Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant.

8034 Background: Multiple myeloma (MM), a monoclonal plasma cell disorder, is one of the most common hematologic malignancies in the US. In preclinical studies, metformin demonstrated plasma cells cytotoxicity. However, there is lack of studies translating the effect of metformin into the clinical setting. Therefore, we assessed the clinical effect of metformin in patients (pts) with MM. Methods: All MM pts who underwent stem cell transplant (SCT) at the Mayo Clinic Rochester from 2007 to 2012 were reviewed. Patients were grouped based on metformin use. Initial diagnosis at our institution and ≥12 months of follow up were required. Kaplan-Meier method and Cox regression were used for time-to-event and multivariate analysis. Results: Out of 687 pts, 78 (11.4%) were using metformin at the time of MM diagnosis. Baseline characteristics in the metformin (Mt) and no-metformin (NMt) groups were similar (Table). Median (M) metformin dose was 2000 mg daily and m duration of metformin use from MM diagnosis was 22 months. Pts on the Mt group achieved higher rates of CR after SCT (41% vs. 29%, p<0.02). Median PFS after SCT was longer in the Mt group, 31.3 months (95% CI: 10.4-52.2) vs. 16.6 months in the NMt group (95%CI: 14.5-18.7) p<0.04. There was a trend towards longer OS in the Mt group, but it was not statistically significant (170 vs. 106 months, p<0.10). In a multivariate analysis of metformin use, age, ISS, LDH, and cytogenetics/FISH, the former was an independent predictor of PFS after SCT (OR: 0.38, 95%CI: 0.20-0.68, p<0.001). Conclusions: Metformin use was associated with a better PFS and higher CR after SCT in our MM cohort. A trend towards better OS was also noted in the Mt group. Larger studies are needed to enhance our understanding of the clinic effect of metformin on MM. [Table: see text]

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Phase II Randomized Trial of Bevacizumab Versus Bevacizumab and Thalidomide for Relapsed/Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.2571.2571 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2571-2571 ◽

Cited By ~ 3

Author(s):

George Somlo ◽

William Bellamy ◽

Todd M. Zimmerman ◽

Paul Frankel ◽

Joe Tuscano ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Plasma Cells ◽

Progression Free Survival ◽

Staining Intensity ◽

Cell Transplant ◽

Myeloma Cells ◽

Anti Vegf ◽

Grade 3

Abstract Vascular endothelial growth factor (VEGF) plays a seminal role in neo-angiogenesis. VEGF is present on myeloma cells, and its receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR) are detectable on the surface of neighboring myeloid and monocytic elements. Hence, VEGF is implicated in the pathogenesis of multiple myeloma (MM). Thalidomide, an important agent in the treatment of MM, among its many postulated mechanisms of actions also inhibits VEGF-mediated neo-angiogenesis. We set out to test the feasibility and explore the efficacy of combining an anti-VEGF agent with thalidomide. With the availability of the anti-VEGF antibody rhuMAB bevacizumab, a trial of bevacizumab 10 mg/kg given intravenously every 2 weeks alone (in thalidomide-exposed patients) versus a randomized comparison of bevacizumab +/− thalidomide 50–400 mg/day (in thalidomide naive patients) was initiated by the California Cancer Consortium. Twelve patients (median age:58 years; range:50–75) with initial stages of I (n:2), II (n:2) and III (n: 8), all with refractory MM have been enrolled. Patients received a median of 1 prior regimen (range:0–5). Six patients had failed an autologous stem cell transplant prior to enrollment. In patients who have received bevacizumab alone, grade 3 toxicities included fatigue and neutropenia (1), hypertension (1), and hyponatremia (1). In the group receiving bevacizumab and thalidomide, grade 3 lymphopenia was observed in 1 patient during cycle 3, and one patient was taken off study due to exacerbation of pre-exisiting (diet pill induced) pulmonary hypertension and was considered inevaluable. Median time to progression for the 6 patients treated with bevacizumab alone was 2 (range 1–4) months. Progression-free survival for the 5 evaluable patients treated with bevacizumab and thalidomide is 6 +, 7, 8 +, 10, and 30 + months, with 2 patients still on study and in response. Two of these patients did not progress but were taken off study (one for patient’s choice, and one due to the physician’s choice to pursue a stem cell transplant at 7.5 months, this patient is listed above as in response at 30 + months). Immunohistochemical staining (IHC) revealed 2 + to 4 + expression of VEGF on myeloma cells in 7 cases of the available 8 pre-treatment bone marrow samples. Weak staining (1+) of VEGFR1 was observed on the surface of myeloma cells in 5 cases. VEGFR2 expression was also observed on plasma cells by IHC (1+ to 2+) in 5 cases. Myeloma cells from a patient treated with bevacizumab alone for a duration of 4 months, and from a patient receiving bevacizumab and thalidomide for 7.5 months before going on to transplant, demonstrated the strongest staining intensity for VEGF. Due to slow accrual the study had been closed to accrual, although 2 patients continue on the bevacizumab and thalidomide arm. However, in light of our findings further testing of bevacizumab, preferably in combination with other active agents is warranted. Supported by NO1 CM 17101.

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Immunophenotypic and cytogenetic evolution patterns of the neoplastic plasma cells in multiple myeloma relapsed after stem cell transplant

Journal of Hematopathology ◽

10.1007/s12308-018-0330-6 ◽

2018 ◽

Vol 11 (3) ◽

pp. 75-80

Author(s):

Reha M. Toydemir ◽

Anton V. Rets ◽

Jerry W. Hussong ◽

Djordje Atanackovic ◽

Mohamed E. Salama

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Plasma Cells ◽

Cell Transplant ◽

Cytogenetic Evolution

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Minimal residual disease and log‐reduction of plasma cells are associated with superior response after double autologous stem cell transplant in younger patients with multiple myeloma

Cytometry Part B Clinical Cytometry ◽

10.1002/cyto.b.21755 ◽

2018 ◽

Vol 96 (3) ◽

pp. 195-200 ◽

Cited By ~ 5

Author(s):

Giovanni Rossi ◽

Antonietta Pia Falcone ◽

Maria Marta Minervini ◽

Giovanni Pio De Cillis ◽

Chiara De Waure ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Plasma Cells ◽

Residual Disease ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Younger Patients ◽

Log Reduction ◽

Minimal Residual

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The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) Predicts Survival and Non-Relapse Mortality in Lymphoma and Myeloma Patients Undergoing Reduced-Intensity or Non-Myeloablative Allogeneic Stem Cell Transplantations .

Blood ◽

10.1182/blood.v112.11.2144.2144 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2144-2144 ◽

Cited By ~ 1

Author(s):

Lucia Farina ◽

Benedetto Bruno ◽

Francesca Patriarca ◽

Francesco Spina ◽

Roberto Sorasio ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Stem Cell ◽

Hematopoietic Cell Transplantation ◽

Stem Cell Transplant ◽

Conditioning Regimen ◽

Disease Status ◽

Cell Transplant ◽

Comorbidity Index ◽

Reduced Intensity

Abstract The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of toxic mortality after an allogeneic stem cell transplant (alloSCT). Reduced intensity (RIC) and non-myeloablative regimens have decreased the non-relapse mortality (NRM) in heavily pre-treated and elderly patients. We performed a retrospective multicenter study to assess whether comorbidities, according to the HCT-CI, might influence the outcome of lymphoma and multiple myeloma patients undergoing RIC or non-myeloablative alloSCT. Two-hundred and three patients affected by non Hodgkin’s lymphoma (n=108), multiple myeloma (n=69) and Hodgkin’s lymphoma (n= 26) received an alloSCT from HLA matched sibling (n= 121) or unrelated (n=82) donors. Median age at transplant was 53 years (range, 17–69). The median number of previous chemotherapy was 3 (range, 0–7) and 68% of the patients received at least one autologous stem cell transplant (autoSCT). Twenty-five percent of the patients were transplanted in complete remission (CR), 50% in partial response (PR) and 25% in progressive disease (PD). RIC fludarabine-based regimens were used in 154 patients, whereas 49 patients received a non-myeloblative conditioning based on 2 Gy total-body irradiation+/− fludarabine. Variables included in multivariate analysis were age (<55 vs ≥55), HCT-CI (0 vs 1–2 vs ≥3), the Karnofsky Performance Status (PS) (>80% vs ≤80%), disease type (lymphoma vs myeloma), disease status before transplant (CR vs no-CR), the number of previous lines of therapy (≤2 vs >2), a previous autoSCT (0 vs ≥1), the donor type (sibling vs matched unrelated) and the conditioning regimen (non-myeloablative vs RIC). Patients with a HCT-CI of 0, 1–2 and ≥3 were 32%, 31% and 37%, respectively. The cumulative incidence of NRM was 5%, 16%, 20% at 1 year and 6%, 24% and 27% at 2 years, for patients with HCT-CI of 0, 1–2 and ≥3, respectively (p=0.04). The multivariate analysis for NRM showed that a high HCI-CI score (HR=1.60, p=0.03), as well as a low Karnofsky PS (HR=2.12, p=0.04) were correlated with a significantly worst outcome. Similarly, HCT-CI and the Karnofsky PS were able to predict overall survival (OS, HR=1.62, p<0.001 and HR=3.10, p<0.001, respectively) and unexpectedly, only HCT-CI retained significance in multivariate analysis for progression-free survival (PFS, HR=1.43, p=0.002). Univariate lymphoma subgroup analysis revealed that OS was better for patients with HCT-CI of 0 (p<0.001), with Karnofsky PS >80% (p<0.001), in CR at transplant (p=0.01) and receiving a RIC regimen (p=0.03). In myeloma patients, a previous autoSCT influenced OS (p<0.02) and there was a trend towards a significant correlation with HCT-CI of 0 and Karnofsky PS >80% (p=0.09 and p=0.07, respectively). When patients were analysed separately based on the conditioning regimen, OS was different for HCT-CI of 0, 1–2 and ≥3 either with RIC (p=0.001) or non-myeloablative regimens (p=0.02). Patients with HCT-CI 0, 1–2, and ≥3 had a similar NRM (p=0.19 for HCT-CI 0, p=0.87 for HCT-CI 1–2, p=0.33 for HCT-CI ≥3) and OS (p=0.94 for HCT-CI 0, p=0.76 for HCT-CI 1–2, p=0.18 for HCT-CI ≥3) when transplanted with non-myeloablative or reduced intensity conditioning. HCT-CI was inversely associated with Karnofsky PS (p<0.001, rho=−0.34) and the number of previous lines of therapy (p=0.002, rho=0.21), but not with age (p=0.38), time from diagnosis to transplantation (p=0.68) and pre-transplant disease status (p=0.73). Patients with a higher HCT-CI were not at higher risk of grade 2–4 acute GVHD (p=0.72) or chronic GVHD (p=0.77). These results demonstrated that HCT-CI may be a useful tool to predict NRM, OS and also PFS in lymphoma and myeloma patients undergoing RIC or non-myeloablative alloSCT.

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Absolute Lymphocyte Count As Predictor of Overall Survival for Patients with Multiple Myeloma Treated with Single Autologous Stem Cell Transplant: Experience of a Single Centre,

Blood ◽

10.1182/blood.v118.21.4121.4121 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4121-4121

Author(s):

Victor H Jimenez-Zepeda ◽

Donna E. Reece ◽

Suzanne Trudel ◽

Christine Chen ◽

Norman Franke ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Lymphocyte Count ◽

Research Funding ◽

Stem Cell Transplant ◽

Plasma Cells ◽

Absolute Lymphocyte Count ◽

Autologous Stem Cell Transplant ◽

Peripheral Blood Lymphocytes ◽

Cell Transplant

Abstract Abstract 4121 Post-Autologous stem cell transplant (ASCT) studies have demonstrated that early absolute lymphocyte count (ALC) recovery is associated with prolonged survival in some hematological malignancies. Peripheral blood lymphocytes from Multiple Myeloma (MM) were shown to have direct anti-MM activity by proliferative and cytotoxic responses to autologous and allogeneic myeloma plasma cells Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

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255. Breakthrough Mucormycosis (BT-MCR) on Antifungals Having Mucorales Activity Portrays Worse Prognosis compared with BT-MCR on Mold-Active Antifungals with no Mucorales Activity

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.330 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S142-S142 ◽

Cited By ~ 2

Author(s):

Dierdre B Axell-House ◽

Ying Jiang ◽

Andreas Kyvernitakis ◽

Russel E Lewis ◽

Issam I Raad ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplant ◽

Cox Regression ◽

Hematologic Malignancies ◽

Categorical Variables ◽

Cancer Center ◽

Cell Transplant ◽

Continuous Variables ◽

Group A ◽

Group B

Abstract Background BT-MCR is known to develop in the setting of agents having Aspergillus but no Mucorales activity. However, BT-MCR can occur even with the use of antifungals having with Mucorales activity in patients with hematologic malignancies and or stem cell transplant (HM). Methods We reviewed the records of HM patients treated for MCR (1994 to 2019) at MD Anderson Cancer Center. We identified patients with BT-MCR on antifungals having Mucorales activity: posaconazole (POSA), isavuconazole (ISA), and amphotericin B (AMB) (group A), and patients with BT-MCR on agents having Aspergillus but no Mucorales activity: voriconazole (VRC), itraconazole (ITZ), echinocandins (group B). BT-MCR was defined as MCR diagnosis (dx) after ≥7days (d) of antifungal use. The primary outcome was 42d mortality after the BT-MCR dx. Chi-square or Fisher’s exact test was used for categorical variables and Wilcoxon rank-sum test used for continuous variables. Cox regression model was used to evaluate the independent variables on outcome. Results We identified 11 patients in group A (3 POSA, 5 ISA, 3 AMB) and 81 patients in group B (61 VRC, 13 echinocandins, 7 ITZ). Both groups were not different in terms of age, sex, underlying HM (AML/MDS in 100% vs. 88% in groups A and B, respectively), status of HM (active disease in 82% vs. 67%), prior stem cell transplant (45% vs. 54%) or GvHD (80% vs. 84%), neutropenia at dx (55% vs. 42%), prior receipt of >600 mg of prednisone (45% vs. 41%) or ICU at MCR dx (36% vs. 26%). Similarly, Mucorales species (Rhizopus spp. in 55% vs. 49%) and type of infection (sino-pulmonary in 73% vs. 68%) were no different between the groups. However, both d42 (82% vs. 46%, P = 0.025) and d84 (100% vs. 60%, P = 0.007) mortality was worse in group A. Similarly, median time to death was faster in patients in group A (26d, range 7-80d), vs. group B (42d, range 4–3146d, P = 0.031). Kaplan–Meier analysis showed a similar difference (Figure 1). In multivariate analysis, neutropenia (P = 0.038) and ICU at dx (P = 0.002) were independent factors on day 42d mortality in all 92 patients with prior Mucorales–active antifungals showing a trend associated with poor outcome (P = 0.17). Conclusion BT-MCR on agents having Mucorales activity is a marker of poor prognosis in HM patients. Early use of investigational immunotherapy and salvage antifungal chemotherapy studies is needed in that subgroup of patients. Disclosures All authors: No reported disclosures.

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