Combined immune score of lymphocyte to monocyte ratio and immunoglobulin levels predicts treatment-free survival of multiple myeloma patients after autologous stem cell transplant

Abstract Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.

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Oligoclonal and monoclonal bands after single autologous stem cell transplant in patients with multiple myeloma: impact on overall survival and progression-free survival

Leukemia & Lymphoma ◽

10.3109/10428194.2013.873537 ◽

2014 ◽

Vol 55 (10) ◽

pp. 2284-2289 ◽

Cited By ~ 2

Author(s):

Victor H. Jimenez-Zepeda ◽

Donna E. Reece ◽

Suzanne Trudel ◽

Norman Franke ◽

Andrew Winter ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplant ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Free Survival

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A Comparison of Two Different Reduced Intensity Conditioning (RIC) Allograft Strategies In Patients with Multiple Myeloma, An EBMT Analysis

Blood ◽

10.1182/blood.v116.21.3512.3512 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3512-3512

Author(s):

Firoozeh Sahebi ◽

Laurent Garderet ◽

Simona Iacobelli ◽

Anja van Biezen ◽

Gösta Gahrton ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Calendar Period ◽

Reduced Intensity Conditioning ◽

Free Survival ◽

Reduced Intensity

Abstract Abstract 3512 Recent studies in multiple myeloma patients using reduced intensity conditioning (RIC) allograft following autologous stem cell transplant in a planned tandem fashion (auto-allo) have reported low transplant related mortality (TRM) in a range of 10–15% and long term disease control in approximately one third of the patients. Similar results are reported with reduced intensity allogeneic stem cell transplant either as upfront or salvage treatment for patients who have failed prior autologous stem cell transplant. It is not clear if RIC allograft without preceding autologous stem cell transplant can produce the same outcome. The objectives of this retrospective study are to evaluate and compare the results of planned tandem autologous-RIC allograft (auto-allo) and early RIC allograft as first transplant in order to address whether or not cytoreductive autologous stem cell transplant (ASCT) is needed in patients who are candidates for RIC allograft and patients can be spared from morbidities of autologous stem cell collection and transplant. Study: We performed a retrospective analysis of the EBMT database. Five hundred and four multiple myeloma patients were identified as auto-allograft or early RIC allograft recipient between 1998 – 2007. Three hundred and fifty six patients were assigned to planned tandem auto-allograft and 148 patients received early RIC allograft as their first transplant. All patients underwent transplant within 1 year from diagnosis. Two hundred and fifty-three of 356 patients in the auto-allo group received their planned allograft, 88 patients did not undergo the planned allograft and 15 patients had a second autologous stem cell transplant. There were no significant differences in disease stage, disease subtype, sex, use of T-cell depleted allograft and donor type (sibling vs. unrelated donor) between the 2 groups. However patients in the early RIC group were younger (median age 51 vs. 53 years old P=0.03), received transplant in earlier calendar period (51% between 1998–2002 vs. 33% P <0.001), had longer interval from diagnosis to transplant (9 vs. 6 mo. P=0.0001) and were more in CR at the time of transplant (17% vs. 9% P=0.008). The B2 microglobulin and cytogenetic data were missing in the majority of patients and therefore not included in this analysis. Results: Results are reported on an intention to treat (ITT) analysis. With a median follow up of 52 mo. (48-55) in the auto -allo and 48 mo. (39-55) in the early RIC group best response occurred more frequently in the auto-allo group than early RIC with complete response rate of 62% vs. 47% respectively. Progression-free survival at 3 and 5 years were significantly better in the auto-allo group (43% and 31% respectively) as compared to the early RIC group (30% and 17% respectively, P<0.001). Overall survival was also significantly improved in favor of the auto-allo group with 3 and 5 year OS of 68% and 60% as compared to 52% and 37% in the early RIC group (P<0.001). Non Relapse Mortality (NRM) rates at one year were 9% and 18% in the auto-allo and early RIC group respectively (p <0.001). There were no differences in the incidence of acute GVHD (41% vs. 43% P=0.13) and chronic GVHD (60% vs. 56% P=0.19) between the auto-allo and RIC groups respectively. Given the differences in the calendar year we compared the PFS and overall survival between the two groups within the same calendar period (1998-2002 and 2003–2007). Log rank test confirmed significantly better outcome in favor of the auto-allo group in each calendar period suggesting that the observed differences between the 2 groups were independent of the calendar period. (P<0.001). Conclusion: This large retrospective study on an ITT analysis suggest cytoreductive autologous stem cell transplant (ASCT) prior to RIC allograft is associated with improved disease free survival and overall survival in patients with multiple myeloma who are candidates for RIC allograft. Disclosures: Sahebi: Millennium Pharmaceuticals, Inc: Research Funding.

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XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

Molecular Carcinogenesis ◽

10.1002/mc.23121 ◽

2019 ◽

Vol 58 (12) ◽

pp. 2327-2339

Author(s):

Avinash K. Persaud ◽

Junan Li ◽

Jasmine A. Johnson ◽

Nathan Seligson ◽

Douglas W. Sborov ◽

...

Keyword(s):

Multiple Myeloma ◽

Dna Repair ◽

Stem Cell ◽

Stem Cell Transplant ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Free Survival

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A New Prognostic Score Using Lymphocyte to Monocyte Ratio and Immunoglobulin Levels to Predict Progression in Multiple Myeloma Patients Undergoing Autologous Transplant

Blood ◽

10.1182/blood-2018-99-118965 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3442-3442

Author(s):

Karen Sweiss ◽

Gregory Sampang Calip ◽

Jonathan Lee ◽

Nadim Mahmud ◽

Damiano Rondelli ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Treatment ◽

Risk Groups ◽

Cell Transplant ◽

Free Survival ◽

Cell Numbers ◽

Lymphocyte To Monocyte Ratio ◽

Immune Score ◽

Immunoglobulin Levels ◽

Good Risk

Abstract High dose chemotherapy followed by autologous stem cell transplant (ASCT) prolongs progression-free survival (PFS) of patients with multiple myeloma (MM). However, there is wide variability in response and survival after ASCT and therefore prediction of prognosis remains a challenge. Biomarkers of immunologic and inflammatory changes, such as the peripheral blood monocyte and lymphocyte counts have been shown to impact clinical outcomes in other cancers and may have prognostic value in MM. We hypothesized that clinically available surrogates for immune suppression and systemic inflammation occurring in MM including the lymphocyte to monocyte ratio (LMR) and immunoglobulin (Ig) levels tested pre-transplant and at day 90 after ASCT may predict treatment-free survival (TFS). We also determined whether a composite immune score predicts disease progression. One hundred and thirty patients who received melphalan 200 mg/m2 and ASCT between 2002 and 2016 were included in the final analysis. The median age was 59 (range: 34-77) years and most patients were male (n=71, 55%), IgG subtype (n=65, 50%), and ISS stage 3 at diagnosis (n=55, 57%). Sixteen (12%) patients were diagnosed with high risk FISH/karyotype. Median number of prior treatments was 2 (range: 1-5), with the majority being IMiD- (n=82, 63%) or PI-(n=72, 55%) based. The median time to transplant was 8 months (range: 3-144), and approximately half of patients received post-ASCT maintenance treatment (n=60, 46%). Treatment response was at least a very good partial response or better in 28 (27%) patients pre-transplant and 59 (59%) patients post-transplant (p=0.0001). We collected the following values at baseline (Day -2) and Day +90 post-ASCT: absolute lymphocyte count (ALC); absolute monocyte count (AMC); lymphocyte to monocyte ratio (LMR); and the number of Ig levels suppressed. Values were separated into upper and lower quartiles for analysis. For the entire cohort, the median PFS was 25 months. At Day 90 post-ASCT, a high ALC (18 versus 23 months, p=0.04) and low AMC (13 versus. 25 months, p=0.02) predicted for superior TFS. When combined into a lymphocyte-monocyte ratio, we were able to demonstrate that a lower LMR (defined as <2.4) strongly predicted for worse TFS (16 versus 52 months, p=0.004). Finally, we evaluated the impact of low Ig levels on TFS and observed that when compared to patients with normal Ig levels, patients with 2 to 3 suppressed Ig levels had significantly worse TFS (17 versus. 51 months, p=0.04). In a multivariate Cox proportional hazards model, we calculated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for protein subtype, ISS stage, number of prior treatments, novel agent induction, and use of maintenance treatment. A low LMR (95% CI 0.01-0.15, HR 0.01; p=0.001) and suppressed Ig levels (95% CI 1.45-39.71, HR 7.58; p=0.017) were strongly associated with poor TFS. We then developed an immune score by combining the LMR and Ig values. Patients were divided into either poor (low LMR and 2-3 suppressed Ig levels), good (high LMR and normal Ig levels) and intermediate (all other patients) risk groups. The median TFS for poor, intermediate and good risk groups was 7.5 versus 27 versus 79 months respectively (p=0.0004). In order to examine whether autograft composition impacted lymphocyte and monocyte counts at day 90, we compared total infused cell numbers by automated differential counts and CD3 and CD14 expression between the poor and good risk groups. Total infused lymphocyte (1.74x108 versus 2.46x108, p=0.72), monocyte (3.18 x108 versus 3.39 x108, p=0.86), CD3 (1.52 x108 versus 1.37 x108, p=0.92), and CD14 (2.7 x108 versus 1.9 x108, p=0.44) cell numbers were similar between the 2 groups, suggesting that LMR at Day +90 was independent of the infused graft lymphocyte and monocyte numbers. With long-term follow-up, we demonstrate the importance of two readily available biomarkers, the lymphocyte to monocyte ratio and immunoglobulin levels, in determining risk of progression in MM patients after ASCT. We observed that independent of the infused autograft cell composition, at day +90 a combination of the LMR and Ig levels could identify patients who will either have a long duration of remission or patients with very poor prognosis who may thus benefit from more intensified post-ASCT consolidation/maintenance or use of immunotherapy. Disclosures Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

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Salvage Tandem Autologous Stem Cell Transplant with Consolidation for Relapsed Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.5497.5497 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5497-5497

Author(s):

Kamal Kant Singh Abbi ◽

Sonya Behrends ◽

Margarida Silverman ◽

Umar Farooq ◽

Kalyan Nadiminti ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Progressive Disease ◽

Stem Cell Transplant ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Novel Agents ◽

Cell Transplant ◽

Free Survival

Abstract Background: Therapeutic options for patients with Multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (SCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second SCT, with no clear standard of care. Upfront tandem transplantation has been shown to improve both progression free survival and overall survival. But currently, there is little data regarding the application of tandem SCT in relapsed multiple myeloma patients. Methods: We retrospectively analyzed the outcomes of patients who underwent salvage melphalan-based tandem SCT for relapsed MM at University of Iowa Hospitals and clinics. Progression free survival (PFS) was defined as the time from date of the first salvage SCT to disease progression or death, whereas overall survival (OS) was defined from the date of the first salvage SCT to the date of death from any cause. Results: Between 2012 and 2015, 12 patients with MM received tandem autograft (total 24 transplants) for relapsed disease at our center. Conditioning was with VDT-melphalan 200mg/m2 (21/24), VDT-MEL 140mg/m2 (2/24) and Velcade, gemcitabine, BCNU, melphalan and dexamethasone (1/24). The median age at the salvage SCT was 48 years (range 37-58); 7 patients were female. 17% had high risk cytogenetics (including t(4;14), +1q, p53 loss) at the time of salvage SCT. Median time between previous transplant and progression of disease was 34 months (range 8-108). Of the 7 patients, who received re-induction therapy, 71% had chemotherapy refractory disease prior to salvage SCT. Response was assessed at 2-3 months post-SCT. Overall response rate was 92%. 7/12 (58%) patients achieved stringent complete remission, one patient achieved CR, one patient achieved near CR, 2/12 patients achieved VGPR and 1/12 had stable disease (SD). Following salvage tandem SCT, all patients received consolidation therapy with three drug combination, intended to be given for two years. Three patients have shown progressive disease at the time of analysis. The median PFS was 390 days (range 265- 1085) (Table-1); the median OS was 517 days (range 338-1085) (Table-2). Rate of progression free survival in the 10 evaluable patients at one year was 80%. There was no transplant related mortality. One patient died of progressive disease. Conclusions: Salvage tandem SCT is an effective strategy for relapsed MM and is especially effective in patients who had received less intensive therapy initially (single transplant and no maintenance therapy). Incorporation of novel agents (monoclonal antibodies and high doses of carfilzomib) into maintenance strategies may further improve outcomes. Figure 1. Progression free survival for all the patients Figure 1. Progression free survival for all the patients Figure 2. Overall survival for all the patients Figure 2. Overall survival for all the patients Disclosures Farooq: Kite Pharma: Research Funding.

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