Cytogenetic Profile Of Multiple Myeloma In The Inner City: Clinical Presentation and Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5355-5355
Author(s):  
Adam Goldrich ◽  
Anuja Kriplani ◽  
Andriane Melanthiou ◽  
Daniel Fein ◽  
Elizabeth Helzner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Inner City ◽  
Survival Data ◽  
Chromosome Banding ◽  
System Level ◽  
Newly Diagnosed ◽  
Average Survival ◽  
Median Serum ◽  
Trisomy 9 ◽  
African Patients

Abstract Multiple Myeloma (MM), a plasma-cell neoplasia characterized by bone marrow (BM) infiltration, monoclonal protein production, and end organ dysfunction, is the most common hematologic neoplasm in blacks. The subclinical syndrome monoclonal gammopathy of undetermined significance (MGUS) precedes MM, and SEER data as well as more recent reports show that blacks have a 2-3-fold higher risk of developing MGUS and MM suggesting a genetic predisposition that causes the marked racial disparity in the incidence of both conditions. In addition, the recent rate of survival improvement observed in Caucasian patients has not been observed in blacks implying that the clinical course and development of resistance are varied between black and Caucasian MM patients. We have recently reported that in our inner-city, largely Caribbean-African patients MM occurs more frequently in women and at a younger age compared to literature. In this report we present cytogenetic information on 146 of these newly-diagnosed MM patients and their survival data. Patients were identified by tumor registries at UH and Kings County Hospital based on tumor histopathology. Data were collected from hospital records of patients treated between 2001-2011 (n=242).Downstate’s inner-city MM patients in Brooklyn, NY are largely Caribbean-African individuals and descendants. Demographics, disease indicators, and vital statistics were collected. In 146 patients, baseline cytogenetics by chromosome banding studies were available. In 63 of these patients baseline FISH used locus-specific probes del13 (13q14), IGH translocation (14q32), del17 and t(11;14)(q13;q32). Patients were treated with standard combination therapies. 146 patients had active, advanced newly-diagnosed MM. Median age=66 (range 36-91), male/female= 0.8, and evidence for the degree of tumor burden included: median % infiltration with CD138-positive cells within BM=50% (range 7%-99%), median serum M protein 3.3 g/dL (range 0.2-9.1). International Staging System level: Stage II: 28%, Stage III: 72%; median serum creatinine=2 mg/dL (range 0.38-14), median serum beta-2 microglobulin= 5.8 mg/dl (range 0.96-20.2). Further, 58% of patients with cytogenetic information had diffuse skeletal involvement with multiple lytic lesions (48%) and fractures (10%). Contrary to expectations from patients with advanced MM, chromosome banding and FISH showed abnormal cytogenetics (AC) in only 26% (n=38). At present, 50% of the patients have expired in both the normal cytogenetics (NC) and AC groups. In the AC group who expired, average time with MM was 2 years (range 0.5-5.6), whereas in the NC patients, average survival was 3.4 years (range, 0.6-5.2). Frequency of trisomies 5 and 9 indicative of hyperdiploidy, were twice as common in patients who are surviving with AC. In these latter patients as well as in surviving patients with NC, average survival time with MM is 4 years (range 0.4-15). In addition, IGH translocation was twice as common in AC patients who expired compared to the NC group. Other AC findings including hypodiploidy, del13, chr1 loss, and trisomies involving chromosomes 1, 7, 11, 19, and 21 were equally frequent in expired and living patients with AC. Using clinically available methods we found IGH translocation, trisomy 5 and trisomy 9 to be prognostically significant in this cohort of 145 inner-city, largely Carribean-African patients. Subtle presentation of cytogenetic abnormalities suggest that genome-wide analyses are needed to asses this patient populations’ MM biology.Cytogenetic Abnormality (frequency)Alive (n)Expired (n)Mean Survival in Years of Expired Patients with AC (Range)del 13 (12.3%)8101.2 (0.1-3.6)IGH translocation (13.0%)7121.7 (0.1-4.1)Chr 1 gain (8.2%)571.1 (0.1-2.4)Chr 1 loss (4.8%)342.3 (0.5-4.1)Hyperdiploidy (19.9%)15141.8 (0.1-5.6)Hypodiploidy (8.9%)761.7 (0.1-4.1)Trisomy 5 (12.3%)1261.7 (0.1-5.6)Trisomy 7 (6.9%)641.2 (0.5-2.3)Trisomy 9 (15.1%)1482.1 (0.1-5.6)Trisomy 11 (12.3%)992.0 (0.1-5.6)Trisomy 15 (11.6%)1161.5 (0.1-5.6)Trisomy 19 (13.7%)1371.7 (0.1-4.1) Disclosures: No relevant conflicts of interest to declare.

Multiple Myeloma in the Afro-Caribbean Inner City Population: Conventional Cytogenetics and Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5710-5710
Author(s):  
Dhvani Thakker ◽  
Charles Yun ◽  
Adam Goldrich ◽  
Helzner Elizabeth ◽  
Daniel Fein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Logistic Regression ◽  
Survival Data ◽  
Poor Prognosis ◽  
Regression Models ◽  
Chromosome Banding ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
Logistic Regression Models ◽  
Adjusted Logistic Regression

Abstract Background: Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States. African Americans have among the highest risks of MM and MGUS with several distinct features compared to existing literature. Furthermore, the prevalence of MM is even higher in the Afro-Caribbean population. Cytogenetic and molecular genetic abnormalities predict outcome in patients with MM. Hyperdiploid MM (H-MM) generally has a better prognosis than nonhyperdiploid MM (NH-MM). In addition, patients with additional chromosome 1 abnormalities, loss of chromosome 13, translocation t(14;16) and t(4;14) tend to have a worse survival while patients with translocations t(11;14) are associated with improved survival. In our patient population, the most common cytogenetic abnormalities and their effect on survival remain unknown. Objective: This study was performed to establish a profile of Afro-Caribbean patients with newly diagnosed Multiple Myeloma in order to gain further insight into unique cytogenetic abnormalities and their effects on survival. Methods: Patients with Multiple Myeloma at Kings County Hospital Center and University Hospital at Brooklyn from 2000-2013 were identified by our tumor registries (n=311). We included all the newly diagnosed patients from 2000-2013 who underwent a bone marrow biopsy and conventional cytogenetic by chromosome banding and FISH (n= 173). Patients who did not have a cytogenetic analysis were excluded. Data was collected at the time of initial presentation to include demographics and cytogenetic abnormalities. Survival data was obtained from Social Security Death Index. Differences in frequency of each cytogenetic abnormality by mortality status were examined using Chi-Square or Fisher’s Exact Tests. Two sets of age-adjusted logistic regression models were used to examine potential cytogenetic correlates of both poor (less than two years) and good (4 years or more) survival. Data analysis was performed using SPSS Advanced Statistics. Results: The median age at the time of diagnosis was 65 (Range 36-90). Chromosome banding and FISH showed abnormal cytogenetics in 46% of our patients (n=79). These patients were also found to have multiple abnormal clones. NH-MM was found in 24% (n=19) and H-MM was found in 39% (n=31) of the 79 patients. The most commonly affected abnormalities were trisomiesof odd-numbered chromosomes; +1 (47%), +3 (19%), +5 (21%), +7 (24%), +9 (47%), +11 (42%), +15 (44%), +17 (9%) and +19 (29%). Thirty five percent of 173 patients have expired (n=60). The median survival in the deceased patients was 6.2 years (Range 0.34-12.9). When we examined all patients who lived greater than four years post-diagnosis (n=152), we found significant abnormalities including +5 (p=0.052), NH-MM (p=0.009) and t(11;14) (p=0.03) (See Table 1). Indicators of poor prognosis including 1q gain (p=0.13), loss of chromosome 13 (p=0.21) and del17 (p=0.08) were not significant. In patients who are living, 19% (n=29) have not yet reached the four-year post-diagnosis survival. Less than ten percent underwent autologous stem cell transplantation. Excludes patients who lived less than 3 months post diagnosis August 5 2014 Table 1: Age-Adjusted Logistic Regression Models Predicting Good Survival (lived 4 years or more post-diagnosis) Chromosome abnormality ( + gain, - loss) Age-Adjusted Odds Ratio (95% CI) N=152 P-value 1+ 0.77 (0.26, 2.29) 0.63 1- 2.91 (0.58, 14.57) 0.19 3+ 1.05 (0.35, 3.17) 0.93 5+ 0.47 (0.22, 1.00) 0.052 7+ 0.39 (0.14, 1.10) 0.08 11+ 0.80 (0.36, 1.75) 0.57 14+ 2.07 (0.62, 6.91) 0.24 15+ 0.74 (0.34,1.60) 0.44 19+ 1.20 (0.46, 3.13) 0.71 X- 0.42 (0.11, 1.50) 0.18 Y- 0.40 (0.13, 1.26) 0.12 Hyperdiploidy 0.88 (0.39, 2.00) 0.88 Nonhyperdiplody 0.24 (0.08, 0.70) 0.009 t(4;14) 0.76 (0.27, 2.15) 0.60 t(11;14) 0.18 (0.04, 0.86) 0.03 Conclusion: In this group of Afro-Caribbean patients, median survival (6 years) was higher than Surveillance, Epidemiology, and End Results (SEER) data and more recent review of literature. Gain of chromosome 5 and t(11;14) are consistent with existing data for good prognosis. However, NH-MM which is usually an indicator of poor prognosis was also highly significant in the four-year post-diagnosis survival. This further supports the notion that prognostic value of cytogenetic analysis in this population requires further exploration. Disclosures No relevant conflicts of interest to declare.

High-Cut Off Dialysis In Multiple Myeloma Patients With Dialysis Dependent Acute Renal Failure Shows Durable Renal Recovery: A Long-Term Follow Up Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3199-3199
Author(s):  
Britta Besemer ◽  
Martina Guthoff ◽  
Lothar Kanz ◽  
Nils Heyne ◽  
Katja Weisel
Keyword(s):  
Survival Data ◽  
Renal Recovery ◽  
Renal Outcome ◽  
Newly Diagnosed ◽  
Cast Nephropathy ◽  
Median Serum ◽  
Myeloma Cast Nephropathy ◽  
Long Term Follow Up

Abstract Acute kidney injury (AKI) either in primary diagnosis or at relapse is one of the frequent complications in multiple myeloma (MM). Myeloma cast nephropathy is induced by mechanical occlusion of the distal tubule by casts consisting of free light chains (FLC) and Tamm Horsfall protein. Impairment of renal function affects prognosis, with particularly poor outcomes in patients requiring hemodialysis with a historically reported median survival of 3-4 months. Introduction of novel therapeutic agents in MM therapy has improved MM response as well as renal outcome mainly due to a short time to initial response and consecutively reduction of the toxic FLC component. Extracorporeal light chain elimination in addition to chemotherapeutic treatment has been discussed controversially so far. We and others introduced the high-cut off (HCO) dialysis which allows effective elimination of FLC in an extended standard dialysis protocol. Recently, we demonstrated the efficacy of combined systemic and extracorporeal therapy regarding time to FLC reduction and renal recovery in a first case series of MM patients with dialysis-dependent AKI (Heyne et al., Ann Haematol 2012). Here, we report long-term renal outcome and overall survival data. 19 MM patients with dialysis dependent AKI were treated between November 2006 and October 2009 with HCO dialysis in parallel to systemic chemotherapy. The applied chemotherapy was chosen by the treating haematologist. All data was calculated by intent-to-treat (ITT) analysis. Progression-free survival (PFS) was analysed from the first day of HCO dialysis to progression or death, whichever occurred first. Overall survival was calculated from the first day of HCO dialysis to death. For statistical analysis GraphPad Prism (GraphPad Software Inc., La Jolla/CA, USA) and R (R Foundation for Statistical Computing, Vienna) biostatistical software was used. The ITT cohort consisted of 19 patients. Median age was 69 (range 50-83) years. 10 patients had newly diagnosed, 9 relapsed or refractory MM. All patients had ISS stage III disease. Median serum FLC concentration at baseline was 8,580 (1 590-66 100) mg/L. Median serum creatinine was 6.8 (4.4-11.6) mg/dL, median eGFR 7.0 (3.3-10.9) mL/min/1.73m². Four (21%) early deaths occurred in the first three months of treatment, 2 patients with newly diagnosed and 2 patients with relapsed disease. Chemotherapy consisted mainly of bortezomib based regimens. As we reported previously, sustained renal recovery was achieved in 73.7% or 14/19 patients with a median time to independence of hemodialysis of 15 (4-64) days. In the long-term follow up analysis with a median follow-up of 62 months, 11/14 dialysis independent patients remained free of dialysis during further disease course. 3 patients again requiring dialysis all showed terminally refractory disease. Median PFS of the IIT population was 7.8 months for primary diagnosed and 4.8 months for relapsed and refractory patients, median OS of the whole population was 9.5 (range 2.8-not reached) months for primary diagnosed patients and 4.8 (range 1.0-19.8) months for the relapsed and refractory group. Combination of systemic treatment and HCO dialysis in patients with myeloma cast nephropathy and dialysis dependent renal failure results in durable renal remissions in the majority of patients. Close monitoring of patients and early treatment intervention can prevent recurrent severe AKI in myeloma relapse. Survival data reflect the critically ill patient population with high tumor burden and high-risk of early death, but also show encouraging long-term myeloma and renal remissions. The benefit of the additional HCO dialysis in addition to conventional chemotherapy is currently investigated in a randomised multicenter trial (EuLITE study). Disclosures: Weisel: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Profile of multiple myeloma in the inner city: Disease presentation and clinical course.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8594-8594
Author(s):  
Adam Goldrich ◽  
Andriane Melanthiou ◽  
Anuja Kriplani ◽  
Elizabeth Helzner ◽  
Arvind Babu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Inner City ◽  
Cord Compression ◽  
Advanced Stage ◽  
Female Ratio ◽  
Hematologic Neoplasm ◽  
Median Serum ◽  
Male Female Ratio ◽  
Seer Data ◽  
Beta 2 Microglobulin

8594 Background: Multiple myeloma (MM) is the most common hematologic neoplasm in blacks in the US. Based on SEER data of all Americans, the disease is more common in men, has a median diagnosis age of 70 and median survival of 3-6 years. The subclinical syndrome MGUS precedes MM, and blacks have a 2-3-fold higher risk of developing MGUS and MM. Further, recent improvements in survival observed for white patients are not observed in blacks. To gain new insight into pathogenesis and to optimize patient care, we characterized our inner city, largely Caribbean-African population in Brooklyn, NY, in terms of disease presentation and course. Methods: MM patients were identified by tumor registries based on histopathology. Data including survival were collected from records of patients diagnosed between 2001-2011 (n=242). Data analysis was performed using SPSS Advanced Statistics. Results: Median age was 64 (range 35-91), male: female ratio was 0.70. The most common presenting pathology was the presence of multiple skeletal lesions with fractures (67% of patients). Spinal cord compression and spinal compression fractures occurred in 33% and 32% of patients, respectively. Renal disease was present in 26%, indicated by serum creatinine >2 mg/dL. Consistent with advanced stage and renal failure, median serum beta-2 microglobulin was 4.25 (range 0.96-82.8). Chromosome banding and FISH was available on 133 patients and showed no cytogenetic abnormalities in 53%; hyperdiploidy (30.4%). Common trisomies included chr 1, 5, 15 and 19. Other abnormalities were del 13 (13%) and chr 14 translocations (11%). Comorbidities include hypertension (65%), diabetes (35%) and obesity (BMI over 30 in 24%). While recent improvements in acquiring health insurance have improved access, less than 10% of patients received HDCT and ASCT. As of October 1, 2012, 36% of all patients are living. Survival analyses are underway. Conclusions: MM presents at an advanced stage and affects younger AA’s in the Downstate community. Strategies for identifying and treating patients with progressive MGUS and at earlier disease stages may enhance survival.

Treatment of Newly Diagnosed, Inner-City Multiple Myeloma Patients with Zoledronate, Dexamethasone, and Low-Dose Thalidomide: A Phase II Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5124-5124
Author(s):  
Uwe Klueppelberg ◽  
Eric L.P. Smith ◽  
Marc J. Braunstein ◽  
David Kahn ◽  
Olcay A. Batuman
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Inner City ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Hiv Patients ◽  
Long Term Treatment

Abstract Background: This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide with dexamethasone and zoledronate (TDZ) in newly diagnosed multiple myeloma (MM) in an inner-city population in which AIDS is the third-leading cause of death. Although the incidence of MM is increased in HIV+ patients, guidelines for treatment of MM in this population are not yet known. The TDZ regimen was intended to be non-myelotoxic and compatible with HAART. Because zoledronate mitigates tumor growth and angiogenesis as well as bone resorption, it was expected to boost the therapeutic effect of thalidomide and dexamethasone. Method:Of 45 consecutive enrollees, 38 (27F/11M; median age = 60.4 years) were evaluable. All patients had skeletal involvement of varying severity; baseline levels of *2-microglobulin (4.3 mg/dL; SE = 0.68) and serum albumin (3.3 mg/dL; S.E.= 0.38) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P < .001), with marginally higher *2-microglobulin levels (P = .076). Seven of the HIV+ patients were on HAART at the time of treatment. The TDZ regimen, given for 24 months or until progression, consisted of: thalidomide, 100 mg daily; dexamethasone, 10–40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Response was stratified by reduction of M protein levels: > 75% (very good partial response [VPR]), > 50–75% (partial response [PR]), or 25–50% (minor response [MR]). Results: Age-adjusted one-year survival was 74.4%, and is identical to NCI SEER data (73.7%). Mean duration of TDZ treatment was 21.4 months (range = 13–24). VPR was achieved in 32% (n = 12), PR in 39% (n = 15), and MR in 18% (n = 7). Three patients had stable disease, and one progressed. Median time to maximum response was 3.0 months. Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was not affected by HIV status, age, or sex. Baseline creatinine clearance both for HIV+ and HIV− patients was within normal limits, and was not adversely affected by monthly treatment with zoledronate (P > .2 for both). Despite prophylactic ASA, thromboembolism occurred in 6 patients (16%), all of whom were successfully treated with full anticoagulation. Other toxicities ≥ Grade 2, were not observed. Skeletal events occurred in 8% of patients; osteonecrosis of the jaw was not encountered. Death occurred in 10 patients, 9 of whom were evaluable; 6 deaths were due to progression or complications of MM, and 4 were from unrelated causes. Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue). Conclusion: Thalidomide administered at less than half the standard sage in combination with zoledronate and dexamethasone provided safe and effective long-term treatment of MM both in HIV− and HIV+ patients. The modest frequency of toxicity and skeletal events under this regimen indicates improvement in quality of life as well as survival.

scholarly journals Outcomes of Patients with Multiple Myeloma Harboring Gain/Amplification 1q in the Era of Modern Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Xiao Hu ◽  
Cherng-Horng Wu ◽  
Janet Cowan ◽  
Raymond L. Comenzo ◽  
Cindy Varga
Keyword(s):  
Multiple Myeloma ◽  
Survival Data ◽  
Research Funding ◽  
The United States ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Rank Tests ◽  
Treatment Regimens ◽  
The Impact ◽  
Log Rank Tests

Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States. Fluorescence in-situ hybridization (FISH) is a popular tool to detect cytogenetic alterations which in turn, can contribute to the risk stratification of patients with MM. Gain or amplification of CKS1B gene at chromosome 1q21 region (gain 1q) is detected in 35-40% of newly diagnosed MM cases, and has been reported to be associated with inferior prognostic outcomes. It also frequently occurs with the deletion of CDKN2C at chromosome 1p32.3 (del 1p). There is a distinct lack of data on patients harboring this cytogenetic alteration in the era of novel agents. We sought to look at outcomes of this patient population at a single institution over the last 5 years. Methods: This retrospective study included all patients with MM as defined by the International Myeloma Working Group (IMWG) with available FISH studies identifying gain 1q between 01/01/2015 to 04/30/2020 at Tufts Medical Center. The study was approved by the Institutional Review Board. Baseline demography, disease characteristics, and treatment history were extracted from the electronic medical records. With death as primary event, overall survival (OS) was defined as the survival time from the discovery of gain 1q to death. Progression free survival (PFS) was defined as the time from discovery of gain 1q to first progression/relapse or death, whichever occurred first. Kaplan-Meier method was used to estimate survival data. Differences in survival between two groups were analyzed by log-rank tests. Multivariable cox regression adjusting for baseline characteristics and significant concurrent cytogenetic alterations were performed to explore the impact of treatment regimens on survival. Results: Of the forty-nine subjects included in this study, the age range was 39 to 85 years; 31 patients (63.3%) were over the age of 65 years, and 28 (57.1%) were male. Twenty-eight (57.1%) subjects with gain 1q were newly diagnosed while the remaining 21 (42.9%) were identified at relapse. Gain 1q was present in more than 20% of clonal cells in 73.5% of subjects and 29.6% had del 1p as well. Patients with gain 1q were more likely to have deletion 13q (65.3%) and hyperdiploidy (61.2%). Regarding treatment, 75.7% of patients received bortezomib, 70.3% received lenalidomide, 38.9% underwent autologous stem cell transplant (ASCT) and 64.9% received daratumumab. At the time of analysis, 41 patients were still alive. For the entire cohort, the estimated median OS was not reached (NR) (95% confidence interval [CI], 24.1-NR), and the estimated median PFS was 15.27 months (95% CI, 4.77-NR). In log-rank tests, presence of extra medullary disease was associated with shorter PFS (4.8 vs 24.1 months, P=0.003), while IGH abnormalities including complex IGH rearrangements or losses were associated with longer PFS (NR vs 8.2 months, P=0.046). Lenalidomide-based treatment was associated with prolonged OS (NR vs 17.2 months, P=0.048). Bortezomib-based therapy and upfront ASCT were associated with improved PFS (15.3 vs 4.7 months, P=0.036; NR vs 4.8 months, P =0.019 respectively). Further multivariate analyses adjusting for age, number of CKS1B copies, International Staging System stage, baseline creatinine, clone size, del 1p, lactate dehydrogenase, extra medullary disease, and IGH abnormalities revealed that administration of daratumumab after the discovery of gain 1q was associated with superior OS (Hazard Ratio [HR]=0.023x10^-2, 95% CI [0.002x10^-4, 0.299], P =0.022) compared with those not receiving this agent; both the use of bortezomib (HR=0.210, 95% CI [0.064, 0.687], P =0.010) and daratumumab (HR=0.126, 95% CI [0.015, 1.036], P =0.054) were associated with prolonged PFS. The use of lenalidomide or upfront ASCT lost prognostic benefit after adjusting for additional variables in multivariate models. Conclusions: The outcomes of MM patients with gain 1q were evaluated according to clinical characteristics, concurrent chromosomal alterations and treatment regimens. In our small cohort, daratumumab and daratumumab-bortezomib combination regimens were found to have a favorable impact on survival. Future prospective clinical trials with larger sample sizes are warranted to confirm the results and further improve the outcomes of MM patients with this cytogenetic alteration. Disclosures Comenzo: Amgen: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Unum: Consultancy; Caleum: Consultancy; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding.

Treatment of Newly Diagnosed, Inner-City Multiple Myeloma Patients with Low-Dose Thalidomide in Combination with Dexamethasone and Zoledronate: A Phase II Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5180-5180 ◽  
Author(s):  
Uwe Klueppelberg ◽  
Iuliana Shapira ◽  
Eric Smith ◽  
Marc Braunstein ◽  
David Kahn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Inner City ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Therapeutic Effects ◽  
Newly Diagnosed ◽  
Hiv Patients ◽  
Β2 Microglobulin

Abstract Background: Although the incidence of multiple myeloma (MM) is increased in HIV+ patients, optimal treatment of MM in the HIV setting remains unknown. This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide in combination with dexamethasone and zoledronate (TDZ) in newly diagnosed MM in an inner-city population, in which the HIV infection rate is high. The TDZ regimen was thus intended to be non-myelotoxic and compatible with HAART. Because it mitigates tumor growth and angiogenesis as well as bone resorption, zoledronate was expected to boost the therapeutic effects of thalidomide and dexamethasone. Methods: Of 45 consecutive enrollees, 38 (22F/16M; median age = 61 years) were evaluable. All patients had bone disease, and baseline levels of β2-microglobulin (4.9 mg/dL; SE = 0.76) and serum albumin (3.3 mg/dL; SE = 0.11) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P <.001) and had higher β2-microglobulin levels (P =.003), and 6 were receiving HAART. The TDZ regimen consisted of thalidomide, 100 mg daily; dexamethasone, 10–40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Patients were treated for 24 months or until disease progression. Response was stratified by reduction of M protein levels: > 90% (near-complete response [N-CR]), > 50–90% (partial response [PR]), or 25–50% (minor response [MR]). Results: Mean duration of TDZ treatment was 18 months (range = 3–24). Age-adjusted one-year survival was 74.4%, and was identical to SEER data (73.7%). N-CR was achieved in 30% (n = 11, [7 HIV−/4 HIV+]) and PR in 68% (n = 26, [22 HIV−/3 HIV+] of evaluable patients. One patient did not respond. Median time to maximum response was 4.5 months in HIV− patients and 2.5 months in HIV+ patients (P <.05). Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was not affected by HIV status, age, or sex. Baseline creatinine clearance both for HIV+ and HIV− patients was within normal limits, and was unaffected by TDZ. Even with prophylactic ASA, thromboembolism occurred in 6 patients (13%), necessitating additional anticoagulation with warfarin. No other significant toxicity was observed. Of the 10 patients who died, 9 were HIV− and 1 was HIV+; deaths were due to progression of MM (n = 3), complications of MM (n = 3), and causes unrelated to MM (n = 4). Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue). Conclusions: Thalidomide administered at less than half the standard dosage and in combination with zoledronate and dexamethasone is a safe and effective treatment in the long-term management of MM both in HIV− and HIV+ patients. The potential synergy of thalidomide and zoledronate in the treatment of MM should be evaluated in a larger randomized study. In addition, the faster response to TDZ in HIV+ MM patients on HAART suggests a cooperative interaction between the two regimens that should be further evaluated.

First-Line Treatment of Multiple Myeloma with a Combination of Thalidomide, Dexamethasone, and Zoledronate (TDZ) in an Inner-City Population with High HIV Prevalence.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4932-4932
Author(s):  
Uwe Klueppelberg ◽  
Eric Smith ◽  
Laurie Chen ◽  
Chona M. Aloba ◽  
Iuliana Shapira ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hiv Infection ◽  
Inner City ◽  
Antiretroviral Treatment ◽  
M Protein ◽  
Newly Diagnosed ◽  
Hiv Status ◽  
Hiv Patients ◽  
Β2 Microglobulin

Abstract Background: The combination of thalidomide and dexamethasone is a rescue regimen for multiple myeloma (MM) in relapse, and for pretransplant in newly diagnosed patients. The bisphosphonate zoledronate mitigates bone resorption and possibly tumor growth and angiogenesis. The long-term utility of this combination in a newly diagnosed inner-city MM population with high prevalence of HIV-infection is addressed in this phase II trial. MM is reported with increased frequency in patients with HIV infection, and optimal treatment of MM in these patients is unknown. Methods: Of 30 consecutive enrollees, 22 (16F/6M) were evaluable. Mean age was 61 years (range = 43–82); all had skeletal lesions, and 27% (n = 6) were HIV+ (mean age = 47, range 46–50, all female). Patients received thalidomide 100 mg QD, dexamethasone 10–40 mg PO on Days 1–4, 9–12, and 17–20 monthly for six months, then on Days 1–4 monthly; and zoledronate 4 mg IV monthly, until progression or relapse. Baseline β2-microglobulin indicated high risk for all patients (mean = 6.2 μg/ml, SD = 3.8). At enrollment, 4 patients had AIDS, and 3 were on HAART. Results: Overall response rate (> 50% decrease in M protein) was 72% (n = 13), and 83% (n = 5) in HIV+ patients. In 27% (n = 6), M protein levels were < 0.3 g/dL, including 3 HIV+ patients on HAART. In 23% (n = 5), M protein was reduced by < 50%. Median time to response was 2 months, and mean time on TDZ was 11 months. TDZ treatment decreased serum β2-microglobulin (P <.001). Two patients relapsed, and one patient with HIV and concomitant plasmacytoma did not respond. All three eventually died. Response to treatment was unaffected by HIV status or antiretroviral treatment. Side effects of TDZ were reversible by anticoagulant therapy or dexamethasone reduction. Conclusions: TDZ had significant activity against newly diagnosed MM, suggesting that zoledronate may facilitate response with lower doses of thalidomide. HIV status did not affect response, indicating that this regimen is compatible with concomitant antiretroviral treatment and is equally effective in HIV+ patients. These findings underscore the potential effectiveness of this combination of anti-myeloma agents as a long-term alternative, particularly in patients for whom transplant therapy is not feasible.

Thalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5185-5185
Author(s):  
Johnny McHugh ◽  
Colm Keane ◽  
Brian W. Otridge ◽  
Patrick Thornton ◽  
Peter O’Gorman
Keyword(s):  
Multiple Myeloma ◽  
Dose Group ◽  
Thromboembolic Event ◽  
Venous Thromboembolic Event ◽  
Newly Diagnosed ◽  
Bence Jones Protein ◽  
Cell Percentage ◽  
Median Serum ◽  
Venous Thromboembolic ◽  
Bone Marrow Plasma

Abstract PURPOSE: Thalidomide and dexamethasone has been shown to have excellent antimyeloma activity in both relapsed and newly diagnosed patients. This combination offers a potential oral, less toxic alternative to standard regimens. This retrospective study evaluates the activity of the combination of thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. METHODS: Thirty-two patients with newly diagnosed multiple myeloma were treated with thalidomide and dexamethasone. The median age of the patients was 69yrs (range 46 to 83). The median serum paraprotein level was 38g/l (range 2 to 76g/l). The median bone marrow plasma cell percentage was 50% (range 10% to 99%) The first sixteen patients were commenced on thalidomide at 200mg od with the dose increased by 200mg every two weeks if tolerated to a maximum of 800mg od. The most recent sixteen patients were commenced on thalidomide at 100mg od with the dose increased to a maximum of 200mg if tolerated. All patients received dexamethasone 10mg qds 4-days-on/4-days-off for the first four weeks and for a four day pulse every four weeks subsequently. RESULTS: Twenty-two of the thirty-two patients (69%) showed a greater than 50% reduction in serum paraprotein and/or urinary Bence Jones protein (BJP) from baseline. From the lower thalidomide dose group thirteen out of sixteen patients(81%) showed a greater than 50% reduction in serum paraprotein and/or urinary BJP from baseline compared with nine out of sixteen (56%) in the higher thalidomide dose group. Thirteen patients (40%) showed a reduction in serum paraprotein and/or urinary BJP of greater than 90%, eight from the lower thalidomide dose group and five from the higher thalidomide dose group. Six of the patients failed to complete one month of treatment due to toxicities. They were all from the higher thalidomide dose group. Toxicities included drowsiness (eleven patients), constipation (six patients), rash (four patients) and peripheral neuropathy (four patients). None of the patients have suffered a venous thromboembolic event. Fewer toxicities were noted in the lower dose thalidomide group. CONCLUSION: The combination of thalidomide and dexamethasone is safe and effective in the treatment of newly diagnosed multiple myeloma. There is less toxicity and no loss of efficacy with lower doses of thalidomide.

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