI values and continue on combination therapy for 3 and 1.5 years, respectively with stable disease.Conclusion: Agents such as IL-1Ra that specifically inhibit paracrine IL-6 production are more effective at targeting the proliferative component than apoptosis inducing agents such as Dex; the combination may be especially useful in patients that have an elevated PCLI at presentation.

High Plasma Cell Labeling Index (PCLI) Is an Adverse Prognostic Factor in Bortezomib-Treated Patients with Relapsed Myeloma.

Del(13) is a powerful adverse prognostic factor in patients with myeloma. A small subset analysis from a randomized multi-center study comparing dexamethasone to bortezomib for relapsed myeloma suggested that the outcome of bortezomib-treated patients was not affected by del(13) (Jagannath et al, ASCO 2005). We studied patients with relapsed myeloma treated with bortezomib on whom complete karyotype data were available to determine the effect of del(13) on response rates and survival. To ensure consistency, this analysis was confined to 47 patients (44–85 y; median 62) who received all their therapy at Northwestern and in whom all cytogenetic analyses were performed in a single laboratory. 40 had failed prior thalidomide and 32 had failed prior high-dose therapy. All patients were treated with bortezomib as a single agent in the standard fashion initially. Dexamethasone ± thalidomide were added if there was no response. Progression after initial response or lack of response to bortezomib ± thalidomide ± dexamethasone was classified as treatment failure. Overall response rate (≥50% decline in paraprotien) was 72%. Complete clearance of paraprotein was seen in 32%. The median event-free (EFS) and overall (OS) survival durations from the start of therapy were 227 and 777 days. OS was higher in responders (777 vs 373 days; P=0.015) as was EFS (259 vs 120 days; P=0.0001). As the table shows, del(13) did not affect response rates.Response to bortezomib by del(13) status (P=0.69)Paraprotein responseDel(13) (n=13)No del(13) (n=34)No response5 (38%)8 (24%)50–94% decline3 (23%)10 (29%)95–99% decline2 (15%)4 (12%)100% decline3 (23%)12 (35%)Any response vs no response; P=0.31No variable influenced response significantly in Cox analysis. However, there was a trend (P=0.07) towards lower response rates in patients relapsing after prior transplant. When PCLI (available in 34 patients) was included in the model, there was a trend (P=0.08) towards lower likelihood of 100% responses with del(13). Response to bortezomib and age ≤ 60 were associated with significantly better EFS with/without PCLI in the model. PCLI ≥1% was the only factor associated with poorer OS when included in the model. When PCLI was excluded, response to bortezomib was associated with significantly superior OS. [Display omitted] While OS and EFS did not seem to be influenced by del(13), the curves shown below suggest that differences may become apparent with longer follow-up in a larger number of patients. [Display omitted] Thus, small patient numbers in this study and that of Jagannath et al, and a trend towards a lower likelihood of complete paraprotein clearance with del(13) in our experience suggests that more data are needed before any definitive conclusions can be drawn on the impact of del(13) on bortezomib therapy.

Flow Cytometric Detection of Circulating Myeloma Cells Pretransplant in Patients with Multiple Myeloma: A Simple Risk Stratification System.

Background: The presence of circulating myeloma cells (CMC) detected by flow cytometry at the time of diagnosis of multiple myeloma is associated with a shortened response to therapy and reduced overall survival (OS). We hypothesized that the presence of CMC at the time of stem cell collection prior to high dose therapy (HDT) and autologous stem cell transplantation (ASCT) would identifies a cohort of patients with a high risk of rapid progression.Methods: The Mayo Clinic myeloma transplant database was queried for patients who were mobilized using cyclophosphamide and hematopoietic growth factors. CMC was determined using flow cytometry by gating on a population of CD38 bright and CD45 negative cells. The impact of CMC on OS and time to progression (TTP) and its role in the context of established prognostic parameters was evaluated.Results: Of 246 patients with MM undergoing ASCT, 95 had CMC. Patients with CMC had significantly higher plasma cell labeling index, adverse cytogenetics, B2-M and resistant disease. Complete response (CR) rates post transplant were 32% and 36% for patients with and without CMC (p=0.5034). OS was 33.2 and 58.6 months (p=0.0052) while TTP was 14.1 and 22 months respectively (p=0.0005). [Display omitted] On multivariate analysis, CMC remained an independent prognostic factor in a model that included cytogenetics and disease status at time of transplant (p=0.0314). A prognostic system based on the presence or absence of CMC and karyotype abnormalities was developed. Patients with neither, one or both parameters had a median, OS of 55, 48 and 21.5 months respectively (p<0.0001) while TTP was 22, 15.4 and 6.5 months for the same groups (p<0.0001).Conclusion: The presence of CMC at the time of HDT and ASCT is an independent prognostic factor. The combination of CMC and cytogenetics provides a simple yet powerful scoring system that stratifies patients and guides their management.

Malignant pleural effusion of multiple myeloma: Prognostic factors and outcome

Malignant pleural effusion (MPE) in multiple myeloma (MM) is rare. Approximately 80 cases have been reported. To delineate optimal treatment and prognostic variables in these patients, we reviewed 11 MM patients with MPE. MPE developed at median of 12 months from diagnosis of MM. All the patients had high-risk disease based on complex karyotypic abnormalities including deletions of chromosome-13 (n=9), elevated beta-2 microglobulin (B2M) (n=9), high C-reactive protein (CRP) (n=8), high plasma cell labeling index (n=5) or high LDH (n=5). A significant increase in B2M, LDH, and CRP was observed at the onset of MPE. The initial diagnosis of MPE was based on positive cytology (n=9), pleural fluid cIg/DNA (n=9) or pleural fluid cytogenetics (n=4). Pleural tissue infiltration was found on pleural biopsy and autopsy in one patient each. Systemic chemotherapy comprising dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) (n=7) and pleurodesis (n=7) were effective in resolving MPE but survival was short. High dose chemotherapy with peripheral blood stem cell support for MPE in six patients conferred no clear survival advantage. These patients died at median of four months from onset of MPE. Patients with bone marrow complex karyotypic abnormalities including deletion-13 (n=9) had a shorter (median--18 months) overall survival compared to patients with normal cytogenetics (median--38 months). MPE in patients with MM is often associated with high-risk disease including deletion 13 chromosomal abnormality and heralds a poor prognosis despite aggressive local and systemic treatment.

Gene expression signatures of conventional prognostic factors in multiple myeloma

6606 Background: Recent advances in Multiple Myeloma have led to identification of novel therapeutic targets and new agents highlighting the need for patient specific treatment plans. We have initiated molecular studies of MM plasma cells (PC) to correlate conventional prognostic factors with the genomic signature of MM PCs. Factors with high discriminatory value will allow clinicians to tailor therapy to the patient, decreasing toxicity and improving outcome. Methods: Gene expression profiling was performed on CD138 sorted PCs from 14 pts with newly diagnosed MM using the Affymetrix U133A platform. The data was analyzed using dChip software (V1.3). Results: We have identified differentially expressed genes with biological relevance that correlates with the important prognostic factors; plasma cell labeling index (PCLI), circulating PCs, LDH and β2 microglobulin. High PCLI was associated with upregulation of growth and proliferation related genes (IGFBP-7, WHSC1 [mapped to 4p16 and correlated with t(4;14)], TIMP1 [related with STAT3 phosphorylation] and down regulation of wnt5a, CD79a (MB1, member of Ig superfamily gene), NEDD9 (associated with β1 integrin signaling), BCR1 (B cell receptor signaling) and Lysosomal associated multispanning membrane protein 5 (described in MM progression). Increased number of circulating PCs was associated with modulation of adhesion-related and migration associated genes such as CD86, metastasis associated protein S100A4, galectin-1 (associated with β1 integrin), hsp27, glucosamine-6-sulfatase, NCAM1, and cyclin D1, among others. Similar analyses performed grouping patients according to LDH, β2 microglobulin also revealed differentially expressed genes that may have correlative significance.Conclusions: Identification of differentially expressed genes that correlates with MM-related prognostic factors can help understand the biological basis for these factors. Additionally, identification of non-overlapping discriminatory genes for individual prognostic factors can lead to development of focused arrays that can be used clinically for prognostication. Ongoing studies with additional patients as well as in vitro studies are underway to validate these results. No significant financial relationships to disclose.

Clinical Course of Patients With Relapsed Multiple Myeloma

To study the clinical course of patients with multiple myeloma (MM) that relapses after initial therapy. Patients with MM, seen at the Mayo Clinic in Rochester, Minn, between January 1, 1985, and December 31, 1998, were identified from a prospectively maintained database. Our study population consisted of 578 patients with newly diagnosed MM who were followed up and monitored throughout their clinical course at our institution. The median age of the 578 patients with MM was 65 years (range, 26-92 years); 228 patients (39%) were women. The median follow-up of 71 surviving patients was 55 months (range, 0-202 months). The overall survival (OS) for the 578 patients at 1, 2, and 5 years was 72%, 55%, and 22%, respectively; the median OS from initial therapy was 28.4 months. The median OS of 355 patients who experienced relapse after initial treatment was 17.1 months from initiation of the second therapy, and 84% died within 5 years. The duration of response decreased consistently with each successive regimen. Patients with a high plasma cell labeling index (> or = 1.0%), low platelet count (< 150 x 10(9)/L), high creatinine level (> or = 2.0 mg/dL), and low albumin level (< 3.0 g/dL) had a poorer prognosis. Our study revealed decreasing response duration with increasing number of salvage regimens, probably reflecting acquired drug resistance and an increasing proliferative rate of the myeloma cells. Patients who experienced relapse after initial treatment and received salvage therapy had a median survival of nearly 1.5 years. This must be remembered when making treatment decisions for these patients and must be factored in when assessing the efficacy of new therapies.

A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications.

Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone marrow stromal cells through an interaction between adhesion molecules present on myeloma plasma cells and their respective receptors that are present on bone marrow stromal cells. In addition, control over production of IL-6 may be exerted by other ILs such as IL-1beta and IL-10. Among target cells, the growth of normal and myeloma plasma cells is supported by IL-6, which also induces the differentiation of myeloma plasmablastic cells into mature plasma cells. This last action also is shared by IL-3, IL-4, and, most likely, IL-8. Evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor (sIL-6R), and soluble IL-2 receptor (sIL-2R), together with the activity exerted by IL-3 and IL-4 on some cellular subsets, may constitute an additional element in the differential diagnosis of borderline cases. However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high beta(2) microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity. Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to beta(2) microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.

A high bone marrow plasma cell labeling index in stable plateau–phase multiple myeloma is a marker for early disease progression and death: Presented in abstract form at the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, Louisiana, May 20-23, 2000.

AbstractThe 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.

Effect of complete response on outcome following autologous stem cell transplantation for myeloma.

We studied the effect of complete response (CR) among 126 consecutive patients who underwent stem cell transplantation (SCT) for myeloma. The CR rate with SCT was 33%. Median overall survival (OS) from diagnosis of myeloma was 56 months. OS following SCT was 22 months. Progression-free survival (PFS) was 12 months. OS was not different between patients who achieved CR and those who did not, median survival 25 vs 24 months, P = 0.5. Corresponding median times for PFS were 15 and 11 months, P = 0.2. The plasma cell labeling index (PCLI) was high (> or = 1%) in 36% (high risk group) and was associated with poor OS and PFS (P < 0.001). Achieving CR did not influence OS or PFS in either the high or the low risk group. In contrast, OS and PFS were significantly influenced by high PCLI both in patients who achieved CR and those who did not. OS was poor (< 30 months) in high risk patients regardless of CR status and in low risk patients who did not achieve CR, compared to low risk patients achieving CR (57 months), making them candidates for novel post-transplant treatment options. Outcome following SCT is dependent more on biological variables such as the PCLI than on CR status.

High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH

Multiple myeloma (MM) is a hypoproliferative malignancy yielding informative karyotypes in no more than 30% of newly diagnosed cases. Although cytogenetic and molecular deletion of chromosome 13 is associated with poor prognosis, a MM tumor suppressor gene (TSG) has not been identified. To localize a minimal deleted region of chromosome 13, clonotypic plasma cells from 50 consecutive patients with MM were subjected to interphase fluorescence in situ hybridization (FISH) analysis using a panel of 11 probes spanning the entire long arm of chromosome 13. Whereas chromosome 13 abnormalities were absent in plasma cells from 25 normal donors, 86% of patients with MM demonstrated such aberrations. Heterogeneity, both in deletion frequency and extent, was confirmed by simultaneous FISH with 2 chromosome 13 probes. Deletion hot spots were noted at D13S272 (70%) and D13S31 (64%), 2 unlinked loci at 13q14. Homozygous deletions at these loci occurred in 12% (simultaneously in 8%) of the cases. Molecular deletions were found in all 14 patients with morphologic deletions, in 21 of 24 with uninformative karyotypes, and 8 of 12 patients with karyotype abnormalities lacking chromosome 13 deletion. Homozygous deletion of any marker was noted in 4% with low and in 36% with higher plasma cell labeling index greater than 0.4% (P = .01). The absence of increasing deletion incidence and extent with therapy duration suggests that the observed lesions are not induced by treatment. The high incidence and extent of chromosome 13 deletions require the correlation of specific deletion(s) with poor prognosis. These analyses will provide valuable guidance toward cloning of an MM-TSG.

High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH

AbstractMultiple myeloma (MM) is a hypoproliferative malignancy yielding informative karyotypes in no more than 30% of newly diagnosed cases. Although cytogenetic and molecular deletion of chromosome 13 is associated with poor prognosis, a MM tumor suppressor gene (TSG) has not been identified. To localize a minimal deleted region of chromosome 13, clonotypic plasma cells from 50 consecutive patients with MM were subjected to interphase fluorescence in situ hybridization (FISH) analysis using a panel of 11 probes spanning the entire long arm of chromosome 13. Whereas chromosome 13 abnormalities were absent in plasma cells from 25 normal donors, 86% of patients with MM demonstrated such aberrations. Heterogeneity, both in deletion frequency and extent, was confirmed by simultaneous FISH with 2 chromosome 13 probes. Deletion hot spots were noted at D13S272 (70%) and D13S31 (64%), 2 unlinked loci at 13q14. Homozygous deletions at these loci occurred in 12% (simultaneously in 8%) of the cases. Molecular deletions were found in all 14 patients with morphologic deletions, in 21 of 24 with uninformative karyotypes, and 8 of 12 patients with karyotype abnormalities lacking chromosome 13 deletion. Homozygous deletion of any marker was noted in 4% with low and in 36% with higher plasma cell labeling index greater than 0.4% (P = .01). The absence of increasing deletion incidence and extent with therapy duration suggests that the observed lesions are not induced by treatment. The high incidence and extent of chromosome 13 deletions require the correlation of specific deletion(s) with poor prognosis. These analyses will provide valuable guidance toward cloning of an MM-TSG.

Abnormal cytogenetics predict poor survival after high-dose therapy and autologous blood cell transplantation in multiple myeloma.

We compared the prognostic value of conventional cytogenetic analysis and established factors such as beta2-microglobulin and plasma cell labeling index in 70 patients undergoing autologous blood cell transplantation for multiple myeloma. Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Factors studied were age, sex, beta2-microglobulin, response to prior therapy, plasma cell labeling index, cytogenetic analysis, bone marrow plasma cell percentage, lactate dehydrogenase and C-reactive protein. Twenty-eight of 65 patients (43%) had abnormal marrow cytogenetics. Overall survival measured from transplantation was significantly better in patients with normal cytogenetics than in those with abnormal cytogenetics (median survival, 25 vs 12 months, P = 0.003). Progression-free survival was better, with median times of 12 vs7 months, respectively (P = 0.005); overall survival measured from the time myeloma was first diagnosed was also longer, with median survivals of 62 and 39 months, respectively (P = 0.001). Median plasma cell labeling index was 1.5% in patients with abnormal cytogenetics and 0. 2% in those with normal cytogenetics (P < 0.001). Abnormal bone marrow cytogenetics predict poor survival after blood cell transplantation for myeloma. There is a significant correlation between abnormal cytogenetics and high plasma cell labeling index, suggesting that certain cytogenetic abnormalities may offer a proliferative advantage to myeloma cells.