TWO MAJOR TYPES OF NORMAL 7S γ-GLOBULIN

Normal 7S human γ-globulin was found to contain two fundamental antigenic groups of molecules. The group 1 molecules of normal γglobulin correspond antigenically to group 1 multiple myeloma proteins and Bence Jones proteins; and group 2 molecules of normal γ-globulin correspond antigenically to group 2 multiple myeloma proteins and Bence-Jones proteins. Among pooled human Fr II and several individual γ-globulin preparations, approximately 60 per cent of molecules belong to group 1 and approximately 30 per cent of molecules to group 2 in this classification. The possible existence of a third minor antigenic group, constituting about 10 per cent, is discussed. Antisera to Bence Jones proteins of antigenic group 1 and group 2, in conjunction with I-131-labeled 7S γ-globulin proved to be the most useful system for defining the antigenic groups of normal γ-globulin. The group-specific antigenic determinants of normal 7S γ-globulin molecules were located on the S fragments of these proteins.

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CLASSIFICATION OF MYELOMA PROTEINS, BENCE JONES PROTEINS, AND MACROGLOBULINS INTO TWO GROUPS ON THE BASIS OF COMMON ANTIGENIC CHARACTERS

Journal of Experimental Medicine ◽

10.1084/jem.116.6.859 ◽

1962 ◽

Vol 116 (6) ◽

pp. 859-877 ◽

Cited By ~ 82

Author(s):

Mart Mannik ◽

Henry G. Kunkel

Keyword(s):

Multiple Myeloma ◽

Antigenic Determinants ◽

General Category ◽

Myeloma Protein ◽

Myeloma Proteins ◽

Protein Molecules ◽

Bence Jones Proteins

Antisera to normal 7S γ-globulin and to Bence Jones proteins permit the grouping of myeloma proteins (gamma and beta 2A types), Bence Jones proteins, and the Waldenström type macroglobulins into two fundamental antigenic groups. The antigenic determinants responsible for this grouping are common to all these proteins which fall in the general category of immunoglobulins. Antisera to Bence Jones proteins were particularly useful for this classification since they failed to react with the proteins of the opposite group. These antisera also permit the grouping of normal 7S γ-globulin into two major types. The Bence Jones proteins from individual patients were found to correspond in antigenic group to that of the serum myeloma protein. Studies with antisera to 7S γ-globulin and to Bence Jones proteins indicated that the Bence Jones proteins were antigenically identical to a portion of the corresponding multiple myeloma protein molecules.

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Optimization of Plerixafor Utilization Based on Peripheral Blood CD34+ Count for Autologous Peripheral Blood Stem-Cell Collection

Blood ◽

10.1182/blood-2020-140171 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-41

Author(s):

Gaurav K. Gupta ◽

Sera Perreault ◽

Stuart Seropian ◽

Christopher A. Tormey ◽

Jeanne E. Hendrickson

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Medical Center ◽

Tertiary Care ◽

Peripheral Blood Cd34 ◽

Tertiary Care Medical Center ◽

Group 2 ◽

Group 1

Introduction: Peripheral CD34+ cells may be mobilized using filgrastim (G-CSF) alone or in combination with chemotherapy. However, some patients also require plerixafor, an inhibitor of C-X-C chemokine receptor type-4, for adequate mobilization. Given its cost, judicious utilization of plerixafor is warranted. Material and Methods: A retrospective analysis of autologous stem-cell mobilization was performed at a tertiary-care medical center in adult patients with multiple myeloma and lymphoma; here we will focus on the utility of repeat plerixafor dosing. Patients were mobilized at the treating physician's discretion with filgrastim plus plerixafor or chemotherapy plus filgrastim plus plerixafor. Collections were initiated once peripheral CD34+ counts reached 20/µL (or 10/µL if chemotherapy mobilized); plerixafor was administered if these counts were not reached after 4 or 8 days, respectively, of filgrastim treatment. Results: Patients with multiple myeloma (86) or lymphoma (30) were evaluated. One hundred five were mobilized by filgrastim plus plerixafor and 11 by chemotherapy plus filgrastim plus plerixafor. No patient that received plerixafor with a CD34+ count <5/µL after chemotherapy mobilized the next day. The end collection goal was achieved in 86 (81.9%) of the filgrastim plus plerixafor group and 7 (63.6%) of the chemotherapy plus filgrastim plus plerixafor group. Patients given at least one dose of plerixafor were divided into groups based on collection goal, peripheral blood CD34+ cell count after 1 dose and the first day collection yield: Group 1) Goal of 3x10^6/kg and CD34+ count ≥ 30 cell/µL vs < 30 cell/µL; Group 2) Goal of 6x10^6/kg and ≥ 50% of collection goal after 1 day of collection vs CD34+ count < 50 cell/µL or < 50% of collection goal. Forty of 42 (95%) patients in Group 1 with a CD34+ count ≥ 30 cell/µL achieved their end collection goal after one plerixafor dose. Eighteen of 19 (95%) patients in Group 1 with a CD34+ count <30 cell/µL received a second dose of plerixafor and 8 (44.4%) achieved their end collection goal. Twenty-eight of 32 (87.5%) patients in Group 2 with ≥ 50% of collection goal achieved on the first day of collection reached their end collection goal after one plerixafor dose. Nine of 12 (75%) patients in Group 2 with a CD34+ count of < 50 cells/µL or <50% collection goal received an additional dose of plerixafor and 6 (66.7%) achieved their end collection goal. Conclusion: Based on these data, we have developed the following repeat plerixafor dosing algorithm: 1) for a collection goal is 3x10^6/kg, administer a second dose of plerixafor if the CD34+ count on the first day of collection is < 30 cell/µL, and 2) for a collection goal of 6x10^6/kg, administer a second dose of plerixafor if the CD34+ count on the first day of collection is < 50 cell/µL or if the first day of collection yields <50% of the end goal. This algorithm optimizes pharmacy, apheresis and stem cell processing resources. Disclosures No relevant conflicts of interest to declare.

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A Comparison Between Next-Generation Sequencing and ASO-qPCR For Minimal Residual Disease Detection In Multiple Myeloma: The Clinical Value In ASCT Setting

Blood ◽

10.1182/blood.v122.21.1843.1843 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1843-1843

Author(s):

Hiroyuki Takamatsu ◽

Ryoichi Mura ◽

Jianbiao Zheng ◽

Martin Moorhead ◽

Terasaki Yasushi ◽

...

Keyword(s):

Multiple Myeloma ◽

Next Generation Sequencing ◽

Minimal Residual Disease ◽

Residual Disease ◽

Myeloma Cells ◽

Sequencing Method ◽

Group 2 ◽

Generation Sequencing ◽

Minimal Residual ◽

Group 1

Abstract Background Although molecular complete remission (mCR) in multiple myeloma (MM) can be assessed by allele-specific oligonucleotide (ASO)-PCR, this technique requires preparation of clonotype-specific primers for each individual which is laborious and time-consuming. We utilized a sequencing method, termed the LymphoSIGHT™ platform, which employs consensus primers and high-throughput sequencing to amplify and sequence all rearranged immunoglobulin gene segments present in a myeloma clone. The sequencing method is quantitative at frequencies above 10-5 and the lower limit of detection is below 10-6. Usage of the sequencing method for minimal residual disease (MRD) detection in MM may provide increased sensitivity and specificity, while overcoming the challenges associated with ASO-PCR. Methods We compared the LymphoSIGHTTM method with ASO-qPCR for MRD detection in autografts in the autologous peripheral blood stem cell (PBSC) transplantation (ASCT) setting. Because myeloma cells exist patchily in bone marrow (BM), myeloma cells in PBSC autografts may reflect the whole amount of tumor in vivo. Thirty-six Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients had achieved a partial response (PR) or complete response (CR) after ASCT. BM slides from 28 MM patients and fresh BM cells from 8 MM patients at diagnosis as well as autografts were obtained for DNA extraction. IGH-based ASO-qPCR was performed as described previously (Methods Mol Biol 2009). Using universal primer sets, we amplified IGH variable (V), diversity (D), and joining (J) gene segments, IGH-DJ, and IGK from genomic DNA. Amplified products were subjected to deep sequencing using next-generation sequencing (NGS). Reads were analyzed using standardized algorithms for clonotype determination. Myeloma-specific clonotypes were identified for each patient based on their high frequency in BM samples. The presence of the myeloma clonotype was then assessed in follow-up samples (Faham et al, Blood 2012). Results MRD in autografts could be assessed 36 of 36 (100%) by NGS and 30 of 36 (83%) by ASO-qPCR. MRD in autografts was detected in 27 of 36 (75%) by NGS and 11 of 30 (37%) by ASO-qPCR (Figure 1A). Although we observed a high correlation between NGS and PCR MRD results at MRD levels of 10-5 or higher, ASO-qPCR could not detect myeloma cells at MRD levels of 10-5 or lower. Two cases where MRD was not detected by NGS (MRDNGS(-)) and 14 MRDNGS(+) cases received post-ASCT therapy using novel agents such as bortezomib/lenalidomide/thalidomide while 7 MRDNGS(-) cases and 13 MRDNGS(+) cases were followed without post-ASCT therapy. The best post-ASCT responses were as follows: 6 (67%) mCR, 1 (11%) sCR and 2 (22%) VGPR in 9 MRDNGS(-) cases; 2 (14%) mCR, 2 (14%) sCR, 2 (14%) CR, 8 (58%) VGPR in 14 MRDNGS(+) cases with post-ASCT therapy; 2 (15%) sCR, 10 (78%) VGPR and 1 (7%) PR in 13 MRDNGS(+) cases without post-ASCT therapy. The MRDNGS(-) cases tended to show a better PFS than the MRDNGS(+) cases with post-ASCT therapy (P = 0.400) and showed a significantly better PFS than those without post-ASCT therapy (P = 0.032) (Figure 1B) although overall survival rates were comparable among the three groups. To investigate the value of sensitive detection by NGS, we compared PFS in 7 MRDNGS(-) cases (Group 1) with the 6 MRDNGS(+) cases where MRD was not detected by ASO-qPCR (MRDASO(-)) (Group 2). The patients in both groups did not receive any post-ASCT therapy. Group 1 tended to show a better PFS than Group 2 (P = 0.091) (Figure 1C). This underscores the value of sensitive detection of MRD in MM. Conclusions A high correlation between NGS and PCR MRD results was observed, and MRD-negativity in PBSC autografts revealed by NGS may be more closely associated with durable remission of MM than that revealed by ASO-qPCR. Disclosures: Zheng: Sequenta, Inc.: Employment. Moorhead:Sequenta, Inc.: Employment. Faham:Sequenta, Inc.: Employment.

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Exploration of Survival Stratification of Patients with Multiple Myeloma after First Relapse Using Real World Data

Blood ◽

10.1182/blood.v128.22.2417.2417 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2417-2417 ◽

Cited By ~ 1

Author(s):

Roman Hájek ◽

Jiri Jarkovsky ◽

Walter Bouwmeester ◽

Maarten Treur ◽

Lucy DeCosta ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Treatment Decision ◽

Advisory Committees ◽

Patient Risk ◽

First Relapse ◽

Survival Expectations ◽

Group 2 ◽

Group 1

Abstract Risk stratification tools in multiple myeloma (MM), such as the International Staging System (ISS) and the revised-ISS (R-ISS), have improved understanding of survival expectations using the strongest known predictors at time of diagnosis. Given their value at diagnosis, these have been used to define risk after first relapse in clinical trials and standard practice. Although these tools have not been validated in this setting, their use arises because of the need to better characterize patients in order to define survival expectations and treatment decisions. Once the patient has relapsed, there are additional variables that may need to be considered in order to systematically assess patient risk, understand drivers of disease progression and ensure that treatment strategies are aligned with patient risk. Using data from the Czech Registry of Monoclonal Gammopathies (RMG), this study assessed predictors of overall survival (OS) and developed a new Risk Stratification Tool (RST) to predict OS at time of treatment decision after first relapse (TTD1). The RST was developed by estimating the strongest predictors of OS at both diagnosis and TTD1 to define the final parameters for inclusion. The cut-offs for each parameter reflect conventional cut-offs used in clinical practice and some were supported by evidence using a K-adaptive Partitioning for Survival (KAPS) approach, which stratified data based on distinct survival expectations. The hazard ratio (HR) of the selected predictors was used to assign a score per parameter at a patient level where missing data were entered with a contribution equal to 1. Using the full RMG data set at TTD1 (N=1418) the (KAPS) method was run to define 4 distinct group of patients based on survival expectations. The RST consists of 4 dimensions and 12 item questions based on the strongest predictors of survival at TTD1, "Patient Factors" (age and Eastern Cooperative Oncology Group (ECOG) performance status), "Existing Stratification Factors (R-ISS at diagnosis and ISS at TTD1), "Disease Factors" (calcium level, number of bone lesions, extramedullary disease, thrombocyte count, clonal cells in bone marrow aspiration cytology, lactate dehydrogenase [LDH]) and "Treatment history" (refractory to prior therapy, time-to-next-treatment [from initiation of treatment of first anti-myeloma drug to initiation of treatment at first relapse]) (Table 1). Subsequently, we explored each group based on distribution of frailty-driven measures (age and ECOG) and aggressiveness of the disease (rest of parameters) to understand what is driving stratification. Figure 1 shows the KM curve of survival after TTD1 for each of the 4 groups estimated by KAPS. The new analysis shows strong differentiation in survival expectations between the 4 groups (Table 2), showing significantly different OS for all groups compared with reference. The median OS and Confidence Intervals per group did not overlap, supported by the positive association of HR across groups. The distribution of the Total Score (Figure 2) is between 1 and 2, which shows sufficient sensitivity to differentiate these groups by survival expectations. The RST can then be split into Frailty Score and Aggressiveness Score (Figure 3a & b) to understand what is driving disease severity. The distribution of these two scores shows that group 1 consists of low patient frailty and low disease aggressiveness, whereas group 4 shows high on both elements. Group 2 has an increased score for frailty and marginal increase in aggressiveness compared with group 1, and group 3 stratification is driven by an increase in aggressiveness over group 2. The analysis showed that predictors, patient's experience of prior treatment and level of disease impact at the point of treatment decision after first relapse provided an initial framework to demonstrate strong differentiation between groups based on patient severity and what is driving patient risk (patient frailty vs aggressiveness of disease). The RST has shown promising results when applied to the RMG, however further validation of this work is required using other real-world and clinical trials data. Nevertheless, this analysis is a first step in systematically assessing patient risk to improve the selection of treatments based on improved understanding of patient profiles. Disclosures Hájek: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy; Celgene: Consultancy, Research Funding. Bouwmeester:Amgen: Consultancy. Treur:Amgen: Consultancy. DeCosta:Amgen: Employment, Other: Holds Amgen Stock. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Raab:BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Schoen:Amgen: Employment, Other: Holds Amgen Stock. Szabo:Amgen: Employment, Other: Holds Amgen Stock. Lucie:Amgen: Consultancy. Gonzalez-McQuire:Amgen: Employment, Other: Holds Amgen Stock.

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Influence of First-Line Regimens on the Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.931.931 ◽

2004 ◽

Vol 104 (11) ◽

pp. 931-931 ◽

Cited By ~ 1

Author(s):

Bimalangshu R. Dey ◽

Benjamin Cox ◽

A. Jo Chien ◽

Martin Caron ◽

Steven L. McAfee ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Dose Chemotherapy ◽

High Dose ◽

Newly Diagnosed ◽

First Line ◽

Conventional Chemotherapy ◽

Hematopoietic Stem ◽

Group 2 ◽

Group 1

Abstract Randomized trials that incorporated high-dose chemotherapy (HDC) plus autologous hematopoietic stem-cell transplantation (Au-HSCT) into the early treatment of patients with newly diagnosed multiple myeloma demonstrated superior overall and event-free survival (EFS) in patients 65 years of age or younger, who received Au-HSCT, as compared with patients who received conventional chemotherapy. Based on these encouraging results, Au-HSCT is recommended for patients with myeloma as part of their initial treatment, and today, myeloma is the most common indication for HSCT in the world. All patients in these trials received four to six months of conventional chemotherapy prior to HDC and Au-HSCT. In practice, however, both in the community as well as in academic hospitals, patients are undergoing Au-HSCT after being treated with various first-line regimens, including chemotherapeutics, high-dose dexamethasone (HDex), immunomodulatory drugs such as thalidomide and recently, proteasome inhibitors. In this retrospective study, we examined the impact of first-line therapy on the outcomes following Au-HSCT. Our objective was to compare two treatment groups - chemotherapy versus non-chemotherapy, prior to Au-HSCT - with respect to survival after Au-HSCT. Between 1997 and 2004, 37 previously untreated evaluable patients with myeloma, received either chemotherapy (group 1, n=25; vincristine, adriamycin and dexamethasone (VAD), n=24; melphalan and prednisone (MP), n=1) or non-chemotherapy regimens (group 2, n=12; HDex, n=9; thalidomide plus HDex, n=3), then received HDC followed by cyclophosphamide plus granulocyte colony stimulating factor-mobilized HSCT. The median age of patients in group 1 was 58 (range, 44–73) years and in group 2 was 55 (range, 41–67) years; 22 patients in group 1 (88%) and 10 patients in group 2 (83%) had stage III disease; the median times from diagnosis to HSCT were 6 (range, 5–16) and 8 (range, 5–25) months, respectively, in groups 1 and 2. The rates of complete and near-complete response were 44% in group 1 and 42% in group 2; the rates of partial responses were also similar: 48% and 42% respectively. The median duration of EFS was 31 (range, 7–89) months, and the median overall survival (OS) was 55 (range, 12–98) months in group 1, as compared with group 2 where EFS and OS were 21 (range, 12–40) and 31 (range, 16–76) months, respectively. The EFS at 3 years was 44% in group 1 and 25% in group 2, and OS at 5 years was 32% in group 1 and 8% in group 2 (statistically not significant). In conclusion, patients with newly diagnosed myeloma, when treated with chemotherapy prior to Au-HSCT, may have long-term overall and EFS advantages, as compared with patients who are treated with first-line non-chemotherapy regimens. The reasons for the longer duration of response in the chemotherapy group despite similar response rates in the two groups are unknown, but may be due to more effective suppression of residual disease or non-specific damage to the marrow microenvironment, which is necessary for the growth of myeloma cells. Although, the difference in survival outcomes following Au-HSCT between the two groups did not achieve statistical significance, our results raise an important question regarding the “adequacy” of different first-line regimens prior to Au-HSCT, and therefore, justify the need for prospective randomized studies to evaluate optimal pre-AuHSCT induction therapy.

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Impact of Peripheral Blood Stem Cell Recruitment on Outcome of Single or Double Autologous Hematopoietic stem Cell Transplantation for Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.5221.5221 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5221-5221

Author(s):

Mauricette Michallet ◽

Quoc-Hung Le ◽

Anne-Sophie Michallet ◽

Anne Thiebaut ◽

Emmanuelle Tavernier ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Stem Cell ◽

Light Chains ◽

Hematopoietic Stem ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Multiple myeloma remains one of the best indication for intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoT). Intensive therapy followed by autologous transplantation is superior to conventional chemotherapy and it was demonstrated that two autoT were superior to one except for patients in very good partial response or in complete response after the first autotransplant. Peripheral blood stem cells (PBSC) can be used as well as bone marrow as HSC source with the same efficacy but very few data have been reported regarding PBSC recruitment. The main goal of our work was to study the impact on overall and event-free survival (OS and EFS) of PBSC recruitment using either growth factors (GF) alone (steady state) or chemotherapy followed by GF. Secondly, we performed a multivariate analysis studying influence on OS and EFS of sex, age, lines of therapy, pretransplant status, TBI, PBSC recruitment and number of autoT. We have analyzed 193 PBSC autoT (1 autoT=160, 2 autoT=33) performed for 160 MM patients [81 males and 71 females, mean age: 55 years (39–71)]. At diagnosis, 88 patients presented a MM Ig G (70k and 18l), 28 Ig A (16k and 12l), 3 Ig D (1k and 2l), 21 light chains k and 13 light chains l, 3 non secreting and 4 with plasmocyte leukemias. According to Durie and Salmon classification 75% of patients were in stage III, 15% in stage II and 10% in progressive I. Before transplantation, patients have received 1 line of poly-chemotherapy (n=141), 2 lines (n=15) or 3 lines (n=4) and 154 were evaluated for the response with 11 complete remission, 113 partial remission and 30 stable or evolutive disease just before transplant. As HSC (n=189), patients received PBSC which were recruited by GF alone (n=105) or cyclophosphamide+GF (n= 84). Conditioning (n=189),consisted in melphalan and TBI (n=51), melphalan alone (n=132), melphalan associated to cyclophosphamide or busulfan (n=6). We divided the population into 4 groups : group 1 who received one autoT of PBSC recruited by GF (n=76), group 2 one autoT of PBSC recruited by chemotherapy+GF (n=50), group 3 two autoT of PBSC recruited by GF (n=16) and group 4 two autoT of PBSC recruited by chemotherapy+GF (n=17). The median follow-up (FU) of the 4 groups were different with shorter FU (group 3: 9.9 months, group 4: 13 months) for patients who received tandem autoT because of the recent character of this strategy as compared to a long term follow-up for patients who received only one transplant (group 1: 35months, group 2: 55.3 months). Probabilities of OS and EFS at 2 years were 76% (95%CI 67–87) and 60% (95%CI 49.5–73) for group 1, 77% (95%CI 65–90.5) and 70% (95%CI 57.5–85) for group 2, 87.5% (95%CI 73–100) and 72.9% (95%CI 49–100) for group 3, 100% and 66.7% (95%CI 36–100) for group 4. The difference was not significant because of follow-up differences between the 4 groups and small number of patients in groups 3 and 4. In addition, multivariate analysis did not show any significant influence of the different studied parameters on OS and EFS. Nevertheless, because of these interesting preliminary results, a longer follow-up is warranted for definitive conclusions.

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Use of Lenalidomide (Revlimid® +/− Corticosteroids in Relapsed/Refractory Multiple Myeloma Patients with Elevated Baseline Serum Creatinine Levels.

Blood ◽

10.1182/blood.v108.11.3548.3548 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3548-3548 ◽

Cited By ~ 4

Author(s):

Donna E. Reece ◽

Esther Masih-Khan ◽

Christine Chen ◽

Lisa Wang ◽

Saima Dean ◽

...

Keyword(s):

Multiple Myeloma ◽

Platelet Count ◽

Serum Creatinine ◽

Median Number ◽

Bleeding Complications ◽

Baseline Serum ◽

Prior Therapy ◽

Group 2 ◽

Grade 3 ◽

Group 1

Abstract Lenalidomide (Revlimid®; Rev) is an important novel agent for the treatment of multiple myeloma (MM) patients (pts). Since MM pts are at risk for renal insufficiency, we evaluated whether an abnormal serum creatinine (cr) level affected the outcome of pts treated with Rev +/− corticosteroids (CS). Between 12/05 and 07/06, 69 MM pts who had progressed after at least 1 line of prior therapy were treated in our center with Rev +/− CS as part of Celgene’s Expanded Access Program in Canada. Eligibility criteria included a platelet count (pl ct) ≥ 30 x 109/L and neutrophil count ≥ 1.0 x 109/L; a cr level of ≤220 umol/L was required unless a waiver was obtained. Protocol therapy consisted of Rev + dexamethasone (dex) in 44, Rev + prednisone in 7, Rev + dex and prednisone at different time points in 5 and Rev alone in 13. The median age was 60 yrs (35–79); 36 (52%) were male; median β2-microglobulin was 214 nm/L (114–1420); Ig subtype was IgG in 42, IgA in 12, IgM in 1 and light chain only in 14. Prior therapy included ASCT in 59 pts (86%), thalidomide in 51 (74%), bortezomib in 21 (30%) and oral cyclophosphamide in 52 (75%); the median number of prior regimens was 2 (1–5). Twenty-three pts (33%) had an elevated baseline cr level (> 89 umol/L for females and 109 umol/L for males in our center). The median cr was 138 umol/L (110–412) in these pts (group 1), compared with 80 umol/L (51–109) in group 2 (control) (p=0.001). Five pts in group 1 had a cr level ≥ 177 umol/L (2 mg/dL). Both groups were similar except that group 1 had more males (p=0.04) and the baseline platelet count (pl ct) was lower (35% vs. 4% with pl ct less than 50 x 109/L; p=0.0007). RESULTS: The median number of cycles of Rev +/− CS given to date was 4 (1–8) in both groups, and the median follow-up is 4 mos (0.5–8). After 3 cycles of Rev, the median cr was 104 umol/L (61–372) in group 1 and 79 umol/L (53–180) in group 2. In group1, cr decreased in 39% and increased in 26%, compared with 39% and 32% in group 2, respectively (p=0.56). The incidence of grade 3–4 neutropenia was 43% vs. 46%, febrile neutropenia 13% vs. 9%, any infection 17% vs. 20% and G-CSF use 66% vs. 57% among pts in group 1 vs. 2 (p=NS for all comparisons). More in group 1 experienced grade 3–4 thrombocytopenia and required at least 1 pl transfusion (52% vs. 17%; p=0.003). In group 1, 6 (26%) pts required pl transfusion in only 1 cycle, 5 (22%) in 2 cycles and 1 (4%) in 3 cycles. However, the only 2 significant bleeding complications were seen in group 2. There were 2 deaths (8.7%) in group 1 and 4 (8.7%) in group 2. Table 1 summarizes the preliminary anti-myeloma results in these 2 groups. CONCLUSIONS: Rev +/− CS can be given safely to selected patients with an elevated baseline cr level; pts with an elevated cr had lower baseline pl cts, and required more pl transfusions; the response rate, PFS and OS to date are similar in patients with a normal vs. elevated cr level. Table 1 Serum cr N nCR/PR PFS 95% CI OS 95% CI PFS=progression free survival; OS=overall survival; the differences are not significant. Elevated 23 61% 30% 11–52% 72% 46–86% Normal 46 54% 50% 31–67% 76% 55–88%

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Surgical Control/Cure of 5TGM1 Murine Multiple Myeloma Model By Thyroparathyroidectomy

Blood ◽

10.1182/blood.v124.21.3387.3387 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3387-3387

Author(s):

Maurizio Zangari ◽

Donghoon Yoon ◽

Hanna Yoo ◽

Young Sik Kim

Keyword(s):

Multiple Myeloma ◽

Parathyroid Hormone ◽

Proteasome Inhibitor ◽

Research Funding ◽

Bone Lesions ◽

Post Surgery ◽

Human Multiple Myeloma ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract The 5TGM1 transplanted C57BL6/KaLwRij mouse is widely used to study murine multiple myeloma development. It recapitulates many features of human multiple myeloma including monoclonal paraprotein as well as bone lesions. Using this mouse model we demonstrated the crucial role of the parathyroid hormone 1 receptor (PTH1R) on the survival of mice exposed to proteasome inhibitor drugs such as bortezomib and carfilzomib; specifically the blockage of the PTH1R function by parathyroid hormone antagonist (PTH 7-34) resulted in significant abrogation of the beneficial survival effect of proteasome inhibitor drugs. To further investigate the effect of the parathyroid hormone (PTH) axis on murine myeloma development we performed thyroparathyroidectomy on the C57BL6/KaLwRij mouse before or after 5TGM1 transplantation. Thyroparathyroidectomy was performed by trained personnel in general anesthesia with isoflurane; all surgical/postsurgical procedures and animal welfare followed an IACUC approved protocol at the University of Arkansas. To prevent hypocalcaemia at postsurgery, 1M CaCl2 solution in the drinking bottle was supplemented for a week. All tested mice received 0.5X106 5TGM1 cell infusion by intravenous injection; mice were divided into three groups; Group 1 control mice (n=10) received 5TGM1 infusion at day 0; Group 2 included 15 mice which on day 10 post 5TGM1 cell infusion underwent thyroparathyroidectomy; Group 3 included 15 mice which at 20 days post-surgery received infusion of 5TGM1 cells. 30% of animals experienced post-surgical complications and died in the first 7 days from procedure; those animals were not included in this survival analysis which is based on 10 animals for each cohort. Blood samples were collected at weekly intervals for IgG2 measurements. The survival curves of mice recovered after surgery are shown in the figure. Figure 1 Figure 1. All control mice (group 1) developed myeloma progression and died within 3 weeks post-transplant; 2 mice from group 2 and 5 mice of the third cohort manifested disease. All 7 animal deaths were pathologically and serologically attributed to myeloma progression. Compared to controls thyroparathyroidectomized mice (Group 2 and Group 3) showed significantly longer survival p<0.001 and p=0.003, respectively. The 13 surviving mice are still alive 6 months post-procedure and have not shown any serological or clinical evidence of disease progression. Two mice from previous experiment set are still alive and healthy after more than 2 years follow-up. In conclusion thyroparathyroidectomy achieves durable control and possibly cure of the 5TGM1 murine myeloma model suggesting an endocrinological control of myeloma progression. Currently the mechanism of action is under investigation. Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.

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Epidemiology Unknown: Developing an Approach to Identify Potential Smoldering Multiple Myeloma Cases

Blood ◽

10.1182/blood-2021-148196 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4722-4722

Author(s):

Raleigh A. Fatoki ◽

Diane M. Carpenter ◽

Adnan Khan ◽

Ryan Stevenson ◽

Joan C. Lo ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cancer Registry ◽

Research Funding ◽

Physician Visit ◽

Lytic Lesions ◽

Group 3 ◽

Race Ethnicity ◽

Group 2 ◽

Group 1

Abstract Background Smoldering Multiple Myeloma (SMM) is an asymptomatic clonal plasma cell disorder that identifies patients at risk for progression to Multiple Myeloma (MM). The standard of care for SMM has traditionally been observation, but some cancer centers are now treating high-risk SMM before progression to MM. The diagnostic criteria for SMM have also changed in recent years, and current estimates of SMM are derived from large MM databases and observations from tertiary centers. The goal of this study was to develop an approach for identifying SMM cases in a large integrated healthcare delivery system to better characterize the epidemiology of SMM in community-based populations. Methods This retrospective, observational study was conducted in Kaiser Permanente Northern California (KPNC) using KPNC SEER-based Cancer Registry data and information from the electronic health record (EHR). Potential SMM cases from 1/1/2010 to 12/31/2018 were identified using three approaches: Group 1 - identified via the KPNC Cancer Registry based on indicators of 'asymptomatic myeloma', 'evolving myeloma', and 'smoldering myeloma'; Group 2 - identified via the KPNC Cancer Registry as MM cases who had a physician visit note containing the word 'smoldering' but did not begin treatment within 1 year of diagnosis; Group 3 - identified via the KPNC Cancer Registry as MM cases who had a physician visit note containing the word 'smoldering' but did begin treatment within 1 year of diagnosis. Chart review was performed for these potential SMM cases (Groups 1-3) to document initial bone marrow biopsy results (bone marrow plasma cell percentage, BMPC) and skeletal findings (presence or absence of lytic bone lesions) around the time of biopsy. When BMPC was reported as a range, the highest value was captured. Patient demographics (age, sex and race/ethnicity) were obtained from the EHR. Bivariate analyses were performed using the chi-squared test and the Wilcoxon-Mann-Whitney nonparametric test. For binomial comparisons by mode of potential SMM case identification, Groups 1 and 2 were combined and compared to Group 3. Results A total of 471 potential SMM cases were identified, including 178 (37.8%) via Group 1, 35 (7.4%) via Group 2, and 258 (54.8%) via Group 3 (Figure). The median age was 71 years (interquartile range, IQR 62-78) and 40.0% were female. The racial/ethnic distribution included 57.1% White, 17.6% Black, 10.8% Hispanic, 13.6% Asian, and 0.9% other/unknown race. There were no significant differences across groups (Group 1+2 vs Group 3) with respect to age (p=0.07), sex (p=0.85), or race/ethnicity (p=0.81). There were 442 (93.8%) who underwent bone marrow biopsy. Among those with BMPC data, the median BMPC for Group 1 was 20.0% (IQR 10.0%-28.0%); for Group 2 was 25.0% (IQR 12.5%-50.0%), for Group 3 was 28.0% (IQR 15.0%-50.0%) (p<0.001 comparing Groups 1+2, combined median 20.0%, IQR 10.0%-30.0%, vs Group 3, 28.0%, IQR 15.0%-50.0%). The proportion with BMPC ≥60% was 4%, 13%, and 22% for Groups 1, 2, and 3, respectively (Figure). There were 413 (87.7%) who had skeletal imaging (n=405, 86.0% with available results) within 6 months of diagnosis. Of those with imaging results available to view, n=68 were found to have lytic lesions; 7.6% among Group 1, 6.9% among Group 2, 24.9% among Group 3 (p<0.001 comparing Groups 1+2, 7.5%, vs Group 3, 24.9%). Discussion This study used a multifaceted approach to identify potential SMM cases from a large real-world clinical population in an integrated health system. We used an approach similar to prior SMM epidemiological studies and also included those with physician visit notes specifically containing the word 'smoldering' within the text. The vast majority of our cohort had BMPC between 10 and 60%, but those who received treatment within 1 year had greater BMPC and a higher proportion of lytic lesions. This suggests those who received treatment, Group 3, may have actually had a MM diagnosis, and physician visit notes containing the word 'smoldering' may have been intended to communicate something other than a SMM diagnosis. Further analyses will determine the effectiveness of each approach by confirming SMM cases according to the International Myeloma Working Group diagnostic criteria with incorporation of laboratory data and additional clinical findings. Among confirmed cases of SMM, the rate of progression to MM and the severity of end-organ damage at time of progression will be assessed. Figure 1 Figure 1. Disclosures Lo: Novartis: Research Funding; Bristol-Myers-Squibb: Research Funding; CSL-Bering: Research Funding.

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Double-intensive therapy in high-risk multiple myeloma

Blood ◽

10.1182/blood.v79.11.2827.bloodjournal79112827 ◽

1992 ◽

Vol 79 (11) ◽

pp. 2827-2833 ◽

Cited By ~ 85

Author(s):

JL Harousseau ◽

N Milpied ◽

JP Laporte ◽

P Collombat ◽

T Facon ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

High Risk ◽

Autologous Transplantation ◽

High Dose ◽

High Dose Therapy ◽

Hematopoietic Stem ◽

Dose Therapy ◽

Group 2 ◽

Group 1

A high remission rate is achieved with high-dose melphalan (HDM) in multiple myeloma (MM), and autologous transplantation of hematopoietic stem cells allows a prompt hematologic recovery after high-dose therapy. We treated 97 patients with high-risk MM (group 1:44 advanced MM including 14 primary resistances and 30 relapses; group 2: 53 newly diagnosed MM) with a first course of HDM. For responding patients a second course of high-dose therapy with hematopoietic stem cell support was proposed. After the first HDM, the overall response and complete remission rates were 71% and 25% with no significant difference between the two groups. The median durations of neutropenia and thrombocytopenia were significantly longer in group 1 (29.5 days and 32 days, respectively) than in group 2 (23 days and 17 days, respectively). This severe myelosuppression led to eight toxic deaths and the fact that only 38 of the 69 responders could proceed to the second course (three allogenic and 35 autologous transplantations). Among the 35 patients undergoing autologous transplantation (10 in group 1, 25 in group 2), 31 received their marrow unpurged collected after the first HDM, and four received peripheral blood stem cells. The median durations of neutropenia and thrombocytopenia after autologous transplantation were 24 days and 49 days, respectively. Two toxic deaths and nine prolonged thrombocytopenias were observed. The median survival for the 97 patients was 24 months (17 months in group 1, 37 months in group 2) and the median duration of response was 20 months. The only parameters that have a significant impact on the survival are the age (+/- 50 years) and the response to HDM. The median survival of the 35 patients undergoing autologous transplantation is 41 months, but the median duration of remission is 28 months with no plateau of the remission duration curve. Patients responding to HDM may have prolonged survival, but even a second course of high-dose therapy probably cannot eradicate the malignant clone.

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