Prognostic Value of Specific High-Risk Cytogenetic Abnormalities and Ethnicity in Outcomes after Autologous Stem Cell Transplant in Multiple Myeloma

Abstract Background: Chromosomal abnormalities in multiple myeloma (MM) patients, identified by either conventional metaphase cytogenetics or fluorescence in situ hybridization (FISH), stratify those at high risk of relapse and poorer survival after treatment. However the prognostic value of high-risk (HR) features in regard to survival after autologous hematopoietic stem cell transplantation is unclear. In addition, recent epidemiologic studies describe difference between Hispanic and non-Hispanic whites (NHW) in incidence, age at presentation, time to initial treatment, and rate of auto-HSCT within one year of diagnosis, but the presence of cytogenetic abnormalities as a prognostic factor in Hispanic patients has not yet been described. Methods: We conducted a retrospective analysis of 367 MM patients at the University of Miami Sylvester Comprehensive Cancer center who underwent auto-HSCT between January 2014 and December 2020. Patients were classified as HR if either conventional cytogenetics or FISH demonstrated at least one of the following: 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16). All other patients with normal chromosomal studies or with trisomies and/or hyperdiploidy were considered standard risk (SR). Survival analysis were performed using the log-rank test, with significance at p-value < 0.05. Results: Male patient comprised 58% of our patient population with 43% of patients of Hispanic ethnicity. Of the 367 patients who underwent auto-HSCT, 183 (50%) had at least one HR cytogenetic abnormality. Overall, HR patients exhibited inferior PFS (32.9m vs 50.6m, p=0.017) and OS (median not reached/NR for both, p=0.0086) compared to SR patients. When evaluating outcomes with specific HR cytogenetic abnormalities, we identified cohorts that did not exhibit survival benefit, either in overall survival (OS) or progression-free survival (PFS) after transplant compared to SR patients, in particular patients with 17p-, 13q-, or 1q+ (Table 1). Patients with 1p-, t(14;16) or t(4;14) derived partial benefit from transplant in terms of PFS but not OS. Notably, patients with 1p- exhibited significantly worse OS compared to other HR patients (38.3m vs NR, p=0.007). We next evaluated differences in outcome when stratifying across ethnicity. Of the 183 patients with HR cytogenetic abnormalities, 75 (41%) were of Hispanic ethnicity, while 58 (32%) were NHW and 46 (25%) were of African-American (AA) ethnicity. The proportion of patients with SR or each individual HR cytogenetic abnormality was mostly equivalent amongst each ethnicity with the exception of 13q- (35% of Hispanic patients, vs. 44% of NHW and 26% of AA patients). Nevertheless, we observed that Hispanic patients with either t(4;14) or 13q- had significantly worse OS and PFS than their NHW and AA counterparts, and similarly observed inferior OS in Hispanic patients with 1q+ (Table 2). Conclusion: In our single-center retrospective analysis of HR MM patients undergoing auto-HSCT, we have identified specific patient populations that derive some survival benefit from transplant as well as populations that did not derive any benefit. Additionally, we demonstrate that despite similar incidence of certain HR abnormalities when comparing across ethnicities, Hispanic patients with particular chromosomal abnormalities have inferior overall survival outcomes after transplant. Further investigation is warranted to identify patient-specific and treatment-related factors leading to inferior outcomes in this patient population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Prospective Comparison Study of Prognostic Value of MRD Detected By 8-Color MFC (EuroFlow-NGF) and NGS in Patients with Multiple Myeloma in ASCT Setting

Blood ◽

10.1182/blood-2021-146441 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3946-3946

Author(s):

Takeshi Yoroidaka ◽

Hiroyuki Takamatsu ◽

Mitsuhiro Itagaki ◽

Satoshi Yoshihara ◽

Kota Sato ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Research Funding ◽

Prognostic Value ◽

Progression Free Survival ◽

Comparison Study ◽

Next Generation ◽

Free Survival ◽

Prospective Comparison

Abstract Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting. Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH. Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF. Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. Figure 1 Figure 1. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

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Impact of Non High-Risk Chromosomal Abnormalities on the Outcome of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.333.333 ◽

2011 ◽

Vol 118 (21) ◽

pp. 333-333 ◽

Cited By ~ 1

Author(s):

Sairah Ahmed ◽

Heather Lin ◽

Veera Baladandayuthapani ◽

Mubeen A Khan ◽

Gary Lu ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Chromosomal Abnormalities ◽

High Dose Chemotherapy ◽

High Dose ◽

Hematopoietic Stem

Abstract Abstract 333 Impact of Non High-Risk Chromosomal Abnormalities on the Outcome of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Background: Despite novel therapeutic agents and high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HCT), most patients eventually progress and die of their disease. Recent advances in cytogenetic, molecular and genomic studies have led to identification of several chromosomal and molecular abnormalities. These abnormalities are important predictors of response to therapy, progression-free survival (PFS) and overall survival (OS). On conventional cytogenetic (CC) analyses, del 13, t(4;14), t(14;16) and del 17p are considered high-risk (HR). On Fluorescence in situ hybridization (FISH) analysis, all except del 13 are considered HR (Munshi, N et al. Blood 2011 117: 4696–4700). However there are a number of chromosomal abnormalities whose significance is not clearly identified (non-HR). In this study we report the impact of these non-HR chromosomal abnormalities on the outcome of patients who received high-dose chemotherapy and auto-HCT. Methods: We performed a retrospective review of patients with multiple myeloma who underwent high dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center. Between 10/1991 and 12/2010, 1570 patients received auto-HCT. The results of CC studies were available for 1329 patients, either at diagnosis or at relapse, but before auto-HCT. The primary objective was to study the impact of non-HR chromosomal abnormalities on PFS and OS, and to compare them to patients without chromosomal abnormalities. Results: Patient characteristics and major outcomes are summarized in the attached Table. In 1329 patients with available CC analyses before auto-HCT, chromosomal abnormalities were identified in 405 (30%) patients. One-hundred and seven (7%) patients had known HR chromosomal abnormalities, while 298 (23%) patients had non-HR chromosomal abnormalities. Fifty (17%) patients with non-HR chromosomal abnormalities and 296 patients (32%) with normal CC achieved complete or stringent complete responses (CR + sCR) (p=0.0001). Median follow up in surviving patients was 36 months. Median PFS in patients with non-HR chromosomal abnormalities and normal CC were 18.2 months (95%CI: 16–22.7) and 32.7 months (95% CI: 27.8–36.3), respectively (p= <.0001) (Figure 1). The OS in patients with non-HR chromosomal abnormalities and with normal CC were 56.5 months (95% CI: 43.2–66.9) and 87.2 months (95%CI: 80.1–102.4), respectively (p= <.0001) (Figure 2). Conclusions: In this large single center study with a long follow up, we demonstrated that non-HR chromosomal abnormalities in myeloma are associated with a lower CR rate and shorter PFS and OS after auto-HCT. Further studies are needed to better define these non-HR abnormalities and their impact on prognosis. Disclosures: No relevant conflicts of interest to declare.

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Impact of Deletion 17p On the Outcome of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.3099.3099 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3099-3099

Author(s):

Caitlin L. Costello ◽

Edward D. Ball ◽

Sue Corringham ◽

Hongying Li ◽

Karen Messer

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Chromosomal Abnormalities ◽

Treatment Plan ◽

Normal Cytogenetics ◽

The Impact

Abstract Abstract 3099 Background: The development of a risk-stratification model that relies on molecular cytogenetic markers to assess disease aggressiveness and provide therapeutic guidance would be beneficial for the management of patients with multiple myeloma (MM). High-risk cytogenetic abnormalities, including deletion 17p (del17p), are known to confer a poor prognosis. Intensified consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) following induction therapy has been proposed as the preferred initial treatment for high-risk MM, such as del17p. With this background, we report the impact of del17p on the timing and outcome of transplant in patients with MM. Methods: We performed a retrospective review of 226 patients with MM who underwent HDT/ASCT at the University of California, San Diego Moores Cancer Center between 1/2000 and 7/2011. Conventional cytogenetic analyses were utilized for all patients either at diagnosis or at relapse, but prior to ASCT. Fluorescence in situ hybridization was also assessed when available. The primary objective was to evaluate the impact of del17p, a known high-risk chromosomal abnormality, on the overall survival (OS) and progression-free survival (PFS) after ASCT, compared with patients without chromosomal abnormalities. A secondary objective was to assess the OS and PFS for patients with del17p who received ASCT within a year of diagnosis, compared with those who underwent ASCT more than 12 months from diagnosis. Results: In 226 patients with conventional cytogenetic data prior to ASCT, chromosomal abnormalities were noted in 82 (36%) patients. Of these, 21 (25%) patients harbored a del17p abnormality. Table 1 shows the patient characteristics and ASCT outcomes. Prior to undergoing ASCT, 4 (19%)patients with del17p achieved a complete remission (CR) or stringent complete remission (sCR), and 6 (29%) achieved a CR or sCR after ASCT. In patients without chromosomal abnormalities, 19 (13%) achieved CR or sCR prior to ASCT, and 45 (31%) achieved it after ASCT. Median follow-up of surviving patients was 47 months (range 5–283). Median PFS after ASCT in patients with del17p and normal cytogenetics were 8.3 months (95%CI: 4.6-N/A) and 33 months (95%CI: 21.7–61.8), respectively (HR 2.15, 95%CI: 1.19–3.89; p=0.011) (Figure 1). Median OS after ASCT in patients with del17p and normal cytogenetics were 47.5 months (95%CI: 19.9-N/A) and 68 months (95%CI 51.1-N/A), respectively (HR: 2.27, 95%CI 1.15–4.48; p=0.018) (Figure 2). Median PFS in patients with del17p who received an ASCT after 12 months and within 12 months from diagnosis was 6.13 months (95%CI: 2.7-NA) and 22.6 months (95%CI: 5.4-NA), respectively (HR=1.22, 95%CI 0.40–3.82; p=0.71). Median OS in del17p patients who received an ASCT after 12 months and within 12 months from diagnosis was 65.6 months (95%CI: 19.3-NA) and 47.5 months (95%CI: 19.9-NA), respectively (HR=0.97, 95%CI 0.26–3.62; p=0.96). Conclusions: In this single center study with long follow up, we demonstrate that a del17p abnormality in MM confers a shorter PFS and OS after ASCT. Furthermore, the use of HDT/ASCT as part of the upfront treatment plan within 12 months of diagnosis does not significantly affect the outcome in patients with a del17p abnormality. Further studies are required to better define a risk-stratified treatment plan for this subset of high-risk multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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Myelodysplasia after Autologous Stem Cell Transplantation for Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.5329.5329 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5329-5329

Author(s):

Gregory Franz ◽

Brian McClune ◽

Francis Buadi ◽

William Walsh ◽

Frank White ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Growth Factor ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Median Survival ◽

Preparative Regimen

Abstract Autologous stem cell transplantation (ASCT) increases the overall survival of patients with newly diagnosed multiple myeloma (MM), and it has become standard of care in this setting. Long-term survivors of ASCT transplanted for lymphoma or Hodgkin’s disease are known to have a high risk of developing myelodysplasia (MDS), but the risk of MDS is not clear for patients transplanted for MM. From 1996 through 2005, 82 patients underwent ASCT for MM at our center, survived at least 6 months and have adequate documentation of follow-up for review. The group included 47 males and 35 females of median age 56 years (range, 37–74 yrs). Median time from diagnosis to ASCT was 8.2 mos (range, 2.6–86.1 mos). Prior to coming to transplantation, 28% had received melphalan (MEL), 98% received some form of chemotherapy, and 34% received radiation. This prior therapy included 1 or 2 regimens for 48% of the patients, and more than 2 regimens for 52% of patients. Mobilization was effected using CYC plus growth factor for 79% of the patients, CAD or VAD plus growth factor for 17%, and growth factor alone for 4%. The median mobilization rate was 28.7 × 106 CD34/L blood processed (range, 2.0–250.1 × 106 CD34/L blood processed). A single ASCT was provided for 68%, and 32% underwent ASCT more than once. High-dose MEL alone was used as the preparative regimen for 83%, and the remainder received at least one ASCT with a more intensive preparative regimen. The median CD34 dose for the first ASCT was 5.1 × 106/kg (range, 0.4–113.0 × 106/kg). Nine patients developed MDS. The 5-yr actuarial risk was 26% (95% CI, 8–43%). On multivariate analysis, there was a trend for an increased risk of developing MDS with a CD34 cell dose <3 × 106/kg (HR 3.0, 95% CI 1.0–16.2, p=0.059), but there were otherwise no significant prognostic factors. Eight of the 9 patients with MDS had a PR or better as the best response to ASCT for MM. Five of the MDS patients had relapse of MM as well. Median survival after the diagnosis of MDS was 18.1 mos. Five patients with MDS have died, two from recurrent myeloma, two from AML, and one from sepsis and MDS. The median survival for all patients was 51.7 mos from ASCT and 69.1 mos from diagnosis, and there were no differences in survivals between those with or without MDS. We conclude that there is a relatively high risk of MDS after ASCT for MM, but development of MDS does not appear to worsen overall survival.

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Outcome of Autologous Hematopoietic Stem Cell Transplantation in Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4626.4626 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4626-4626

Author(s):

Lauren Westfall Veltri ◽

Denái R. Milton ◽

Nina Shah ◽

Krina Patel ◽

Yago Nieto ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Progression Free Survival ◽

Hemoglobin Level ◽

Hematopoietic Stem ◽

Free Survival

Abstract Introduction: Despite the introduction of highly effective novel agents, the outcome of patients with relapsed and refractory multiple myeloma (RRMM) remains poor, particularly in those with disease refractory to both proteasome inhibitors (PI) and immunomodulatory agents (IMiDs). Limited available data suggests that autologous hematopoietic stem cell transplantation (auto-HCT) may be an effective therapy in this patient population. Methods: We retrospectively analyzed all patients with RRMM who underwent first auto-HCT at our center between March 2000 and October 2015. RRMM was defined as never achieving a response (stable disease [SD]) or having progressed while on therapy or within 60 days after discontinuation of therapy. Patients with disease refractory to at least one PI and at least one IMiD either in combination or administered separately were classified as double refractory (DR-MM). Results: 233 patients with RRMM were identified. Of these, 105 (45%) had DR-MM. The remaining 128 (55%) patients were classified as refractory (R)-MM and included all patients with RRMM but without history of being double refractory. Median age at auto-HCT was 59 years (DR-MM 60 vs. 56 years in R-MM, p=0.005). High-risk cytogenetics (IMWG criteria) were noticed in 67 of 140 (48%) patients (DR-MM, 35/89 [39%] vs. R-MM, 32/51 [63%], p=0.009). Median number of prior lines of therapy was 2 (range 1 - 7) (DR-MM, 2 (1 - 7) vs. R-MM, 1 (1 - 5), p<0.001). Eighty-two (35%) patients received induction with triplet chemotherapy regimens (DR-MM, n=55 [52%] vs. R-MM, n=27 [21%], p<0.001). Chemomobilization was used in 94 (40%) patients (DR-MM, n=54 [51%] vs. R-MM, n=40 [31%], p=0.002). Median time from diagnosis to auto-HCT was 9.4 months (DR-MM 12 vs. 8 months in R-MM, p<0.001). Conditioning regimen consisted of melphalan alone in 168 (72%) and various combinations with melphalan in 65 (28%) patients with no significant difference between DR-MM and R-MM. Maintenance therapy was used in 113 (49%) patients (DR-MM, n=63 [60%] vs. R-MM, n=50 [39%], p=0.001). With a median follow up of 36 months post auto-HCT, at least partial response was seen in 188 (81%) patients (DR-MM, n=83 [79%]; R-MM, n=105 [82%], p=0.50). Near complete remission or better was seen in 52 (22%) patients (DR-MM, n=25 (24%); R-MM, n=27 (21%), p=0.64). The cumulative incidence of non-relapse mortality (NRM) at day 100 and 6 months was 1% and 2% (DR-MM, 0% and 1%; R-MM 2% each at day 100 and 6 months, p=0.56), respectively. The median progression-free survival (PFS) was 17.6 months (14.4 months in the DR-MM and 18.2 months in the R-MM, p=0.40) (Figure 1). Median overall survival (OS) was 48 months (39 months in DR-MM and 57 months in R-MM, p=0.27) (Figure 2). When accounting for other significant measures (i.e., hemoglobin level and β2 microglobulin), having high-risk chromosomal abnormalities was significantly associated with worse PFS (p=0.006) while worsening of PFS for patients with ISS stage II or III disease approached significance (p=0.06). A significant association between OS and hemoglobin level, β2 microglobulin, high risk cytogenetics, ISS stage, and induction treatment was observed, however, none of these measures remained significant in the multivariable model. Conclusions: Our findings highlight that auto-HCT is an effective and safe therapy in patients with RRMM including those who are refractory to an IMiD and PI Figure 1 Progression Free Survival Figure 2. Overall Survival Figure 1. Progression Free Survival Figure 2. Overall Survival Figure 2 Figure 2. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

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Outcomes of 252 Patients with High Risk Multiple Myeloma Treated with Hematopoietic Stem Cell Transplantation: Identification of Risk Factors Associated with Early Relapse, Shortened Progression Free and Overall Survival

Blood ◽

10.1182/blood.v120.21.3957.3957 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3957-3957

Author(s):

Emma C. Scott ◽

Stephen D. Smith ◽

Andy I. Chen ◽

Nicky Leeborg ◽

Tarunpreet Bains ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell ◽

Chromosome 1 ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Factors Associated ◽

Secondary Endpoints

Abstract Abstract 3957 Currently used clinical prognostic markers for patients with multiple myeloma (MM) such as the international staging system (ISS) and cytogenetics are inadequate predictors of response and survivorship after hematopoietic stem cell transplant (HSCT). Recently published large studies of HSCT as consolidation after primary therapy have demonstrated 3-year progression free survival (PFS) and overall survival (OS) rates of 45% and 78% respectively after tandem HSCT (BMT CTN 0102; Krishnan, Lancet Onc, 2011) and median time to progression of 46 and 27 after single autologous transplant, with and without lenalidomidemaintenance (CALGB 10104; McCarthy, NEJM, 2012). These studies (which include patients in the current cohort) have established expected PFS and OS benchmarks that allow identification of higher risk subsets. The aim of this study is to describe and further sub- stratify patients with high-risk myeloma (HRMM), with the goal to identify ‘higher’ risk groups that may benefit from alternative treatment strategies. Methods: A retrospective cohort study of HRMM patients who received an HSCT at OHSU between 01/01/2001 and 12/31/2011 was performed. We defined HRMM by the following: FISH and cytogenetic findings of del17p, t(4:14), t(14;16), t(14;20), chromosome (ch) 1 abnormalities, del 13q by cytogenetics; the presence of multiple extra-medullary plasmacytomas; plasmablastic morphology; higher ISS categories (II and III); Salmon- Durie(S-D) stages 2 and 3; recurrence or less than a partial remission (PR) to 2 consecutive lines of therapy prior to HSCT. Outcome measures included PFS and OS. Descriptive statistical analysis was conducted for all primary and secondary endpoints, patients' individual and clinical characteristics, and gene profiles. Kaplan-Meier method was used to estimate the OS and PFS function. Log-rank test was used to assess whether the survival function differs across the groups. Factors that are significantly associated with the primary and secondary endpoints were identified using univariateanalysis. Multivariate analysis is ongoing. Results: Patient and HSCT characteristics are found in table 1. With a median follow up of 40 months, relapse occurred in 127 patients, of which 77 (60%) occurred within 18 months post HSCT. Median PFS and OS are 22.3 (95% CI: 19.7 – 29.3) and 56.67 (95% CI: 40.1–69.9) months respectively. The 2-year PFS and OS rates were 47%, and 72% respectively. Univariate data analysis revealed the following factors that are highly associated with reduced PFS: del 17p (2- year PFS 26.2%; p= 0.09); ch 1 abnormalities (27.4%; p=0.0026); recurrence or < PR after 2 consecutive lines of chemotherapy prior to HSCT (27.5%; p= 0.07). For patients with chromosome 1 abnormalities, the presence of del 13q by cytogenetics further decreased the PFS (22%; p= 0.04;)(Figure 1). Factors associated with highly with a reduced OS are: ch 1 abnormalities (2-year OS 52.5%; p=0.0042); both chromosome 1 and del13q (46.2%; p=0.0016) and having multiple extra-medullary plasmacytomas (55.2%; p= 0.026 (Figure 2). Conclusion: Within the broad group of HRMM, certain groups have significantly inferior outcomes post HSCT, the worst being those with recurrence or < PR to 2 consecutive lines of chemotherapy prior to HSCT, those with any ch 1 abnormality and particularly those with additional del 13q by cytogenetics. Investigation of novel therapeutic and more aggressive strategies is warranted in these groups. Disclosures: Scott: Genzyme: Research Funding; Millenium: Speakers Bureau.

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A Comparative Study Of The Outcome Of Isolated Chromosome 13q and Clonal Progression Detected By I-FISH Do Additional Cytogenetic Abnormalities Impact Survival In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.2160.2160 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2160-2160

Author(s):

Edward Peres ◽

Shatha Farhan ◽

Philip Kuriakose ◽

Susan Michalowski ◽

Alexandra Sitarik ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplant ◽

High Dose Chemotherapy ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

Cytogenetic Abnormalities ◽

Chromosome 13Q

Abstract Background Chromosomal abnormalities detected by interphase fluorescence in situ hybridization (I-FISH) are an important prognostic marker in patients with multiple myeloma (MM). Isolated chromosome 13q has been considered standard risk when identified by I-FISH and high risk by conventional cytogenetics. The impact of additional cytogenetic abnormalities with chromosome 13q identified by I-FISH in regards to prognosis has not been fully defined. In this report, we describe the outcome of patient’s with multiple myeloma with isolated chromosome 13q and 13q+ (additional cytogenetic abnormalities) identified by I-FISH at our institution between January 2003 and January 2013 and had I-FISH analysis prior to treatment. Methods The primary objective was to compare patient’s outcomes in regards to response, time to progression, and overall survival between patients who had an isolated 13q and 13q+ identified by I-FISH in the bone marrow plasma cells. Kaplan & Meier curves were generated to calculate overall survival (OS) between the two groups. Results Between January 2003 and January 2013, we identified 76 patients by I-FISH who had either an isolated 13q or 13q+ in patients with multiple myeloma (Patient characteristics Table 1). Of the patients with an isolated 13q abnormality 33% received a bortezomib-based regimen and 38% in the 13q+ group. Of the patient’s with a isolated 13q 38% went onto receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) while 20% with a 13q+ received ASCT. African American patients with 13q consisted of 65% and 60% with 13q+ in our patient population. For the 13q or 13q+ who underwent high dose chemotherapy followed by autologous stem cell transplant OS was 85% compared to the non-transplant group 45% (p=0.01) (Figure 2). On follow up at a median of 2.5 years mortality occurred in 31% of the 13q patients compared to 62% in the 13q+ group. The overall survival at 5 years was 25% in the 13q+ group compared to 65% in the patient’s with an isolated 13q, With the 13q+ group having an overall poor OS (p=0.03) Conclusion Patients who harbor the 13q and additional cytogenetic abnormalities identified by I-FISH have a significant worse outcome compared to patients with an isolated 13q. These patients should be considered high risk and consideration for treatment with novel agents and autologous stem cell transplant followed by post-transplant maintenance therapy should be considered. Disclosures: No relevant conflicts of interest to declare.

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Presence of Multiple High Risk Cytogenetic Abnormalities Is Associated with Rapid Progression and Shorter Survival in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2020-141783 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-23

Author(s):

Portia Smallbone ◽

Stephanie Clugston ◽

Rebecca De Kraa ◽

Duncan Purtill ◽

Matthew Wright ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Response Rate ◽

Progression Free Survival ◽

Response To Therapy ◽

Newly Diagnosed ◽

Free Survival ◽

Cytogenetic Abnormalities ◽

Double Hit

Background: Detection of cytogenetic abnormalities by fluorescent in situ hybridization (FISH) are a critical component of diagnostic workup and prognostication in patients with multiple myeloma. Higher risk cytogenetic abnormalities are defined as t(4;14), t(14;16) and del(17p),1 with 1q21 gain more recently described, and are associated with reduced overall survival and lower response rate.2 Objectives: To ascertain the impact of presence of multiple high risk cytogenetic abnormalities, "double-hit", on clinical characteristics, response to therapy, overall and progression free survival in newly diagnosed patients with multiple myeloma. Methods: We retrospectively analyzed records of 279 patients with multiple myeloma aged over 18 years reviewed and/or treated across two tertiary hospitals (Fiona Stanley Hospital and Royal Perth Hospital) between 1st January 2008 and 31st of December 2019. Karyotyping and FISH on interphase nuclei on bone marrow cells was recorded. High risk cytogenetic abnormalities (HRC) were categorized in accordance with the International Myeloma Working Group (IMWG) definition and included deletion (17p), t(4;14) and t(14;16). Patients were categorized into three groups based on number of HRC present (HRC=0, HRC=1 and HRC>1). Results: Two hundred and thirty four patients had complete data on HRC and were included in the analysis (n=182 for HRC=0, n=44 for HRC=1 and n=8 for HRC>1). Baseline characteristics for the three groups are listed in Table 1. One or more high risk cytogenetic abnormalities (HRC) were detected in 22.2% of patients, with del(17p) and t(4;14) identified most commonly, at 10.7% and 9.3% respectively. All patients in the HRC>1 cohort had del (17p) with 62% (n=5) having concurrent t(14;16) and 38% (n=3) having t(4;14). Females were more likely to have HRC (41.2% in HRC=0 vs 68.1% in HRC=1 vs 50% in HRC=>1, p=0.0055). Patients in the HRC>1 cohort appeared to have higher ISS stage (60% stage III) however this did not meet statistical significance due to low numbers in the HRC>1 cohort. A greater proportion of patients in the HRC>1 cohort (100%) received bortezomib-based therapy (p=0.05). Overall response rate (ORR) was similar between cohorts, 84.8%, 86.0% and 71.43% in HRC=0, HRC=1 and HRC>1 respectively, p=0.95. High risk cytogenetic abnormalities were associated with a worse overall survival (OS) and progression free survival (PFS) compared to patients with standard risk disease. Median overall survival (OS) was 52, 20 and 8 months for HRC=0, HRC=1 and HRC>1 respectively, p<0.0001 Figure 1a. Median PFS was 43, 12 and 6 months for HRC=0, HRC=1 and HRC>1 respectively, p<0.0001 Figure 1b. Conclusions: Patients with multiple high risk cytogenetics, "double hit" myeloma have an exceptionally poor prognosis with earlier relapse and shorter survival than those with a single high risk abnormality. This represents a significant area of unmet need in myeloma therapy and risk adapted treatment intensification strategies need to be evaluated in clinical trials to improve outcomes in this cohort. Disclosures Leahy: Pfizer: Membership on an entity's Board of Directors or advisory committees. Sidiqi:Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant; Janssen: Honoraria.

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Evidence for ABL Amplification in Multiple Myeloma and Its Role in Treatment

10.21203/rs.3.rs-48781/v1 ◽

2020 ◽

Author(s):

He Huang ◽

Wenjian Guo ◽

Licai He ◽

Ronxin Yao ◽

Ying Lin ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Western Blot ◽

Cell Lines ◽

Gene Amplification ◽

Kinase Inhibitor ◽

Chromosomal Abnormalities ◽

Fusion Gene ◽

Myelogenous Leukemia ◽

Cytogenetic Abnormalities

Abstract Background: The cytogenetic abnormalities are considered as initiating events in the pathogenesis of multiple myeloma (MM) and were assumed to be clinical significance. A number of defined cytogenetic lesions have been reported by genetic analysis techniques, while ABL gene, known as the therapeutic target in chronic myelogenous leukemia (CML), its expression in myeloma has not been deeply explored.Methods: We used publically available method FISH to analyze the chromosomal architecture, clinic features and overall survival of 101 MM patient samples. Additionally, we examined ABL expression in MM cell lines (NCI-H929, LP-1 and U266) through FISH and western blot. After culturing with ABL kinase inhibitor STI571, we analyzed MM cell proliferation by CCK8 assay and detected ABL protein levels by western blot.Results: Together with reported chromosomal abnormalities, we found ABL gene exhibited not as BCR-ABL fusion gene in CML, but its amplification was prevalent, 67 patients (66.3%) had cytogenetic abnormalities with ABL amplification. And the patients with ABL gene amplification indicates no significance with clinical features, adverse cytogenetics (C-MYC amplification, IGH rearrangement, RB1 deletion, P53 deletion and 1q21 amplification) and overall survival comparing to patients with normal ABL expression. Moreover, we revealed ABL amplification in MM cell lines (LP-1 and U266) by FISH, and ABL protein was easy to detect in MM cell lines and some tumor cells. According to CML cells, the cytotoxicity of STI571to MM cells was definitely limited.Conclusions: Our study first discussed ABL gene amplification in MM cells, and we believe ABL gene would potentially be a useful target in the treatment of combination strategy for MM with ABL amplification in future.

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No Adverse Impact of 13q14 and P53 Deletion, t(4;14)(p16;q32) or Overrepresentation of CMYC(8q24) as Detected by Fluorescence In Situ Hybridization on Outcome in Patients with Multiple Myeloma Following Dose-Reduced Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.5038.5038 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5038-5038

Author(s):

Timon Hansen ◽

Georgia Schilling ◽

Peter Liebisch ◽

Rainer Schwerdtfeger ◽

Jose Antonio Perez-Simon ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Chromosomal Abnormalities ◽

Genetic Changes ◽

Significant Difference ◽

Study Population

Abstract Deletions of chromosome bands 13q14 and 17p13 (P53) as well as t(4;14)(p16;q32) or overrepresentation of CMYC are known to be adverse prognostic factors for time to progression (TTP) and overall survival (OS) in myeloma patients receiving conventional or high-dose chemotherapy followed by autologous stem cell transplantation. We investigated the impact of these chromosomal abnormalities as detected by fluorescence in situ hybridization combined with immunofluorescent cytoplasm immunoglobulin staining (cIg-FISH) on outcome after dose-reduced melphalan/fludarabin based allogeneic stem cell transplantation (SCT) in 64 patients (pts) with multiple myeloma (MM). Median age was 52 years (34 – 67 ys.), 38 patients were male, 26 female. 45 pts received stem cell graft from an unrelated donor and 19 pts from HLA-identical sibling. Deletion of 13q14 was found in 35 out of 64 pts (55%), P53 deletion in 7 out of 64 pts (11%), t(4;14)(p16;q32) in 11 out of 56 pts (20%) and trisomy of CMYC in 12 out of 55 pts (22%). The following strong correlations among the genetic changes have been seen: six out of seven pts with P53 deletion also showed deletion in chromosome band 13q14 (86%), which was also found in nine out of eleven pts with t(4;14) (82% del 13) and nine out of twelve pts with CMYC trisomy (75% del 13). The estimated event-free (EFS) and overall survival (OS) at four years for the entire study population was 48% and 57%, respectively. No significant difference of the estimated event-free survival at 3 years was seen for pts with del 13 (42% vs 54%, p=0,4), with P53 deletion (43% vs 49%, p=0,27) and for pts with t(4;14) (46% vs 62%, p=0,69) or CMYC overrepresentation (37% vs 50%, p=0,35). Comparison of pts showing both del 13 and P53 deletion, del 13 and t(4;14), del 13 and trisomy of CMYC or t(4;14) and CMYC trisomy with the rest of the study population did not show a significantly reduced EFS either. Even the comparison of pts with any chromosomal abnormalities and pts without any genetic changes detected by FISH did not show a significant difference in EFS (48% vs 50%, p=0,8). These preliminary data suggest that the negative prognostic impact of chromosomal abnormalities such as deletion of 13q14, P53 deletion, t(4;14) and overrepresentation of CMYC may be overcome by allogeneic SCT probably due to the graft versus myeloma effect.

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