Clinical Outcomes of Newly Diagnosed Multiple Myeloma Patients with Elevated Lactate Dehydrogenase Who Underwent Autologous Hematopoietic Stem Cell Transplantation

Abstract Background Multiple Myeloma (MM) is a clinically heterogeneous disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated with drug resistance and shorter survival. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12) which includes over 1000 newly-diagnosed MM (NDMM) patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing, we identified patients with baseline LDH values. High LDH was defined as LDH greater than the upper limit of normal, (>4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. We sought to determine if there is enrichment of high and standard risk cytogenetic changes when stratified by LDH. Results We identified 871 patients with NDMM who had baseline LDH values. 143 patients had high LDH and 728 patients had a normal baseline LDH. Consistent with prior reports, high LDH was associated with shortened survival, 660 days vs 795 days (p=0.02852) in patients with normal LDH. 385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019). In order to understand this difference, we examined baseline characteristics. Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet therapy (5/10 - lenalidomide, bortezomib, dexamethasone), 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days. Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. 107/213 (50%) received lenalidomide alone and 19/213 (6%) received bortezomib alone. Median duration of maintenance 266 days. There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (hypergeometric test, p=0.009). We used hypergeometric tests to assess for enrichment of high and standard risk cytogenetic changes. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset where there were no statistically significant difference in the presence of t(4;14) (p=0.16) and t(14;16) (p=0.21). There was no difference in good risk hyperdiploid structural changes between the 2 groups. Conclusion Elevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. Among patients who underwent ASCT, those with high LDH have inferior survival, possibly driven by the presence of del(17p13). Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Blood ◽

10.1182/blood.v128.22.1141.1141 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1141-1141 ◽

Cited By ~ 6

Author(s):

Ruth Wester ◽

Bronno van der Holt ◽

Emelie Asselbergs ◽

Mark van Duin ◽

Sonja Zweegman ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Induction Therapy ◽

Research Funding ◽

Fixed Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Significant Difference ◽

Standard Risk

Abstract Introduction A phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplant-eligible patients with multiple myeloma (MM). We report the results of 4 dose levels. Methods In this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m2 in cohort 2, to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m2) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg). The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results All 111 patients with a median follow-up of 55, 42, 35 and 28 months, in cohorts 1 to 4, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively. Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4). Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, ≥ VGPR in 66% of patients, ≥ PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%. Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4;14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%. PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) respectively, and 91% (95% CI, 83% to 95%) in all patients. Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)). Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m2), hypertension (n=2) and chest pain (n=1 at 45mg/m2). Conclusion Carfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m2. Disclosures Zweegman: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kersten:Celgene: Research Funding; Amgen: Honoraria. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

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Risk Stratified Tandem Vs Single Autologous Stem Cell Transplantation for Multiple Myeloma Yields Equivalent Survival

Blood ◽

10.1182/blood-2020-136800 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Kevin Sing ◽

Roy Sabo ◽

James O'Bryan ◽

Matthew Risendal ◽

Catherine H Roberts ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Induction Therapy ◽

Standard Of Care ◽

High Dose ◽

Newly Diagnosed ◽

Significant Difference ◽

Study Population ◽

High Dose Melphalan ◽

Standard Risk

The standard of care for patients with newly diagnosed multiple myeloma who are transplant eligible is induction therapy followed by conditioning with high dose melphalan and autologous hematopoietic cell transplant (HCT). While the value of a single HCT (S-HCT) is established in standard-risk myeloma (SRM), there is controversy about whether tandem transplantation would improve outcomes such as progression-free survival (PFS) or overall survival (OS) in high-risk myeloma (HRM) patients. In this IRB approved retrospective study, the records of 343 multiple myeloma patients, who were referred by community oncologists and underwent HCT at Virginia Commonwealth University from 2008 to 2015, were reviewed. Patients were classified into different disease risk groups and OS and PFS determined. HRM was defined as including at least one of the following prognostic factors at diagnosis: t(4;14), t(14;16), t(14;20), del17p13, or gain of 1q by FISH; del 13 or aneuploidy by karyotyping; and ISS stage 3; patients without these features and with standard risk attributes were classified as SRM, while any patients with missing attribute information were classified as having undetermined risk myeloma (URM). In the study population, there were 135 SRM, 100 HRM, and 104 URM patients. Median age of the entire cohort was 60 years (76-34). The patients underwent hematopoietic cell mobilization and collection with filgrastim ± plerixafor and were conditioned with high-dose Melphalan (140-200 mg/m2). When possible, patients with SRM underwent single HCT (S-HCT) and those with HRM, tandem HCT (T-HCT) based on risk classification, response to prior therapy, insurance mandate and patient/physician preference. In those undergoing T-HCT, the median time to second HCT was 141 days. Evaluating the entire study population, and comparing patients who underwent a T-HCT (median follow up 82 mo.) vs. a S-HCT (85 mo.), there was no significant difference in OS (adjusted HR 1.1, 95% CI: 0.7-1.8; Cox proportional hazard model, adjusted for age, gender and risk group) (Figure 1) and PFS (HR 0.9, 95% CI: 0.6-1.2) between these two treatment groups. Of the 135 SRM patients, 20 underwent T-HCT; there was no significant difference in OS (HR = 1.2, 95% CI 0.5-2.9) and PFS (HR = 0.9, 95% CI = 0.5-1.7) in these patients compared to those undergoing S-SCT. Of the 100 HRM patients, 46 underwent T-HCT (P <0.01 c/w SRM & URM for T-HCT assignment). Again, there was no significant difference observed in OS (HR = 1.3, 95% CI = 0.7 - 2.5) (Figure 2) and PFS (HR = 1.0, 95% CI = 0.6 - 1.8) in the T-HCT recipients as compared to S-SCT amongst the HRM patients. Similar outcomes were observed in the URM patients. There were no differences observed between S-HCT and T-HCT outcomes in patients with deletion of chromosome 17p or in those with ISS stage 3 disease in OS (HR = 1.7, 95% CI = 0.8 - 3.8) and PFS (HR = 1.0, 95% CI: 0.5, 1.9). Overall, HRM patients had a trend for worse, albeit not significantly different, OS (HR 1.4, 95% CI: 0.9-2.2), as well as PFS (HR 1.1, 95% CI 0.7-1.6) compared to SRM; URM demonstrated a similar trend vis a vis SRM. This retrospective review of survival in SRM and HRM transplanted at a single center demonstrates that in the era of induction and maintenance therapy with novel agents, tandem transplantation does not improve OS or PFS in either SRM or HRM patients compared to a single transplant. Standard of care for newly diagnosed multiple myeloma patients who are transplant eligible should remain induction therapy with novel agents followed by single autologous HCT and maintenance therapy. Disclosures No relevant conflicts of interest to declare.

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Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Induction and Consolidation Therapy Before and After Double Autologous Transplantation In Newly Diagnosed Multiple Myeloma: Results From a Randomized Phase 3 Study

Blood ◽

10.1182/blood.v116.21.42.42 ◽

2010 ◽

Vol 116 (21) ◽

pp. 42-42 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Giulia Perrone ◽

Silvia Buttignol ◽

Elisabetta Calabrese ◽

Monica Galli ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Board Of Directors ◽

Induction Therapy ◽

Autologous Transplantation ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Significant Difference

Abstract Abstract 42 We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p<0.0001), double autotransplantation (54% vs 42%, p=0.008) and consolidation therapy (60% vs 44%, p=0.001). Best confirmed overall CR/nCR rate was 71% in the VTD arm compared with 52% in the TD arm (p<0.0001); the corresponding values for VGPR or better were 89% vs 72%, respectively (p<0.0001). To evaluate the role of consolidation therapy we performed a per-protocol analysis of 323 patients, 161 treated with VTD and 162 with TD. Overall, upgraded responses with VTD and TD as consolidation therapy were observed in 55% vs 37% of patients, respectively (p=0.01; OR:1.15-3.77). Furthermore, the probability to improve responses from less than CR before consolidation to CR after consolidation was 28% with VTD vs 15% with TD (p=0.02; OR:1.07-4.57) (p=0.003 using the Mc Nemar's test). Post-consolidation molecular detection of minimal residual disease was the objective of a substudy; detailed results are reported in a separate abstract. Briefly, both qualitative and quantitative analyses confirmed the statistically significant superiority of VTD over TD in effecting higher rates of molecular remissions and reducing the burden of residual myeloma cells after ASCT. Any grade 3–4 non-hematologic adverse events were 10% with VTD (peripheral neuropathy: 1.3%, skin rash: 0.6%) vs 12% with TD. With a median follow-up of 31 months, median PFS was 42 months in the TD arm and was not yet reached in the VTD arm (44-month projected rate: 61%) (HR: 0.62 [CI: 0.45–0.87], p=0.006). Superior PFS in the VTD vs TD arm was retained across patient subgroups with poor prognosis, including those with t(4;14) and/or del(17p). Randomization to VTD overcome the adverse influence of t(4;14) on PFS (40-month projected rates: 69% vs 67% according to the presence or absence of this abnormality, respectively; p=0.6). By the opposite, in the TD arm corresponding median PFS values were 24.5 vs 41.5 months, respectively (p=0.01). The small numbers of patients with del(17p) in both arms of the study precluded a statistical comparison with del(17p)-negative group. In a multivariate analysis, variables favorably influencing PFS were beta2-m lower than 3.5 mg/L (HR:0.47; p=0.000), absence of t(4;14) and/or del(17p) (HR:0.52; p=0.000), randomization to VTD arm (HR:0.57; p=0.002), attainment of at least VGPR (HR:0.50; p=0.009) and CR (HR:0.8; p=0.01). No statistically significant difference between the overall treatment protocols was seen in terms of OS, although curves seemed to initially diverge after 40 months (44-month projected rates: 84% vs 74% for VTD and TD arms, respectively). A multivariate analysis showed the independent role of absence of t(4;14) and/or del(17p) (HR:0.42; p=0.003), ISS stage1-2 (HR:0.49; p=0.02) and randomization to VTD (HR:0.53; p=0.04) in prolonging OS. When time-dependent CR entered the model, absence of t(4;14) and/or del(17p) and less advanced ISS stage retained their positive prognostic value; attainment of CR (strictly related to VTD randomization) was an additional favorable variable. In conclusion, in comparison with the TD arm of the study, 1) VTD induction emerges as a new standard of care for maximizing the degree and speedy of tumor reduction in preparation for ASCT; 2) VTD consolidation effected significantly higher rates of upgraded responses, including CR, and of molecular remissions; 3) double ASCT incorporating VTD as induction and consolidation therapy resulted in significantly longer PFS, a benefit confirmed in a multivariate regression analysis and maintained in the subgroup of patients with adverse cytogenetic abnormalities. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

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Bortezomib and Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity.

Blood ◽

10.1182/blood.v108.11.3528.3528 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3528-3528 ◽

Cited By ~ 11

Author(s):

Ivan Borrello ◽

Anna Ferguson ◽

Carol Ann Huff ◽

Shirley George ◽

Barbara Biedryzcki ◽

...

Keyword(s):

Multiple Myeloma ◽

Performance Status ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Best Response ◽

Similar Disease ◽

Skin Biopsies ◽

Grade 3 ◽

Deep Vein ◽

Thalidomide Treatment

Abstract Introduction: As single agents, Bortezomib (V) and thalidomide (T) have activity in less than 50% of newly diagnosed myeloma (MM) patients whereas combinations with dexamethasone (D) with T (TD) and V (VD) demonstrated response rates of 63% and 85%, respectively. We sought to examine the anti-myeloma activity of VT, a steroid-free regimen. Considering the neurotoxicity of both agents, we examined the baseline neuropathy and progression of neurotoxicity post-VT. Methods: Eligible patients had untreated Salmon-Durie Stage II/III MM and an ECOG performance status ≤2. V was given 1.3mg/m2 i.v. on days 1, 4, 8, 11 every 21 days. T was started at 50mg daily and increased weekly to 150mg. Patients were treated for a minimum of 4 (evaluable), but to a maximum of 8 cycles. The neurologic evaluation utilized the reduced Total Neuropathy Score (rTNS), a validated scoring system combining symptoms, signs and nerve conduction studies. The rTNS was measured at baseline and after every 2 cycles. rTNS scores range between 0 to 32. Results: 30 patients have been enrolled and 27 are evaluable for response. Median age is 59 (37–83), b2-microglobulin 3.3 (1.2–36.9), and albumin 3.6 (2.3–5.2). The mean dose of V was 1.11mg/m2 and of T 110 mg/d. A dose reduction for ≥1 agent was required in all patients. Treatment was discontinued in 5 patients due to neurotoxicity, and 1 due to disease progression. A ≥ 50% reduction in M-spikes was observed in 82% of patients with 31% achieving undetectable levels. Median time to best response was 5 cycles (range 2–8). Clinical evidence of baseline peripheral neuropathy (PN) was noted in 15%, whereas 67% had abnormal baseline skin biopsies. By cycle 5 all patients developed PN: rTNS 2–8, (grade 1) 50%; rTNS 9–16 (grade 2) 31%; rTNS 17–24 (grade 3) 15%; and rTNS 25–32 (grade 4) 4%. There was no correlation between severity of PN and the cumulative V/T doses. Neuropathic symptoms improved with T/V dose reductions. Additional common adverse events (≥ grade 2) included fatigue 57%, constipation 52%, generalized pain 44%, and leg cramps 23%. Although the incidence of thromboembolic events with steroid-containing regimens ranges between 15–20%, no deep vein thromboses occurred in this study. Conclusions: The VT combination achieved an 82% response rate in previously untreated multiple myeloma patients. No DVTs occurred with this steroid-free combination. This study established the baseline PN in newly diagnosed, untreated myeloma patients and demonstrated progression of neuropathy post-VT therapy. Future studies utilizing neuropathic preventive agents, lower doses of VT, or V in combination with other agents may yield similar disease responses with reduced neuropathic toxicities.

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Thalidomide-Interferon Vs. Interferon Maintenance Therapy After Thal-Dex Vs. MP Induction Therapy in Elderly Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2891.2891 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2891-2891

Author(s):

Heinz Ludwig ◽

Zdenek Adam ◽

Elena Tóthová ◽

Roman Hajek ◽

Boris Labar ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Maintenance Therapy ◽

Induction Therapy ◽

Maintenance Treatment ◽

Rank Test ◽

Logrank Test ◽

Log Rank Test ◽

Significant Difference ◽

Standard Risk

Abstract Abstract 2891 Poster Board II-867 Thalidomide maintenance therapy after completion of induction therapy plus ASCT and also after conventional therapy yielded conflicting results with some trials showing improvement in overall survival and others not. This study evaluates the efficacy of Thalidomide plus Interferon a2b (Thal-IFN) in comparison to interferon a2b (IFN) as maintenance therapy in elderly pts with multiple myeloma. For induction therapy, 289 pts had been randomized to either Thalidomide-Dexamethasone or to Melphalan-Prednisolone; results of this part of the study had been reported previously (BLOOD, 113, 3435-3442, 2009). 137 pts who had completed 9 cycles of induction therapy and had achieved stable disease or better were eligible for maintenance treatment, and 128 (median age 72 years, range 54 - 86 years) had finally been randomized to either Thal (starting dose: 200mg/day) in combination with IFN-a2b (Schering-Plough, 3 Mega U, TIW) or IFN a2b (IFN) at the same dose/schedule only. All pts were scheduled for zoledronate 4mg, q 4 weeks. Median follow up from randomization to maintenance: 35 mos. Median duration of maintenance therapy: 13.2 mos and 8.3 mos for pts randomized to Thal-IFN or to IFN, respectively (logrank test p=0.20). Maintenance therapy with Thal-IFN resulted in an improvement in the depth of response from PR to VGPR or CR in 5 (8%) and with IFN in 2 (3%) pts, respectively. Progression-free survival (PFS) was significantly longer in the Thal-IFN (27.7 mos) compared to the IFN only maintenance group (13.2 mos), (HR, 0.55; 95% 95% CI, 0.36-0.86; log-rank test, p=0.0068). Analysis of PFS by either Thal-Dex or MP induction therapy showed a significantly shorter PFS in pts started on Thal-Dex and subsequently randomized to IFN maintenance only (7.8 mos, log-rank test, p=0.037). PFS was 27.7 mos in pts started on Thal-Dex followed by Thal-IFN, 20.2 mos in those with MP induction therapy followed by IFN, and 27.6 mos in pts with Thal-IFN maintenance after MP induction therapy. Overall survival (OS) was similar in both groups (Thal-IFN 52.6 mos and IFN 51.4 mos, HR: 0.93, 95% CI: 0.53-1.66, log-rank test; p=0.81). OS by induction therapy did not vary significantly between the four treatment groups (logrank test, p=0.99). No significant difference in OS was seen between pts younger than 75 years and those aged 75 years or older (logrank test, p=0.39). Survival after progression of disease tended to be longer in pts who received IFN maintenance therapy only compared to those started on Thal-IFN (HR: 1.75, 95% CI, 0.97 – 3.14, logrank test: 0.056), while OS was similar between both groups when analyzed from termination of maintenance therapy (HR: 1.20, 95% CI, 0.65 – 2.20, log rang test 0.57). Baseline scores of the EORTC QLQ C30 items general health (Thal-IFN, mean 56; IFN, mean 59) and overall quality of life (Thal-IFN, mean 58; IFN, mean 60) were markedly below the score obtained in an healthy population (mean 75.3 and 73.3 respectively), but did neither differ at baseline between both groups nor did they vary significantly during the course of the maintenance (statistics will be provided). Cytogenetic data were available in 66 pts. PFS tended to be longer in pts with adverse FISH findings [t (4; 14), t (14; 20) Del 17p and abnormalities of 1q21] compared to the standard risk group, but differences were not significant (median: 31.5 vs. 21.6 mos, HR: 1.69, 95% CI, 0.13 – 3.07, log-rank test 0.084). The median of OS was 72.3 mos in those with standard risk and 39.6 mos in those with high risk features (HR: 1.94, 95% CI 0.91-4.13, log rank test: 0.082). In multivariate analysis (Cox model) only Thal-IFN maintenance therapy was shown to correlate significantly with PFS (HR: 0.61, 95% CI: 0.39-0.89, p=0.04) while for poor performance status, low hemoglobin, and low albumin a statistically non-significant correlation with survival was noted. Hematologic toxicity was similar between both groups. Pts on Thal-IFN maintenance experienced significantly more neuropathy (p=0.0024), constipation (p=0.0007) and skin toxicity (p=0.0063) and increase in renal impairment (p=0.037). In addition, there was a tendency for more dyspnea (p=0.40) and more fatigue (p=0.11) in pts on Thal-IFN maintenance therapy. Other non-hematological toxicities were similarly distributed in both therapy arms. In conclusion, Thal-IFN maintenance therapy resulted in increased PFS compared IFN maintenance treatment only, but OS was similar between both groups. Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Hajek:Janssen-Cilag: Honoraria. Kuhn:Schering-Plough: Employment.

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Persistent Benefit of VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Long-Term Follow-up of a Randomized Phase 3 Pethema/GEM Study

Blood ◽

10.1182/blood.v124.21.3457.3457 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3457-3457 ◽

Cited By ~ 2

Author(s):

Laura Rosiñol ◽

Albert Oriol ◽

Ana Isabel Teruel ◽

Dolores Hernandez ◽

M Jesús Blanchard ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Induction Therapy ◽

Combination Chemotherapy ◽

Phase Iii ◽

Long Term Results ◽

Significant Difference ◽

Standard Risk

Abstract Background: The randomized PETHEMA/GEM phase III trial GEM05menos65 (www.clinicaltrials.gov NCT00461747) demonstrated that pretransplant induction therapy with VTD resulted in a significantly higher CR rate both, pretransplant and postransplant and in a significantly longer progression-free survival (PFS) when compared with thalidomide/dexamethasone (TD) and combination chemotherapy plus bortezomib (VBMCP/VBAD/B) (Rosiñol et al, Blood 2012). We report here the long-term results of the trial, five years after the last patient was included. Methods: From April 6, 2006 to August 5, 2009, 386 patients younger than 65 years with newly diagnosed symptomatic multiple myeloma (MM) were randomized to receive three different induction regimens: six 4-week cycles of TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) vs. six 4-week cycles of VTD (TD at identical doses plus i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) vs. combination chemotherapy plus bortezomib (4 cycles of alternating VBMCP and VBAD chemotherapy followed by two cycles of i.v. bortezomib at the usual dose of 1.3 mg/m2 on days 1,4,8,11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. All patients were planned to undergo ASCT with high-dose melphalan at 200 mg/m2 followed by maintenance therapy with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN) for 3 years. One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics [t(4;14), t(14;16) and/or 17p deletion]. Patient characteristics at diagnosis and prognostic factors such as ISS, cytogenetics and maintenance arm were similarly distributed in the 3 arms. Results: After a median follow-up of 70.6 months, VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (56.1 vs 29.2 vs 39.9 months, p=0.005) (Figure 1). The estimated overall survival (OS) at 8 years was 60% with no significant differences among the 3 arms. In the overall series, the PFS was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk (15.7 vs. 44.3 months, p=0.003). In the TD and in the VBMCP/VBAD/B arm patients with high-risk cytogenetics had a significantly shorter PFS than patients with standard-risk (8.9 vs 32.8 months, p=0.04 in TD group; 14.1 vs. 43.3 months, p=0.05 in VBMCP/VBAD/B group). However, there was no significant difference in the VTD arm (23.6 vs 56.1 months, p=0.2). Patients with high-risk cytogenetics had a significantly shorter OS in the overall series (median 42.1 months vs not reached, p=0.00001) and this was observed in the three treatment arms: VTD median 37.1 months vs not reached (p=0.001), TD median 54.2 months vs not reached (p=0.06), VBMCP/VBAD/B median 30.2 months vs not reached (p=0.007). The achievement of a deeper response at the end of induction was associated with a longer PFS and OS. Thus, patients achieving CR at the end of induction had a significantly longer PFS than patients achieving a lower degree of response (median 62 vs. 28 months, p=0.00001), irrespective of the treatment arm. Furthermore, on an intention to treat basis, patients who were in postrasplant CR had a significantly longer PFS (p<0.00001) and OS (p<0.00001) than those who did not reach CR after ASCT (p<0.001). In the overall series the OS after progression was 30.5 months and was not significantly different among the 3 arms (VTD 25.4 months, TD 50 months, VBMCP/VBAD/B 30.2 months, p=0.4). Patients with high-risk cytogenetics had a significantly shorter OS after relapse in the overall series (13.3 months vs. 37.5 months, p=0.001), in the VTD arm (13.3 vs 33.9, p=0.01) and in the VBMCP/VBAD/B arm (8.5 vs 38 months, p=0.01). Conclusions: Our long-term results confirm that induction with VTD results in a significantly longer PFS when compared with TD and VBMCP/VBAD/B. Patients with high-risk cytogenetics had a worse outcome even with the use of novel drugs. Finally, the PFS of 56 months achieved with VTD is the longest ever reported in the first line treatment of younger patients with MM elegible for ASCT and support the use of VTD as the standard of care for pretransplant induction therapy. Figure 1: PFS according to the induction arm Figure 1:. PFS according to the induction arm Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Gutierrez:Janssen: Honoraria; Celgene: Honoraria. Martinez-Lopez:Janssen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.

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A Phase II Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD lite) for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3454.3454 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3454-3454 ◽

Cited By ~ 8

Author(s):

Elizabeth O'Donnell ◽

Jacob P. Laubach ◽

Andrew J Yee ◽

Carol Ann Huff ◽

Frank Basile ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Response Rate ◽

Performance Status ◽

Pharmacokinetic Analysis ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Advisory Committees

Abstract Background: Multiple myeloma (MM) is primarily a disease of older adults with a median age at diagnosis of 66 years. Despite significant improvements in patient outcomes, there is a lag in survival in older transplant-ineligible patients compared to their younger counterparts. Traditionally, melphalan and prednisone-based regimens were the most widely accepted treatment options in this older, transplant-ineligible population. More recently, the FIRST trial has explored the use of lenalidomide and dexamethasone in these patients. Here, we sought to incorporate optimal novel agent-containing regimens in transplant-ineligible, older patients that balance efficacy with toxicity. Building on our prior experience with RVD in predominantly younger patients, our study evaluated a 3-drug regimen of modified RVD in the transplant-ineligible population. Methods: Modified RVD (“RVD-lite”) was administered over a 35-day cycle. Lenalidomide was given as a single daily oral dose of 15 mg days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously on days 1, 8, 15, and 22; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 for patients ≤75 yrs and days 1, 8, 15, 22 for patients older than 75 yrs. Intravenous bortezomib was used only in cycle 1 for the first 10 patients for pharmacokinetic analysis. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal and hematologic function. The primary objective was to evaluate the objective response rate (ORR) of modified RVD in transplant-ineligible patients. Secondary objectives included evaluation of the safety profile of modified RVD, progression free survival, overall survival, time to response, response duration, the response rate with respect to cytogenetics, and the pharmacokinetic profile of intravenous and subcutaneous bortezomib. Exploratory analysis will determine minimal residual disease (MRD) status by genotyping and correlate with outcomes in patients who achieve a VGPR or better. Results: Forty-one eligible patients have enrolled between 4/17/13 and 7/18/14, and of those 38 received at least one dose of therapy. Median age at study entry was 73 years (range 65-91) with 22 women and 16 men. ECOG performance status of patients enrolled was 0 in 19 (46.3%), 1 in 15 (36.6%), and 2 in 6 (14.6%) patients. The ISS stage was I in 15 (36.6%), II in 9 (22.0%), and III in 10 (24.4%) patients. Treatment-related toxicities were reported for 34 subjects. Fatigue was the most commonly reported toxicity occurring in 17/34 (50.0%), and of those 16/17 were grade 1 or 2 and manageable. Peripheral neuropathy of any grade was reported in 14/34 (41.2%) of patients including Grade 1 -7 (20.6%), 2 – 6 (17.6%), and 3 – 1 (2.9%). 12/34 (35.3%) reported edema of which 11/12 (91.7%) were grade 1. Grade 3 or greater toxicities included hypophosphatemia - 11 (32.3%), Rash - 4 (11.8%), and mood changes - 2 (5.9%). Pharmacokinetic data comparing intravenous and subcutaneous dosing of bortezomib has been completed and analysis is in process. At a planned interim analysis after 4 cycles that included 33 patients, the investigator-reported ORR of PR or better was 81.8% (CR -5, VGPR – 11, PR - 11, SD 3). Three patients withdrew from the study after less than 1 cycle. Of those, one withdrew for worsening adrenal insufficiency, one for rash attributed to lenalidomide, and one for an unrelated toxicity prompting withdrawal at the Investigator’s discretion. Five additional patients have enrolled but have not completed 4 cycles. Of those, responses thus far include 1 CR, 2 PRs, 1 SD, and 1 patient who has not completed one cycle at the time of this analysis. Exploratory data on bone marrow samples on patients achieving VGPR or better have been collected and analysis for MRD is in process. Conclusions: ModifiedRVD appears to be a well-tolerated and highly effective regimen in the transplant-ineligible population. The ORR rate after up to 4 cycles suggests that this combination at the modified doses and on a weekly schedule is very active. The side effect profile proved manageable and well-tolerated in an older population despite the variance of performance statuses at study entrance. Interim analysis of 38 patients suggests that alternative dosing and schedule of RVD may both improve tolerability and enhance clinical benefit in newly diagnosed, transplant-ineligible MM patients. Disclosures Laubach: Onyx, Novartis, Millenium, Celgene: Research Funding. Huff:Celgene, Millenium: Consultancy. Basile:Celgene: Speakers Bureau. Ghobrial:Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium: Consultancy. Munshi:Celgene, Onyx, Janssen, Sanofi-Aventi, Oncopep: Consultancy; Oncopep: Equity Ownership; Oncopep: Oncopep Patents & Royalties. Richardson:Celgene, Millenium, Johnson&Johnson: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen, Novartis, Onyx, Celgene, Millenium: Consultancy; Eli Lilly, Acetylon: Research Funding.

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A Phase II Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD-lite) for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.4217.4217 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4217-4217 ◽

Cited By ~ 5

Author(s):

Elizabeth K. O'Donnell ◽

Jacob P. Laubach ◽

Andrew J. Yee ◽

Carol A. Huff ◽

Frank G. Basile ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Performance Status ◽

Plasma Concentrations ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Multiple myeloma (MM) is primarily a disease of older adults with median age at diagnosis of 66 years. Although melphalan and prednisone-based regimens were traditionally the most accepted treatment options, recent use of lenalidomide and dexamethasone in this older, transplant-ineligible population as presented in the FIRST trial is the new standard of care in these patients (pts) (NEJM 2014). Here, we sought a regimen that incorporates optimal novel agents in transplant-ineligible, older pts that balances efficacy with toxicity. Building on our promising prior experience with RVD in predominantly younger pts (Blood 2010), our study evaluated a 3-drug regimen of modified RVD in the transplant-ineligible population. Methods: Modified RVD ("RVD-lite") was administered over a 35-day cycle. Lenalidomide 15 mg was given on days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously (SC) on days 1, 8, 15, and 22; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 for pts ≤75 yrs and days 1, 8, 15, 22 for pts older than 75 yrs. Intravenous (IV) bortezomib was used in cycle 1 for the first 10 pts for pharmacokinetic (PK) analysis. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal and hematologic function. The primary objective was to evaluate the objective response rate (ORR) of modified RVD in transplant-ineligible pts. Secondary objectives included evaluation of the safety profile, progression free survival (PFS), overall survival, response rate with respect to cytogenetics, and the PK profile of IV and SC bortezomib. Exploratory analysis will determine minimal residual disease (MRD) status by deep sequencing and correlate with outcomes in patients who achieve a VGPR or better. Results: Fifty-three eligible pts have enrolled between 4/17/13 and 7/25/15, and of those, 50 received at least one dose of therapy. Median age at study entry was 72 years (range 65-91) with 29 women and 24 men. ECOG performance status of pts enrolled was 0 in 25 (47%), 1 in 20 (38%), and 2 in 8 (15 %) pts. The ISS stage was I in 21 (40%), II in 16 (30%), and III in 16 (30%) pts. Treatment-related toxicities were reported for 49 pts. Fatigue was the most commonly reported toxicity occurring in 31/49 (63%), and was mostly grade 1 or 2 and manageable (25/31). Peripheral neuropathy of any grade was reported in 21/49 (43%) pts including grade 1 (11, 22%), 2 (9, 18%), and 3 (1, 2%). Grade 3 or greater toxicities included hypophosphatemia in 15 (31%) and rash in 5 (10%) pts. PK data comparing IV and SC dosing showed no significant differences in plasma concentrations of bortezomib at 5 hours. In the SC route, high body mass index (BMI) patients tended to have low concentration at both the 5 and 30 minute measures but not at 5 hours. There was no correlation with BMI using the IV route. At the planned analysis after 4 cycles that now includes 40 pts, the investigator-reported ORR of PR or better was 90% (CR - 10, VGPR - 14, PR - 12, SD - 4). Five pts withdrew from the study after less than 4 cycles. Of those, one withdrew for worsening adrenal insufficiency, one for rash attributed to lenalidomide, one at the Investigator's discretion, and two for excessive travel distance. Five additional pts have been enrolled but have not completed 4 cycles. Of 48 evaluable patients, the median survival has not been reached. Median duration of follow-up is 17.2 months and the 1-year PFS is 95% (95% CI 0.888, 1) and 2-year PFS is 68% (95% CI 0.512, 0.908). Exploratory data on bone marrow samples on pts achieving VGPR or better have been collected and analysis for MRD is in process. Gene expression profiling was performed using MMprofiler (SkylineDx). High-risk signature will be correlated with pt outcomes. Conclusions: ModifiedRVD is a well-tolerated and highly effective regimen in the transplant-ineligible population. The ORR rate after 4 cycles suggests that this combination at modified doses and on a weekly schedule is very active. The side effect profile proved manageable and was well tolerated in an older population despite the variance of performance status at study entry. There were no significant differences in plasma concentrations of bortezomib observed between IV and SC dosing. The study is fully accrued and this analysis suggests that alternative dosing and schedule of RVD may both improve tolerability and enhance clinical benefit in newly diagnosed, transplant-ineligible MM pts. Disclosures O'Donnell: Millennium: Consultancy. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Schlossman:Millennium: Consultancy. Anderson:Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership; Celgene: Consultancy. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Raje:AstraZeneca: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy.

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Hemostasis in Newly Diagnosed Multiple Myeloma Patients before and after Induction Therapy

Blood ◽

10.1182/blood.v126.23.5388.5388 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5388-5388

Author(s):

Evdokia S. Urnova ◽

Larisa P. Mendeleeva ◽

Olga S. Pokrovskaya ◽

Marina A. Gracheva ◽

Eduard G. Gemdzhian ◽

...

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Stage Iii ◽

Normal Rate ◽

Newly Diagnosed ◽

Complex Disorders ◽

Significant Difference ◽

Before And After ◽

The Status ◽

D Dimer

Abstract Background: Course of multiple myeloma (MM) is associated with hemostatic disorders that can lead to bleeding or thrombosis. According to previous studies the most risky period of time for thrombotic complication is the first year after diagnosis. Aims: The study was aimed to analyze of hemostasis conditions in newly diagnosed (ND) MM patients (pts) and to compare their initial status with the status after induction therapy (IT) and with the status of healthy volunteers (HV). Patients and Methods: 17 pts with ND MM: 10 males, 7 females at the age of 26-72 (median age - 54) were involved in the study. The distribution of the stages among the participants according to Durie-Salmon system: stage I - 1 pts, stage II - 5 pts, stage III - 8 pts, stage III in 8 pts. Immunochemistry variants: IgG - 11 pts, IgA - 2 pts, MM B-J - 4 pts. Average paraprotein (PP) level was 34g/L (0,8 - 78). HV group consisted of 26 persons without serious diseases, 40 - 70 y.o., (median age 50). Hemostasis analysis was taken place twice: before and after the IT which included 4-8 bortesomib-containing cycles (PAD, VCD, VD). After the IT 6 pts achieved CR, 5 pts - VGPR, 4 pts - PR and 1pt was resistant. Average value of PP decreased to 8 (0,1 - 29,7). Routine tests: activated partial thromboplastin time (APTT, normal rate 25-38 sec), international normalized ratio (INR, normal rate 0.85-1.15), D-dimer concentration (normal rate 0-500 mkg/l). Two global tests: thrombin generation test by using endogenous thrombin potential (ETP, normal rate 760-1450 nM*min) and thrombodinamics (TD), characterized by the initial clot growth velocity (Vi, normal rate 36-56 um/min), stationary velocity (Vst, normal rate 20-30um/min), and density of a fibrin clot measured by light scattering from clot (D, normal rate 16000 - 32000 conventional units). Hypocoagulability wasassessedby data APTT > 38 sec, INR> 1.15, ETP < 760 nM*min, Vi < 36 um/min, Vst < 20 um/min, D < 16000 cu. Hypercoagulability was considered in cases when APTT < 25 sec, INR < 0,85, D-dimer > 500 ng/ml, ETP > 1450 nM*min, Vi > 56 um/min, Vst > 30 um/min, D > 32000 cu. Statistics. Ðaired t-test and Pearson correlation coefficient (r) have been got with SAS 9.1. 95- percent CI has been used. Results: ND MM APTT evaluation demonstrated normal coagulation in 13pts and extended one in 4pts (48 sec [38-57]). INR was normal in 13 and increased in 4 cases (1.3% [1.2-1.5]). Increased concentration of D-dimer was revealed in 7pts (3810 ng/ml [350-7270]). ETP was normal in 12 and increased in 5 cases (1592 nM*min [1406-1779]). Vi was normal in 11 and increased in 6pts (62 um/min [58-65])). Vst was reduced in 1pts (15um/min), normal in 10pts and increased in 6pts (36um/min [28-44]). Density of clot was normal in 8 pts and decreased in 9pts (9769 UE [6379-13160]). (Tab. 1) After IT only 1 pt had elongated APTT (44sec), the results of the others were normal. INR was normal in all cases. D-dimer concentration was normal in 12pts and increased in 5pts, but this data was statistically less (1080ng/ml [500-1003]) than in ND MM. ETP was normal in 13pts, elevated in 4 pts (1604 nM*min [1099-2109]). Vi was normal in 12pts and increased in 4pts (61 um/min [57-65]). Vst was decreased in 2pts (13 and 14um/min), normal in 13pts and increased in 2 (32 and 43um/min). Density of clot became normal in 14pts, but clot remained not dense enough in 3 pts (9512 [13606-15779]). (Tab. 1) We found that inverse linear relationship between PP level and blood clot density was more significant in ND MM (Fig. 1, fig.2). Statistically significant difference was revealed between clot density in ND MM and pts in PR or CR and between them and HV (Fig. 3). Furthermore, a significant difference was identified between D-dimer concentration in ND MM pts and after IT (Fig. 4). Conclusions: MM pts have complex disorders of hemostasis characterized by a tendency to hyper- and hypocoagulation at the same time. In spite of an increased tendency to thrombosis confirmed by D-dimer, ETP, TD, pts are under risk of bleeding related to the formation of defective clot and elongated APTT. According to the obtained results one can assume that PP embedded in the clot and disorder its structure. However, further studies are needed to confirmthat assertion. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

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The Impact of Hyperglycemia on Risk of Severe Infections during Early Period of Induction Therapy in Patients with Newly Diagnosed Multiple Myeloma

BioMed Research International ◽

10.1155/2014/413149 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Sung-Hoon Jung ◽

Hee-Chang Jang ◽

Seung-Shin Lee ◽

Jae-Sook Ahn ◽

Deok-Hwan Yang ◽

...

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Performance Status ◽

Univariate Analysis ◽

Elevated Serum ◽

Poor Performance ◽

Poor Performance Status ◽

Newly Diagnosed ◽

Serious Infections ◽

The Impact

The association between hyperglycemia and infections during induction chemotherapy has been reported in a number of hematologic disorders. This retrospective study evaluated the incidence of hyperglycemia during induction therapy in 155 patients with newly diagnosed multiple myeloma (MM) and its effect on serious infections during the first 60 days of induction. A total of 20 (12.9%) patients developed overt hyperglycemia (≥200 mg/dL) during induction therapy. Serious infections occurred in 28 (18.1%) of 155 patients and infection-related mortality within 2 months after treatment was 0.6% (1 patient). In a univariate analysis, overt hyperglycemia, poor performance status (≥2), International Staging System III, lymphopenia (<500/μL), and elevated serum creatinine (≥2 mg/dL) were found to be associated with serious infections. In multivariate analysis, only overt hyperglycemia (HR 7.846, 95% CI 2.512–24.503,P<0.001) and poor performance status (HR 5.801, 95% CI 1.974–17.050,P=0.001) remained significant. In conclusion, this study demonstrated an association between hyperglycemia and serious infections during induction therapy in patients with MM.

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