The Clinical Features of Multiple Myeloma with AL Amyloidosis

Background Multiple myeloma and AL amyloidosis are both caused by the clonal proliferation of the abnormal plasma cells. Although, the difference of the genetic features of multiple myeloma and AL amyloidosis has been reported, we see some patients present with both cases. We retrospectively investigated the clinical features of patients diagnosed with multiple myeloma and AL amyloidosis. Methods We reviewed medical records of patients who were diagnosed with multiple myeloma and AL amyloidosis before initiating treatment during January 2009 to November 2019 in our institution. We excluded patients who did not reach 10% of the plasma cells in the bone marrow. Patients diagnosed with light chain deposition disease were excluded. Treatment regimens were at the discretion of the treating physician. Results Forty-two patients were diagnosed with multiple myeloma and AL amyloidosis. The median follow-up time since diagnosis was 20 months [0-89]. The median age was 63-year-old [43-85]. There was no difference between the sex (male: female=1:1). Twenty-nine (69.0%) patients had lambda type of light chain. Patients with ISS stage I, II, and III were 13(31.7%), 21(51.2%), and 7(17.1%). Patients with R-ISS stage I, II, and III were 4(10.3%), 30(76.9%), and 5(12.8%). Patients with Revised Mayo Clinic AL amyloidosis Staging System 1, 2, 3, and 4 were 3(10.0%), 4(13.3%), 8(26.7%), and 15(50.0%). Twelve (35.3%), 2 (6.9%), 1 (3.4%) and 1 (4.0%) patients had t(11;14), t(4;14), t(14;16) and del(17p) by FISH analysis, respectively. Fourteen (33.3%), 16(38.1%), and 8(19.0%) patients were diagnosed with cardiac, renal, and hepatic amyloidosis, respectively. Thirty-five (83.3%) patients received Bortezomib containing regimen for the initial treatment (e.g., Bortezomib+Dexamethasone(7.1%), Cyclophosphamide+Bortezomib+Dexamethasone(23.8%), Bortezomib+Melphalan+Dexamethasone(7.1%), Bortezomib+Melphalan+Prednisolone(9.5%), Bortezomib+Lenalidomide+Dexamethasone(35.7%)). Thirteen (31.0%) patients underwent autologous stem cell transplantation with high dose melphalan. Median PFS was 25 months and the median OS was 82 months. There were no significant differences in OS between the I-SSS, R-ISSS, and Revised Mayo Clinic AL amyloidosis Staging System groups. Patients diagnosed with cardiac or hepatic amyloidosis had significantly worse outcome. The median OS diagnosed with and without cardiac amyloidosis were 14 and 28 months (p value = 0.034), and the median OS diagnosed with and without hepatic amyloidosis were 8 and 24 months (p value = 0.012). Conclusion Multiple myeloma with AL amyloidosis, especially cardiac or hepatic amyloidosis, has a poor prognosis even if treated with novel agents. Searching for the optimal treatment for these patient groups remains to be an issue. Disclosures Nashimoto: Janssen: Speakers Bureau; Celgene: Speakers Bureau. Tsukada:Takeda pharmaceutical co: Speakers Bureau. Ishida:Ono pharmaceutical co: Speakers Bureau; Takeda pharmaceutical co: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria.

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Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis

Blood ◽

10.1182/blood-2018-06-858951 ◽

2019 ◽

Vol 133 (3) ◽

pp. 215-223 ◽

Cited By ~ 36

Author(s):

Brian Lilleness ◽

Frederick L. Ruberg ◽

Roberta Mussinelli ◽

Gheorghe Doros ◽

Vaishali Sanchorawala

Keyword(s):

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Light Chain ◽

Cardiac Involvement ◽

Staging System ◽

Stage I ◽

Stage Iiib ◽

Stage Ii ◽

Al Amyloidosis ◽

Derivation Cohort

Abstract Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.

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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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Clinical Features and Treatment Response of Light Chain (AL) Amyloidosis Diagnosed in Patients With Previous Diagnosis of Multiple Myeloma

Mayo Clinic Proceedings ◽

10.4065/mcp.2009.0547 ◽

2010 ◽

Vol 85 (3) ◽

pp. 232-238 ◽

Cited By ~ 40

Author(s):

Sumit Madan ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

Francis Buadi ◽

Suzanne R. Hayman ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Response ◽

Clinical Features ◽

Light Chain ◽

Al Amyloidosis ◽

Previous Diagnosis

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Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8010 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8010-8010 ◽

Cited By ~ 3

Author(s):

Ping Zhou ◽

Adin Kugelmass ◽

Denis Toskic ◽

Amandeep Godara ◽

Teresa Fogaren ◽

...

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Plasma Cells ◽

Unmet Need ◽

Al Amyloidosis ◽

Cell Transplant ◽

Rt Pcr ◽

Smoldering Multiple Myeloma ◽

Increased Risk ◽

Germline Genes

8010 Background: In systemic AL amyloidosis (AL), caused by clonal Ig free light chains (LC) produced in 75% of cases by λ clones, patients often present with advanced organ damage, making earlier diagnosis a critical unmet need. Five λ IGLV germline genes account for 75% of AL λ-type ( IGLV 6-57, 1-44, 2-14, 1-51, 3-1) (Blood 2017;129:299), representing 56% of all AL patients. Relative risk of AL versus MM with these clonal genes can be high (7.3, 6-57; 2.5, 1-44), intermediate (1.7, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1). Progression to AL from smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) occurs but is not well appreciated (JCO 2014; 32:2679). SAVE is a trial for λ SMM or λ MGUS patients with a κ:λ FLC ratio < 0.26 and difference between involved and uninvolved FLC > 23mg/L (JCO 2014;32:2699). Methods: Eligible patients ship peripheral blood (PB) or bone marrow (BM) samples to us for RT-PCR with cDNA from CD138+ cells, using primers for the Vλ families (Blood 2001;98:714). Amplicons are sequenced and the IGLV germline genes identified in IMGT (ImMunoGene-Tics, www.imgt.org). If the germline gene is AL-related, further evaluation is pursued. Results: Twenty asymptomatic λ patients from 18 states have been enrolled (3M, 17F) and 23 PB and 4 BM specimens obtained. Medians of months from diagnosis, involved FLC, κ:λ ratios, MNC and CD138-selected cells were 20.5 months, 113mg/L, κ:λ 0.06, 8.1x106 (0.8-24) and 3x105 (0-30), respectively. Seventeen patients have had IGLV genes identified, 12 with the first and 5 with additional specimens including 4 BM. Increased risk of AL was identified in 7 patients, 2 of whom had undiagnosed AL (both with IGLV2-14 germline genes). One patient with SMM diagnosed in 2016 had AL λ-type with GI involvement and is 9 months status post MEL 200 stem cell transplant (SCT), and the second with SMM diagnosed in 2009 had cardiac AL λ-type by heart biopsy with an NT-proBNP 171 (but with a suggestive MRI) and is en route to SCT. Conclusions: The SAVE trial enables early diagnosis of AL λ-type based on the λ IGLV gene used by the clonal plasma cells. By RT-PCR in this pilot study we identified the clonal λ gene 85% of the time. Earlier diagnosis will enable treatment with effective therapy such as MEL 200 SCT. Clinical trial information: NCT02741999.

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A case of light chain (AL) amyloidosis associated with IgD multiple myeloma (MM): clinical features, laboratory findings and outcome

Amyloid ◽

10.3109/13506129.2011.574354043 ◽

2011 ◽

Vol 18 (sup1) ◽

pp. 117-118

Author(s):

R. Rizzi ◽

R. Miccolis ◽

E. Rinaldi ◽

B. Bonerba ◽

M. Rossini ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Features ◽

Light Chain ◽

Al Amyloidosis ◽

Laboratory Findings

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Performance of Free Light Chain Assays in Clinical Practice.

Blood ◽

10.1182/blood.v104.11.757.757 ◽

2004 ◽

Vol 104 (11) ◽

pp. 757-757 ◽

Cited By ~ 3

Author(s):

Jerry A. Katzmann ◽

Angela Dispenzieri ◽

Roshini S. Abraham ◽

Robert A. Kyle

Keyword(s):

Multiple Myeloma ◽

Clinical Practice ◽

Light Chain ◽

Test Performance ◽

Plasma Cells ◽

Clinical Laboratory ◽

Lymphoproliferative Disease ◽

Free Light Chain ◽

Al Amyloidosis ◽

Light Chain Deposition Disease

The quantitative assay for free light chains (FLC) is a recently introduced commercial product (FREELITETM, The Binding Site, Ltd.) that has been reported to be sensitive and specific for detecting and monitoring free light chain diseases such as primary systemic amyloidosis (AL), light chain deposition disease (LCDD), non-secretory multiple myeloma (NSMM), and LCMM (light chain multiple myeloma). We have prospectively evaluated the test performance in clinical practice. Results : In 2003, our Clinical Laboratory received samples for FLC assays from 1020 Mayo Clinic patients. The majority of these patients (88%) had plasma cell disorders (PCD). All 120 patients who did not have PCD had normal K/L FLC ratios. Among these, 52 had non-AL amyloidosis: localized amyloid (23), hereditary (16), senile (6), secondary (3), and amyloid of unknown type (4). The 68 other patients who did not have a PCD were being tested because of peripheral neuropathy, rule out AL, anemia, proteinuria, lymphoproliferative disease, and a number of other indications with small numbers of patients (n=13). Among the monoclonal gammopathy patients were 330 with MM, 269 AL, 115 MGUS, 72 SMM, 22 plasmacytomas, 20 NSMM, 9 macroglobulinemia, 7 LCDD, and a variety of other diagnoses with smaller numbers of patients. The sensitivity of the K/L FLC ratio was 100% in LCDD (7/7) and 70% in NSMM (14/20). The 6 NSMM patients with normal K/L FLC ratios had all been treated with SCT and 5 of the 6 had achieved hematologic remission by bone marrow plasma cells. Among the 110 AL patients who had not been previously treated and who had a FLC assay performed within 120 days of diagnosis, the sensitivity of the K/L FLC ratio was 92% compared to 71% for serum IFE and 84% for urine IFE. Using all 3 assays, there was 99.1% (109/110) sensitivity for detecting monoclonal light chain in AL. Conclusion : The performance of the FLC assay in this prospective analysis matches the results from published retrospective validation studies.

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Macrofocal Multple Myeloma Is a Particular Subgroup of Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.1855.1855 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1855-1855 ◽

Cited By ~ 1

Author(s):

Jianling Fan ◽

Jian Hou ◽

Juan Du ◽

Lina Jin ◽

Lihui Peng ◽

...

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Plasma Cells ◽

Progression Free Survival ◽

Staging System ◽

Tumor Burden ◽

Bone Lesions ◽

Serum Free Light Chain ◽

Secretory Type ◽

Stage 1

Abstract Some young multiple myeloma (MM) patients, coined macrofocal MM, have been reported to present with multiple lytic bone lesions and less than 10% bone marrow plasma cells (BMPCs). They usually have low tumor burden and favorable outcome. To further understand the clinical and laboratory features of macrofocal MM, we retrospectively analyzed about 1000 symptomatic MM patients of two centers and found that 49 (4.9%) patients fulfilled the criteria of macrofocal MM. Median age was 54 years; 39 (80%) were male. The immunoglobulin subtype included IgG (13), IgA (5), IgD (4), light chain only (4) and non-secretory type (23). International Staging System (ISS) stage 1 in 45 (92%), and no stage 3 patient. Durie-Salmon (DS) Staging System stage 3A in 48 (98%), and 2A in 1. Extramedullary plasmacytomas (EMPs) in 39 (80%) patients. The mean percentage of BMPCs was 2.1%, and 44 (90%) patients had less than 5% BMPCs. No patients had hypercalcemia and renal impairment. FISH cytogenetics, available in 11 patients, showed IgH translocation in 7, 13q del in 2, t(4;14) in 1, 1q21 amp in 6 and p53 del in 2 patients. Serum free light chain (sFLC), available in 14 patients, showed abnormal sFLC in 7 of 14 patients and 4 in 7 non-secretory type patients. Thirty eight (77.6%) patients received new drug-based induction therapies and 14 patients received autologous stem cell transplantation (ASCT) as consolidation therapy. After a median follow-up of 36 months,the estimated median progression-free survival (PFS) was 41 months and the median overall survival time (OS) had not been reached. Forty four macrofocal MM with ISS stage 1 and DS stage 3A were compared to all (93) typical symptomatic MM patients who were diagnosed at the same period with the same stages according to both ISS and DS Staging System. For macrofocal MM, there were significantly more male patients and EMPs, higher hemoglobin levels and lowerb2-microglobulin (b2M) levels than that of typical MM. There were no significant differences in the proportions of patients received novel agents-based chemotherapy and ASCT between two groups, however, the estimated median PFS of macrofocal MM was significant superior to typical MM (41 vs 23 months, respectively; P= 0.001) (Figure 1), and the estimated median OS was also better in macrofocal MM than typical MM (not reached vs 61 months; P= 0.004) (Figure 2). Multivariate analysis showed that only the type of disease was the independent prognostic factor of both PFS and OS. In summary, Macrofocal MM is a particular subgroup of MM with multiple bone lesions and lower tumor burden, higher frequency of EMPs, and better survival than typical symptomatic MM. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Fan: The National Natural Science Foundation of China: Research Funding. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees.

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Splenic plasma cells can serve as a source of amyloidogenic light chains

Blood ◽

10.1182/blood-2008-04-154484 ◽

2009 ◽

Vol 113 (7) ◽

pp. 1501-1503 ◽

Cited By ~ 6

Author(s):

Alan Solomon ◽

Sallie D. Macy ◽

Craig Wooliver ◽

Deborah T. Weiss ◽

Per Westermark

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Monoclonal Antibodies ◽

Light Chain ◽

Plasma Cells ◽

The Body ◽

Light Chains ◽

Al Amyloidosis ◽

Hematopoietic Organ ◽

Significant Evidence

Abstract Bone marrow-derived clonal plasma cells, as found in systemic amyloidogenic light chain–associated (AL) amyloidosis, are presumed to be the source of light chains that deposit as fibrils in tissues throughout the body. Paradoxically, people with this disorder, in contrast to multiple myeloma, often have a low percentage of such cells, and it is unknown whether this relatively sparse number can synthesize enough amyloidogenic precursor to form the extensive pathology that occurs. To investigate whether another hematopoietic organ, the spleen, also contains monoclonal light chain–producing plasma cells, we have immunostained such tissue from 26 AL patients with the use of antiplasma cell, antifree κ and λ, and anti-VL subgroup-specific monoclonal antibodies (mAbs). In 12 cases, there was statistically significant evidence of a monoclonal population bearing the same κ or λ isotype as that within the bone marrow and identical to the amyloid. Our studies have shown that the spleen may be another source of amyloidogenic light chains.

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The Association of International Staging System (ISS) Stage with Disease and Symptom Burden in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.2115.2115 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2115-2115

Author(s):

Mark A Fiala ◽

Michael Slade ◽

Jesse Keller ◽

Keith Stockerl-Goldstein ◽

Michael Tomasson ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Performance Status ◽

Symptom Burden ◽

Staging System ◽

Stage I ◽

Stage Iii ◽

Newly Diagnosed ◽

Bone Marrow Plasma ◽

International Staging System

Abstract Background: The clinical presentation of multiple myeloma (MM) varies greatly but often includes bone pain, anemia, renal dysfunction, hypercalcaemia, and/or constitutional symptoms. There are no signs or symptoms that are disease specific. The earliest staging system for MM, the Durie-Salmon (DS), associated disease and symptom burden with prognosis; however, it has been largely replaced by the International Staging System (ISS), which is easier to compute and better identifies patients with the poorest prognosis. It is unclear if ISS stage, like DS, is associated with disease or symptom burden. Objective: To compare disease and symptom burden of patients with newly diagnosed MM by ISS Stage. Methods: Data was extracted from the open-access Multiple Myeloma Research Foundation (MMRF) Researcher Gateway corresponding with interim analysis 6 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data and patient reported quality of life (EORTC QLQ-C30 and QLQ-MY20), as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator and/or a proteasome inhibitor for initial MM treatment; and no prior malignancies in the past 5 years. All clinical data was reported by trained data analysts at the enrolling center with the exception of flow cytometry which was performed centrally; raw lab values for beta-2 microglobulin and albumin were entered and stage was subsequently calculated by the analysts for this study according to the ISS (Greipp et al, JCO 2005). Twenty-six patients with unknown ISS were excluded from the analysis. Data was analyzed using SPSS 21. Categorical variables were compared using χ2, continuous with one-way ANOVA tests. Results: 599 patients were eligible for analysis. Sex, race, and heavy and light chain isotypes were all evenly distributed among the ISS stages; however, median age for ISS stage III was 67, 65 for stage II and 62 for stage I (p<0.001). Stage I and II patients were similar in disease burden, but stage III patients had higher serum M-proteins (p<0.001), LDH (p=0.002), bone marrow plasma cells (p<0.001), circulating plasma cells (p<0.001), and creatinine (p<0.001), and lower hemoglobin (p<0.001) and platelets (p=0.001). Further, stage III patients had poorer performance status (p<0.001), global health (p<0.001), physical functioning (p<0.001), social functioning (p<0.001), and role functioning (p<0.001), and increased fatigue (p<0.001) and pain (p=0.016). Results are summarized in Table 1. Conclusions: Stage III had a higher disease and symptom burden than stage I and II patients. Stage I and II patients were similar in most measures suggesting that ISS may not discriminate between these groups well, this is supported by other studies that have failed to find outcomes differences between stage I and II patients. Table 1. Stage I n= 204 Stage II n = 210 Stage IIIn = 185 p Demographics Age in years 62 65 67 <0.001 Male 64% 57% 62% NS Race NS White 80% 83% 74% Black 19% 13% 23% Other 2% 3% 3% Heavy Chain NS IgG 80% 80% 75% IgA 20% 20% 25% Light Chain NS Kappa 65% 61% 60% Lambda 34% 38% 38% Biclonal 1% 2% 2% Disease Burden Serum M-Protein g/dL 1.9 2.0 3.2 <0.001 LDH μkat/L 2.7 2.8 3.0 0.002 Bone Marrow Plasma Cells* 7% 9% 13% <0.001 Circulating Plasma Cells* 0% 0% 0.1% <0.001 Calcium mmol/L 2.4 2.3 2.4 <0.001 Creatinine μmol/L 82 88 149 <0.001 Hgb mmol/L 7.4 6.4 5.8 <0.001 Platelets x109/L 222 212 199 .001 Bone Lesions 61% 52% 53% NS Symptom Burden/Quality of Life Measures ECOG Performance Status <0.001 0 47% 42% 22% 1 49% 42% 54% 2 5% 8% 15% 3-4 0% 8% 9% Global Health Scale 66 66 50 <0.001 Physical Functioning Scale 86 80 63 <0.001 Cognitive Functioning Scale 83 83 83 NS Emotional Functioning Scale 75 75 75 NS Social Functioning Scale 83 83 66 <0.001 Role Functioning Scale 66 66 50 <0.001 Disease Symptom Scale 27 22 27 NS Fatigue Scale 33 33 44 <0.001 Pain Scale 33 33 42 0.016 Note-Median presented unless specified. *- CD38+/CD138+ by flow cytometry Disclosures Vij: Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

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Plasma Cell Proliferation Using Ki67 Antigen Expression Defines Subgroups Related to Short Survival in Multiple Myeloma Especially with Low Beta-2 Microglobulin.

Blood ◽

10.1182/blood.v108.11.5031.5031 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5031-5031

Author(s):

Thomas Gastinne ◽

Xavier Leleu ◽

Anne-Sophie Moreau ◽

Joris Andrieux ◽

Jean-Luc Lai ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Median Survival ◽

Plasma Cells ◽

Staging System ◽

Stage I ◽

Routine Practice ◽

Ki 67 ◽

Beta 2 ◽

Beta 2 Microglobulin

Abstract Background: The current most powerful prognosis model in Multiple Myeloma (MM) combines beta-2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the group I of ISS (high albumin and low b2m) may vary. Proliferative activity of plasma cells has been previously related to prognosis in MM, but methods proposed so far are difficult to apply in routine practice. Ki-67 is a nuclear protein associated with cell proliferation, and its expression is reported as a powerful prognosis marker in solid tumours and several hematological malignancies. We retrospectively evaluated the % of bone marrow plasma cells (BMPC) expressing Ki-67 antigen (Ki67 index) in a series of 174 untreated patients with MM at diagnosis and we looked for its prognostic value on survival in MM. Method: Ki-67 index was determined after double immunocytochemistry on PC from BM cytospins (ABC peroxidase to identify cells expressing Ki-67, and alkaline phosphatase to identify PC expressing either Kappa or Lambda light chain). Conventional cytogenetic study and interphase FISH (research of Rb1 gene deletion) were performed in 114 and in 128 pts respectively. Results: Median survival (± se; months) for pts with stage III, II, and stage I of ISS score were 20 (± 3), 41 (± 3), 51 (± 3) months, respectively (p<0.001). Median Ki-67 index (± se) was of 3.0% (± 1.2), 6.1% (± 1.2), and 6.5% (± 1.4) in ISS stage I, stage II, and stage III patients, respectively (p< 0.004). Independently of the ISS staging system, Ki-67 index ≥ 4% was highly predictive of adverse prognosis, with a median survival of 26 ± 4 months and of 49 ± 10 months over and under that value, respectively (p < 0.0001). B2m (threshold at 3 mg/L) gave identical results than Ki-67 index (p < 0.001), whereas chromosome 13 deletion (del 13) was less powerful (p< 0.02). Ki-67 index correlated well with several markers of intrinsic malignancy, with markers of tumour burden, but it was unrelated to age, serum creatinine and b2m. There was a strong relationship between hypodiploidy and BMPC proliferation: within the group of pts displaying Ki-67 index ≥ 4%, 93% pts were found hypodiploid (p < 0.0001). Within ISS stage I, median survival [± se; RR of death (95%CI)] was of 31 ± 4 months [2.65 (1.5–4.6)] and of 67 ± 6 months in patients with Ki-67 index ≥ 4% and < 4%, respectively (p < 0.001). Chromosome 13 deletion also delineated two groups within ISS stage I pts, but the difference did not reach statistical significance (p = 0.243). Finally, the combination of Ki-67 to b2m produced an efficient prognostic model that appeared the most effective in our series compared to known models such as b2m/chr 13 deletion and ISS. The -2Log (likelihood) scores calculated on 155 patients were 1107.885, 1113.256 and 1116.829 for Ki-67/b2m model, ISS model and b2m/del13 model, respectively. Conclusion: Ki-67 index is easy to perform in routine practice, and is a good prognostic marker, which provides additional survival prognostic information to b2m into the ISS model.

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