Establishing the Velocity of M-Protein Decline (VMD) Value in Response to Multiple Myeloma Therapy That Best Predicts M-Protein of Zero

Introduction: Serum M-protein levels, measured by serum immunoelectrophoresis, have been one of the major tests that determine the type of response to therapy in Multiple Myeloma. Achieving an M-protein of zero is one of the criteria determining complete remission which in turn translates into longer progression-free survival and overall survival. Triplet therapy tends to be the standard therapeutic approach in younger, fit, and transplant candidates. However, in older non-fit patients many oncologists start with doublets and only escalate to triplet combinations upon less optimal response. The predictive value of the velocity of the M-spike decline (VMD) has not been adequately studied. We conducted this study to find the optimal VMD that predicts a serum M-protein of zero. Methods: A sample of mostly non-fit older Multiple Myeloma patients was identified. All patients had regular serum protein electrophoresis with M-protein levels documented every 4-8 weeks until they achieved M-protein levels of zero, plateauing without attaining the target of zero, or rebounding with progression. Best-fit line or curve was constructed and the slope of the decline was calculated. VMD was defined as the slope of the best fit-curve/line. VMD values corresponding to the binary outcomes of achieving or failing to achieve an M-protein value of zero were collected. A ROC curve was constructed to determine the cut-off VMD value that best predicts the outcome of M-protein of zero. Results: A total of 47 patients of mostly non-fit older Multiple Myeloma patients were included in our final sample. The median age of the sample was 71 years. Thirteen percent had triplet therapy. Thirty four percent had proteasome inhibitor based combinations while 64% had IMiD based combinations. Fifty seven percent achieved the target M-protein level of zero while 43% failed. The area under the ROC curve, AUC, was 0.98 (p<0.0001). The cut-off VMD value (the slope of the best fit M-protein curve/line) which best predicts an outcome of M-protein of zero was < -0.276 with a corresponding sensitivity of 89% and specificity of 100%. Conclusions: This exploratory study established the VMD value that best predicts the outcome of M-protein of zero in response to Multiple Myeloma therapy. This may be potentially used by oncologists to make early decisions regarding the need for further optimization or intensification of their therapeutic combinations as they treat their older non-fit Multiple Myeloma patients. Disclosures No relevant conflicts of interest to declare.

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Clarithromycin (Biaxin®), Low Dose Thalidomide and Dexamethasone (BLT-D) in Newly Diagnosed and Previously Treated African American Patients with Multiple Myeloma: A Retrospective, Single Institution Experience.

Blood ◽

10.1182/blood.v106.11.3501.3501 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3501-3501

Author(s):

Jack Jacoub ◽

Joao L. Ascensao ◽

Boyer James ◽

Thomas O’Connor ◽

Reema Batra ◽

...

Keyword(s):

Multiple Myeloma ◽

African American ◽

Partial Response ◽

Plasma Cells ◽

Progression Free Survival ◽

Staging System ◽

Stage I ◽

M Protein ◽

Duration Of Treatment ◽

Previously Treated

Abstract Introduction : African-Americans (AA) are twice as likely to develop multiple myeloma (MM) than Caucasians but are largely underrepresented in clinical trials. Thalidmode plus dexamethasone is an established therapy in MM. Biaxin® may augment the efficacy of this combination possibly via potentiating steroid activity (M. Coleman, et al. Leuk Lymphoma 2002, R. Niesvizky, et al. Blood 2003, Abs #832). Methods : We conducted a retrospective review of all AA patients (pts) with symptomatic MM treated with BLT-D from 2002-present. Treatment consisted of Thalidomide 50–200mg daily, Biaxin 500mg twice daily and dexamethasone 40mg weekly. All pts received monthly bisphosphonate therapy and aspirin 81–325mg daily. Response criteria was defined as follows: complete response (CR) = no detectable M-protein, marrow plasma cells <5%; very good partial response (VGPR) = decrease in M-protein by >90%; partial response (PR) = decrease in M-protein by >50%; stable disease (SD) = M-protein decrease by <50% without clinical progression; no response (NR)= progression with no change or increase in M-protein or response <4wks. Progression free survival (PFS) was defined from the start of BLT-D until discontinuation or change in therapy due to progressive disease as clinically indicated. Toxicity was graded according to WHO criteria. Results :15 pts received BLT-D and their characteristics were as follows: all were males; median age 66 (range 30–78); IgG=53%, IgA=20%, light chain only=27%; Durie-Salmon stage I=20%, II=33%, III=47%; International Staging System stage I=20%, II=47%, III=13%, undefined = 20%; 7 were previously treated (5 pts had 1 prior regimen, 2 pts had ≥2 prior regimens). In previously treated pts (n=7) responses were as follows: no CR, 2 VGPR (28%), 3 PR (43%), 1 SD (14%) and 1 NR (14%) for an overall response rate (ORR) of 87%. Their duration of treatment ranged from 4–32 mos and median PFS in responders (VGPR+PR+SD) was 29.5 mos (range 23–35). 3 pts had BLT-D discontinued after 12–15 months of therapy and remained in stable plateau phase off therapy for > 1 year; one was referred for ASCT after 14 mo; one continues stable at 15 mo and the third relapsed at 12 months but failed to respond again to BLT-D. Responses in treatment naive pts (n=8) were as follows: no CR, 3 VGPR (38%), 1 PR (13%) and 2 SD (25%), 2 NR (25%) for an ORR of 75%. Their duration of therapy ranged from 3–20 mos and median PFS in responding patients was 11 mos (range 7–20). The longest survivor in this group (37 mos) received an ASCT after 12 mos of therapy. 13 pts (87%) remain alive at a median follow-up of 24 mos (range 8–37). Grade 3–4 toxicity consisted of 3 DVTs + 1 PE (27%), 5 hypergycemias (33%), 2 infections (13%) and 1 peripheral neuropathy (7%). Additionally, 1 pt developed superficial thrombophlebitis; 1 QT prolongation resolving with Biaxin discontinuation; 5 others with neuropathy; and 2 others with hyperglycemia. Conclusion : BLT-D is feasible and effective therapy in African-American patients with MM and is capable of inducing durable responses. However, we encountered significant thrombotic and endocrine toxicity that appears out of proportion to what has been previously reported with thalidomide plus dexamethasone alone. Furthermore, aspirin thromboprophylaxis at daily doses of 81–325 mg appears suboptimal in preventing thromboembolic events in this group of patients when prescribed this regimen.

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Comparison of Serum Free Light Chain Levels and 24 Hour Urinary Monoclonal Protein Secretion in Patients with Myeloma: Concordant Changes with Response to Therapy.

Blood ◽

10.1182/blood.v108.11.5064.5064 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5064-5064 ◽

Cited By ~ 1

Author(s):

Shaji Kumar ◽

S. Vincent Rajkumar ◽

Matthew Plevak ◽

Robert A. Kyle ◽

Jerry A. Katzmann ◽

...

Keyword(s):

Light Chain ◽

Protein Level ◽

Free Light Chain ◽

Response To Therapy ◽

M Protein ◽

Serum Free ◽

Protein Levels ◽

Serum Free Light Chain ◽

Data Points ◽

Over Time

Abstract Background: The measurement of monoclonal (M) protein in the serum and urine is critical for response assessment and disease evaluation in patients with multiple myeloma (MM). The serum free light chain (FLC) assay offers a new and sensitive method of assessing response to therapy. An important question that has not been adequately addressed is the correlation between 24 hour urine M protein levels and serum FLC measurements, and the extent to which response to therapy estimated using the FLC assay correlates with that assessed using the 24 hour urine M protein level. Methods: A total of 2194 sets of data, with simultaneous UPEP and serum FLC measurement, were studied. These included 752 unique patients, with individual patients having 1–23 paired assessments over time. FLC estimation was carried out using the serum FLC assay (Freelite; The Binding Site Limited, UK) performed on a Dade-Behring Nephelometer. Based on the established reference range, kappa/lambda FLC ratio <0.26 or >1.65 were defined as abnormal indicating the presence of monoclonal lambda and kappa FLC, respectively. The monoclonal light chain isotype was considered the involved FLC isotype, and the opposite light chain type as the uninvolved FLC type. The Urine M protein by UPEP was compared to the serum levels of the involved light chain using Spearman Rank Correlation. For comparisons in individual patients over time, those with at least 10 measurements each were studied. Results: The median involved FLC level in patients with an undetectable urine M protein was 2.3 mg/dl compared to 32.2 mg/dL among those with a detectable urine M protein (P<0.001). Among the 1676 points with an abnormal FLC ratio, only 75% had an M protein detected in the urine, P < 0.001. Conversely, among patients with a positive urine M-protein, 91% had an abnormal FLC ratio. When all the 2194 data points were considered together, there was a significant correlation between the urine M protein level and the FLC levels (FLC level calculated as the difference between involved and uninvolved levels), rho=0.763, P < 0.001. The correlation did not change when patients with a serum creatinine of over 2.5 were excluded. The correlation between FLC levels and urinary M protein can be affected by several factors such as renal function that will differ across patients. Therefore, we examined whether the correlation between the two variables is stronger when the variations introduced by inter-patient differences in the relationship between the two variables are eliminated. In order to do this, we studied individual patients on whom multiple data points over time were available. One patient who had the maximum number of paired assessments (23 pairs) of serum FLC level and urinary M protein; the correlation between the two variables over time was highly significant, rho 0.981, p<0.001. Similarly 26 other patients who had measurable urine M protein levels in whom 10 nor more paired observations over time were available, also showed significant correlations, rho, range 0.726–0.981, p<0.01. Conclusion: There is a significant correlation between urine M-protein and serum free light chain across patients and the correlation is stronger in individual patients in whom the effect of inter-patient variation in other confounding factors can be eliminated. These data if confirmed in a clinical trial setting would support the use of serum FLC levels instead of urinary M protein measurements to assess response to therapy.

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Elevated Normal Immunoglobulins and Stable M-Protein Levels in Multiple Myeloma Patients on Erythropoietin Treatment.

Blood ◽

10.1182/blood.v110.11.4747.4747 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4747-4747

Author(s):

Noa Gadassi ◽

Sari Prutchi Sagiv ◽

Howard S. Oster ◽

Drorit Newmann ◽

Moshe Mittelman

Keyword(s):

Multiple Myeloma ◽

Immune System ◽

M Protein ◽

Immunological Parameters ◽

Humoral Immune ◽

Protein Levels ◽

Humoral Immune Responses ◽

Human Erythropoietin ◽

Erythropoietin Treatment ◽

Cellular Immune

Abstract Recombinant human erythropoietin (rHuEPO) is a well-known treatment for anemia in multiple myeloma (MM) patients. We have previously reported that rHuEPO treatment was associated with prolonged survival of several patients suffering from advanced disease (Mittelman et al., 1997). Recently we have demonstrated that treatment of MM patients with rHuEPO is associated with significant improvements of certain immunological parameters and functions (Prutchi-Sagiv et al., 2006), mainly related to the cellular compartment. The objective of the present retrospective study was to determine whether rHuEPO treatment, in addition to its effects on the cellular immune compartment, also modulates the humoral arm of the immune system in MM patients. Medical charts of eighteen consecutive IgG and IgA MM patients were analyzed and the levels of normal immunoglobulins (Ig) and M-protein before and during rHuEPO treatment were recorded. We have found a significant increase in the levels of normal Ig (IgG, IgA and IgM) in response to rHuEPO, during the 3–9 months fromtreatment initiation. Importantly, the levels of M-protein remained stable for a period of 10–12 months from treatment initiation. These results are in line with previous studies, including our study in murine models (Katz et al., 2007), demonstrating that EPO improves humoral immune responses. The current study highlights the concept that EPO’s immunomodulatory actions on MM patients might also involve the humoral compartment of the immune system.

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Lenalidomide Consolidation Followed by Maintenance After Autologous Transplantation for Multiple Myeloma Decreases Thymic Output and Terminally Differentiated CD4 and CD8 T Cells but Increases Treg

Blood ◽

10.1182/blood.v120.21.4046.4046 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4046-4046 ◽

Cited By ~ 1

Author(s):

Emmanuel Clave ◽

Corinne Douay ◽

Tereza Coman ◽

Marc Busson ◽

Caroline Bompoint ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Conflicts Of Interest ◽

Negative Impact ◽

Autologous Transplantation ◽

Immune Surveillance ◽

Progression Free Survival ◽

High Dose ◽

Post Transplantation

Abstract Abstract 4046 Treatment with lenalidomide, an immunomodulatory drug, increases the time to progression in relapsed/refractory multiple myeloma. However, due to its pleiotropic effect, it is not known whether the efficacy of this drug is due only to direct tumor toxicity or also to immunomodulatory effects. We assessed in vivo the changes in T-cell reconstitution induced by lenalidomide consolidation and maintenance treatment following autologous peripheral blood stem cell transplantation (ASCT) in a cohort of multiple myeloma patients. Twenty-nine newly diagnosed myeloma patients were treated with the induction combination bortezomib plus dex followed by high dose melphalan (140–200 mg/m2) and ASCT. A first group of 11 patients were treated with lenalidomide consolidation initiated 3 to 6 months post transplantation: 25 mg/day, days 1–21 of a 28 day cycle for 2 months, followed by maintenance (10 mg/day) until disease progression. This group was compared with the 18 patients who did not receive any treatment after ASCT. Blood samples were collected at diagnosis, before the transplant and 1, 3, 6, 9, 12 and 18 months after ASCT. Thymic function was assessed by real-time PCR quantification of T cell receptor excision circles (sjTREC) and percentages and absolute counts of T lymphocyte subpopulations were determined by multicolor flow cytometry. Statistics were performed using the Log-Rank or Mann-Whitney test. The two cohorts had similar baseline characteristics and all 29 patients were in remission after ASCT. With a median follow-up of 4 years, progression-free survival (PFS) was superior with lenalidomide treatment (69% vs 36%, p=0.05) while overall survival (OS) was similar (82% vs 75%, p=0.5). Lenalidomide treatment induced a progressive decrease in sjTREC (median at 18 months, 0.25/μL vs 1.61/μL, p<0.05) and a decrease in the percentages and absolute counts of CD4+ and CD8+ CD45RA+CCR7- effector terminal T cell subpopulations (median at 18 months, 3.2/μL vs 17.6/μL, p<0.05 for CD4+CD45RA+CCR7- and 109/μL vs 345/μL, p<0.05 for CD8+CD45RA+CCR7-). Conversely, lenalidomide treated patients displayed an increase in CD4+CD25+CD127-/low Treg populations, in both percentage and absolute count (median 13% vs 8 %, p<0.05 and 48.9/μL vs 29.3/μL, p<0.05, respectively). No correlation was found with documented infections, relapse or survival. We confirm an increase in PFS with lenalidomide consolidation/maintenance following ASCT. However, our data also suggest that in myeloma patients, the effect of lenalidomide on the myeloma tumor may not be T cell mediated and this treatment may have a negative impact on the T cell immune surveillance. Disclosures: No relevant conflicts of interest to declare.

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Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk

Blood ◽

10.1182/blood.v122.21.1910.1910 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1910-1910 ◽

Cited By ~ 2

Author(s):

Chrystal Landry ◽

Dory Londono ◽

Sean M. Devlin ◽

Alex Lesokhin ◽

Nikoletta Lendvai ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Disease Risk ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Protein Translation ◽

Response To Therapy ◽

Cytogenetic Abnormality ◽

Newly Diagnosed

Abstract Background Multiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods We identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. Results In unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). Conclusions Karyotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures: No relevant conflicts of interest to declare.

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Polyclonal Gamma Globulin Suppression and Risk Of MGUS Progression Into Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1875.1875 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1875-1875 ◽

Cited By ~ 1

Author(s):

Jawad Z. Sheqwara ◽

Mohammad Alhyari ◽

Shannon Keating ◽

Philip Kuriakose

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Plasma Cell ◽

Total Protein ◽

Gamma Globulin ◽

Conflicts Of Interest ◽

Significant Risk ◽

M Protein ◽

Plasma Cell Dyscrasia ◽

Female Ratio

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the most common form of plasma cell dyscrasia, with a prevalence of 3% in the general population above age of fifty. MGUS has a malignant evolution rate of 1% per year. Large longitudinal studies have suggested that virtually all patients diagnosed with multiple myeloma (MM) had a preceding MGUS, with 75 % having detectible Monoclonal (M) protein ≥8 years prior to diagnosis. It is important to identify the features at diagnosis that can predict neoplastic transformation to MM. Purpose We identified 239 patients at our institute in whom MGUS was diagnosed between 2000 and 2010. The presenting clinico-hematologic features were correlated with the frequency of evolution into MM to identify early predictors of evolution. The primary end point was progression to MM. Results The patients' mean age was 70.7 years. The Male/Female ratio was 0.7. The mean concentration of the M component (MC) was 0.7 g/dL. IgG was the most frequent MC (77%), followed by IgA (13%). The median ratio of MC protein to total protein was 0.5. Single or multiple background polyclonal (PC) suppression was noted in 36% of patients. PC suppression of 50% or more was noted in 20.1% of patients, 49.8% had < 50% and 30.1% had no suppression. Mean bone marrow plasma cell percentage was 4.5 percent and mean hemoglobin was 12.4 g/dL. Eighteen of the 239 patients with MGUS progressed into MM over ten years of follow up. Univariate comparisons of all variables between those who progressed and those who did not, showed that the initial concentration of the serum M protein, ratio of M protein to the total protein, number of PC gamma globulins suppressed, degree of PC suppression and IgM gamma globulin suppression were statistically significant risk factors that correlated with progression into MM. Fourteen out of eighteen patients with progressive disease had either PC suppression or background IgM suppression. Conclusions Monoclonal protein concentration, ratio of M protein to the total protein and abnormal serum free light chain ratio are simple variables that have been shown in multiple previous studies to predict the progression of MGUS into MM. In our study, we additionally found that number of PC suppressed, degree of suppression and IgM suppression are also key risk factors that can predict progression. We believe that these variables can be potentially applied into an approach that uses a detailed risk stratification system to predict which cases of MGUS will progress into MM and to provide more intensive monitoring for patients more likely to progress. Disclosures: No relevant conflicts of interest to declare.

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The Expression Of CD200 As a Prognostic Factor In Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3082.3082 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3082-3082

Author(s):

Yi Li ◽

Wenjun Wu ◽

Jingsong He ◽

Xiaoyan Han ◽

Gaofeng Zheng ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Staging System ◽

Newly Diagnosed ◽

New Approach ◽

Myeloma Cells ◽

Targeting Therapy ◽

Molecular Therapeutic

Abstract Introduction multiple myeloma (MM) is currently an incurable hematological malignancy. Discovering molecular therapeutic targets is a new approach to improve the outcome in the treatment of the malignant disease. As CD200 is a type Ⅰmembrane glycoprotein expressed on myeloma cells, we asked if the expression of CD200 could serve as a prognostic marker for MM patients. Our data indicated that the expression level of CD200 is indeed correlated with the prognosis of the MM patients. Methods bone marrow samples from 96 newly diagnosed MM patients from April 2011 to July 2013 were evaluated by flow cytometry, using PE-conjugated anti-CD200 mAb, FITC-conjugated anti-CD138 mAb, and PE-Cy7-conjugated anti-CD45 mAb. PE-or FITC-conjugated normal mouse IgG was used as isotype-matched controls. Results 96 MM patients were investigated in the present study, including 60 men and 36 women, with a median age of 63 years (range 34–86 years). 81/96(84%) MM patients were CD200 positive with a median Mean Fluorescence Intensity (MFI) of 127 as analyzed by flow cytometry, which was consistent with the previous studies. While in 15 of 96 patients, CD200 expression was undetectable. Among the CD200 positive ones 7.40% patients were classified as stage Ⅰ, 12.35% were stage Ⅱ, and 80.25% were stage Ⅲ according to Durie–Salmon staging criteria. 40.74% patients were stageⅠ, 22.22% were stage Ⅱ, and 37.04% were stage Ⅲ, according to the International Staging System (ISS). Analysis of the CD200 positive patients revealed the MFI<127 group had a better progression free survival (PFS) (p=0.046) (Fig 1A) and overall survival (OS) (p=0.069) compared to those with MFI≥127. In the patients with age ≥65 years old, PFS (p=0.023) (Fig 1B) and OS (p=0.044) (Fig 1C) were much shorter in the MFI≥127 group, compared to the MFI<127 ones. Conclusions Our study demonstrated that the expression and MFI of CD200 on primary multiple myeloma cells is correlated with the prognosis of the MM patients. The better PFS and OS were observed in the MFI<127 group compared to the patients with MFI≥127, especially in the patients with age≥65 years old. Improved PFS in CD200 positive ones is likely due to the immune suppression mediated by CD200. Our study suggests that targeting therapy against CD200 may become a new approach to the treatment of MM in clinical practice. Disclosures: No relevant conflicts of interest to declare.

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Final Results from the Phase IIa Study of the Anti-CXCL12 Spiegelmer® Olaptesed Pegol (NOX-A12) in Combination with Bortezomib and Dexamethasone in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2111.2111 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2111-2111 ◽

Cited By ~ 1

Author(s):

Heinz Ludwig ◽

Katja Weisel ◽

Maria Teresa Petrucci ◽

Xavier Leleu ◽

Anna Maria Cafro ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Dose ◽

High Risk ◽

Partial Response ◽

Plasma Cells ◽

Progression Free Survival ◽

M Protein ◽

Dose Titration ◽

Free Survival ◽

Protein Change

Abstract Background Olaptesed, an L-stereo-isomer RNA aptamer, binds and neutralizes the chemokine CXCL12. By interaction with the chemokine receptors CXCR4 and CXCR7, CXCL12 is responsible for trafficking and homing of normal and malignant blood cells to the bone marrow. Preclinical studies have shown synergistic activity of CXCL12-targeting and anti-myeloma agents, specifically bortezomib (BTZ). Thus, targeting the myeloma niche may increase treatment efficacy. Aims This open label single arm study was conducted to assess the activity and safety of olaptesed when added to the combination of BTZ and dexamethasone (DEX) in patients with relapsed / refractory multiple myeloma (MM). Patients and Methods Twenty-eight relapsed or refractory MM patients (males:females 14:14) were enrolled and treated according to a dose titration design. Olaptesed was administered intravenously at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg in cycles 1, 2 and 3, respectively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, olaptesed was dosed at the highest individually titrated dose. BTZ (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral DEX (20 mg) was added on the day of and on the day after BTZ administration. Response was evaluated based on the uniform IMWG response criteria (Rajkumar SV et. al. Blood 2011; 117: 4691-5). Plasma cell mobilization was studied after a pilot dose of 1 to 4 mg/kg olaptesed administered to the initial 10 patients before start of the regular treatment regimen. Results From Aug 2012 to Feb 2014 we enrolled 28 patients who had received a median of 2 (range 1-6) lines of prior therapy. Pretreatments were lenalidomide (LEN) in 20, BTZ in 14 and carfilzomib in 1 patient. Ten patients had autologous stem cell transplantations prior to entering this study. The patient population enrolled presented predominantly with advanced disease and with adverse outcome predictors. Ten patients had ISS stage III. High-risk cytogenetics were identified in 9 of the 20 patients (45%) with FISH testing available for t(4;14), t(14;16) and/or del17p. Eleven patients were refractory to their last prior treatment, which contained BTZ in 8 cases. After two early withdrawals, 26 patients were available for outcome evaluations. The median number of completed cycles was 8. Progression led to treatment termination in 8 patients. The dose of olaptesed was titrated to 4 mg/kg in all 18 patients treated for 3 or more cycles. The single dose of olaptesed administered to 10 pilot-patients effectively mobilized plasma cells, which increased by approximately 200% for up to 3 days. Based on “best response” of the 26 evaluable patients, the overall response rate was 73%: Two patients (8%) achieved a complete response (CR), 6 patients (23%) a very good partial response (VGPR) and 11 patients (42%) a partial response (PR). Minimal response was recorded in 2 patients (8%), 4 patients (15%) had stable disease and 1 patient (4%) progressive disease. In the 9 evaluable patients with high-risk cytogenetics, the clinical responses were similar. The ORR was 67% with VGPR in 3 (33%) and PR in 3 (33%) patients. Of the 14 patients pre-treated with BTZ, 1 had a CR and 8 a PR (ORR 64%). M-protein decreased rapidly from treatment cycle 1 to cycle 4 with a decrease of ≥50% being observed in 15 of the 26 evaluable patients. Figure 1 shows a waterfall plot of the maximum observed decrease in M-protein. Figure 1: Waterfall Plot of Maximum M-Protein Change Figure 1:. Waterfall Plot of Maximum M-Protein Change Median progression-free survival (PFS) of the evaluable population was 6.5 months. It was also 6.5 months in the 9 patients with high-risk cytogenetics and 6.3 months in the 14 patients pre-treated with BTZ (Figure 2). The median follow-up was 6.3 months. Figure 2: Progression-Free Survival Figure 2:. Progression-Free Survival Treatment with olaptesed in combination with BTZ-DEX was safe and well tolerated without any appreciable increase in adverse events. Conclusions A single dose of olaptesed effectively mobilized plasma cells. Olaptesed in combination with BTZ and DEX resulted in an ORR rate of 73% and PFS of 6.5 months. Response rates and PFS were similar in patients with or without high risk cytogenetic features or with or without previous exposure to BTZ. The combination regimen was well tolerated. These findings merit further exploration of this strategy in randomized trials. Disclosures Weisel: NOXXON Pharma AG: Consultancy. Petrucci:Celgene: Honoraria; Jannsen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Leleu:Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laurent:Bristol-Myers Squibb: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Engelhardt:NOXXON Pharma AG: Consultancy.

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The International Multiple Myeloma Research (IMMEnSE) Consortium: Genetics of Multiple Myeloma Risk and Prognosis

Blood ◽

10.1182/blood.v124.21.3421.3421 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3421-3421

Author(s):

Federico Canzian ◽

Katia Beider ◽

Gabriele Buda ◽

Felipe de Arriba de la Fuente ◽

Marek Dudzinski ◽

...

Keyword(s):

Multiple Myeloma ◽

Blood Donors ◽

Genome Wide Association Study ◽

Efflux Pump ◽

Conflicts Of Interest ◽

Association Studies ◽

Methylation Status ◽

Response To Therapy ◽

Healthy Controls ◽

Key Genes

Abstract We established the IMMEnSE (International Multiple Myeloma rESEarch) consortium, to increase our understanding of the genetic determinants of multiple myeloma (MM) risk, response to therapy and survival. At present we have DNA samples of over 3200 MM cases and 3000 healthy controls from 10 countries, mainly in Europe. For the majority of the cases clinical data on known prognostic factors, therapy outcome and survival have been also collected. We already performed several association studies in the context of the IMMEnSE consortium. In particular, associations were found between MM risk and SNPs in the ABCB1 gene, which encodes for an efflux pump that has a key role in protecting cells from chemical damage (rs10264990: odds ratio (OR) =0.79, 95% confidence interval (CI) 0.68-0.91; p=0.001, and rs17327442: OR=1.99; 95%CI 1.32-3.02; p=0.001). We also investigated the 8q24 region, which has been shown to harbor multiple loci of susceptibility to various cancers, and found an association between a SNP mapping in this region and MM risk (rs2456449: OR=1.37; 95%CI 1.12-1.68; p=0.0022). In addition, IMMEnSE cases and controls were also genotyped for three MM risk SNPs from the first genome-wide association study (GWAS), and the association of two of them (rs4487645 on chromosome 7p15.3 and rs6746082 on chromosome 2p23.3) was confirmed. Finally, SNPs of key telomere-related genes were genotyped and telomere length was measured in MM cases and controls, and a pleiotropic and functional variant of the TERT gene was found to be associated with reduced MM risk (rs2242652: OR=0.81; 95%CI 0.72-0.92; p=0.001). A suggestive association between longer telomeres and increased MM risk was also found (ptrend=0.01). We will study new SNPs emerging as promising candidates from ongoing GWAS on MM risk and survival, as well as SNPs of key genes involved in the pathogenesis of MM. Finally, we plan to study methylation status of key genes involved in MM etiology, and mitochondrial copy number. The role of all these factors will be investigated in relation to MM risk and prognosis. Collection of samples and data of MM cases and controls is ongoing, as well as of subjects with monoclonal gammopathy of undetermined significance (MGUS). Table 1. MM cases and healthy controls collected in the IMMEnSE consortium Country Cases Median age(5th-95th percentile) Controls Median age(5th-95th percentile) Control type Italy 232 63 (46-78) 237 59 (42-76) General population Poland 1,286 63 (42-82) 200 68 (43-79) Blood donors Spain 322 64 (46-82) 1,131 66 (43-84) Hospitalized subjects France 642 57 (37-68) 191 48 (18-63) Blood donors Portugal 70 68 (45-82) 100 58 (53-79) Blood donors Hungary 148 68 (34-90) 105 74 (55-87) Hospitalized subjects Denmark 348 56 (43-65) 1,000 63 (52-73) Blood donors Israel 109 60 (41-77) 95 - Blood donors Canada 62 58 (42-70) - - - Japan 51 66 (47-84) - - - Total 3,270 63 (37-84) 3,059 63 (18-92) Figure 1 Centers involved in IMMEnSE Figure 1. Centers involved in IMMEnSE Disclosures No relevant conflicts of interest to declare.

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Predictive Significance of Serum Beta 2-Microglobulin Levels and M-Protein Velocity for Symptomatic Progression of Smoldering Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3379.3379 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3379-3379 ◽

Cited By ~ 7

Author(s):

Tsuyoshi Muta ◽

Shinsuke Iida ◽

Kosei Matsue ◽

Kazutaka Sunami ◽

Jun Isoda ◽

...

Keyword(s):

Multiple Myeloma ◽

Cumulative Incidence ◽

Plasma Cells ◽

M Protein ◽

Bone Lesions ◽

Landmark Point ◽

Protein Levels ◽

Lytic Bone Lesions ◽

Bone Marrow Plasma ◽

Beta 2 Microglobulin

Abstract Background: Smoldering multiple myeloma (SMM) has been defined as precursor state to symptomatic multiple myeloma (MM). Mayo Clinic demonstrated that the presence of bone marrow plasma cells (BMPC) ≥ 10% and M protein levels ≥ 3 g/dL significantly associated with early progression to symptomatic MM and the serum free-light chain (FLC) ratio of < 0.125 or 8 < was an important additional predictors of progression. PETHEMA showed that the proportion of aberrant plasma cells (aPCs) within the BMPC > 95% as assessed by flow cytometry was another important variable for progression. However, NIH demonstrated the discordance of these two risk models. The aim of this project is to develop the method to predict the symptomatic progression more definitely by simple parameters, usually available at medical practice. Methods: We employed the nation-wide retrospective study. The clinical data of SMM patients were collected from 61 medical centers in Japan and risk predictors of progression to symptomatic MM were analyzed. The diagnosis of SMM is made by the presence of the ratio of bone marrow plasma cells (BMPCs) ≥ 10% or serum M-protein levels ≥ 3 g/dL, and the absence of any myeloma derived end-organ damage. Eligible patients were aged 18 to 90 years, previously untreated, and diagnosed between 2000 and 2012. This study was approved by the institutional review board at all participating institutions. Results: Total 301 patients fulfilled the inclusion criteria. The median age was 67 years (rang 27 to 90). IgG is the major (80%) compared to IgA (15%) or Bence Jones protein (3%). Total 145 patients developed to symptomatic MM. The symptoms consisted of anemia in 66%, lytic bone lesions in 43%, and renal impairment in 10%. Both anemia and lytic bone lesions were seen in 16%. The median time to progression was 4.3 years. The cumulative incidence of progression was 30.7% at 2 years, 50.0% at 4 years, 59.8% at 6 years, and 68.6% at 8 years. Based on multivariate analysis, we firstly identify the serum beta 2-microglobulin (B2MG) levels ≥ 2.5 mg/L as a predictor for the early progression (HR 1.59; 95% CI, 1.11 to 2.29, p = 0.01), as well as the known factors: presence of both BMPC ≥ 10% and M protein levels ≥ 3 g/dL (HR 1.89; 95% CI, 1.31 to 2.73, p = 0.0007), IgA or Bence Jones type (HR:1.61; 95%CI, 1.04 to 2.49, p = 0.03), and immunoparesis (HR:1.88; 95%CI, 1.14 to 3.08, p = 0.01). FLC ratio was examined in 52 patients. A significant association with high risk of progression was observed in patients with FLC ratio of < 0.0625 or 16 < (P = 0.04), but not in those with the ratio of < 0.125 or 8 < (P = 0.09). Cytogenetic abnormality was examined with FISH in 82 patients. The cumulative incidence of progression in patients with either t(4;14), t(14;16), or del(17p) was not significantly different from those without such chromosomal aberration (P = 0.4). Notably, we firstly focused on the rate of rise of the M-protein levels over time which is referred to as the "M-protein velocity". We employed the linear regression analysis to estimate the gradient to assess the M-protein velocity of each patient. The receiver operating characteristics curve analysis showed that the M-protein velocity of 1.035 mg/dL/day was a risk-stratification cut-off point with a high specificity of 0.96 and with a moderate sensitivity of 0.60. Based on the landmark analysis, the serum B2MG levels ≥ 2.5 mg/L at diagnosis (HR 2.76; 95% CI, 1.69 to 4.51, P = 5 x 10–5) and the M-protein velocity > 1 mg/dL/day before the 18-month landmark point (HR 2.27; 95% CI, 1.30 to 3.95, P = 4 x 10–3) had independently correlated with subsequent progression to symptomatic MM. The cumulative incidence of progression of the patients with both the serum B2MG levels ≥ 2.5 mg/L at diagnosis and the M-protein velocity > 1 mg/dL/day showed 67.5% at 2 years, 75.6% at 3 years and 100% at 6.3 years after the landmark point. Conclusions: We identify the novel risk factors consisted of serum B2MG levels ≥ 2.5 mg/L and the M-protein velocity > 1 mg/dL/day for subsequent symptomatic progression. Theoretically, it is possible to emphasis that the serum B2MG levels represent the initial tumor burden of SMM and the M-protein velocity reflects the the growth rate of tumor cells. These results also suggest that the quantification of time-dependent change of measured values should be taken into consideration for the precise prediction of symptomatic progression. This study is supported by the National Cancer Center Research and Development Fund in Japan. Disclosures No relevant conflicts of interest to declare.

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