scholarly journals Survival Trends over 18 Years of Patients with Multiple Myeloma Harboring Del(17p) and/or t(4;14): A Retrospective Real-World Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-17
Author(s):  
Thomas Chalopin ◽  
Nicolas Vallet ◽  
Marlene Ochmann ◽  
Mourad Tiab ◽  
Pascal Godmer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Monoclonal Antibodies ◽  
Stem Cell ◽  
In Situ Hybridization ◽  
Research Funding ◽  
Newly Diagnosed ◽  
New Agents ◽  
The Past

Introduction . In multiple myeloma (MM), the presence of translocation t(4;14) and/or 17p deletion, found in around 10 to 15% of the patients, is considered as high-risk feature associated with adverse survival. Despite recent advances in the treatment of MM, t(4;14) and del(17p) are still associated with poor outcome. The aim of this study was to analyze the trends of survival in patients with newly diagnosed MM harboring t(4;14) and or 17p deletion over the past two decades. Methods . Patients from five French centers with newly-diagnosed MM from 2001 to 2019 and displaying del(17p) and/or t(4;14) were retrospectively included. Cytogenetics abnormalities were detected by interphase fluorescence in situ hybridization (FISH) and del(17p) positivity cut-off was 30%. New agents were defined as: pomalidomide, carfilzomib, ixazomib and anti-CD38 monoclonal antibodies. Results . 246 patients carrying either t(4;14) (n=106 patients), del(17p) (n=121 patients) or both (n=19 patients) were included. Median age was 64 years (range, 35-91). ISS and R-ISS score were 3 in 88 patients (36%). Eighty-seven patients (35%) were diagnosed in 2001-2010 period, and 159 (65%) in 2011-2019 period. Front-line autologous stem-cell transplantation (ASCT) was performed in 121 (49%) patients. Among transplant eligible patients, 112 patients (n=93%) received triplet induction, 78 patients (64%) a consolidation regimen and 15 patients (12%) a maintenance therapy. Double-ASCT was decided in 21 patients (17%). Among transplant ineligible patients, 61 patients (49%) received melphalan-based regimen in first line, 36 (29%) a bortezomib-based and 15 patients (14%) a lenalidomide-based regimen. At any line, 92 patients (37%) received at least one of the new agents with only 12 patients (5%) in frontline therapy. Median follow-up was 41 months (IQR: 21-69). Median overall survival (OS) was 58.4 months (IQR: 50.1-66.5) for the entire cohort, 55.5 months (IQR: 46.6-78.3) for del(17p), 62.5 months (IQR: 54.2-76.1) for t(4;14) and 48.6 months (18.1-not reached) for patients with both (p=0.2). Median of first progression-free survival (PFS1) was 25.6 months (IQR: 22.2-29.8), with no difference between del(17p), t(4;14) or both (p=0.57). Importantly, no improvement of median OS was observed in patients diagnosed between 2001-2010 in comparison with patients diagnosed between 2011-2019 (63.7 versus 53.2 months, p=0.32). In univariate and multivariate analysis: age (continuous and cut-off 71 years-old) and ASCT significantly were associated with risk of death (HR: 1.03, 1.09 and 0.45, respectively). Median OS of patients eligible to ASCT was 76.1 months (IQR: 62.5-90.3) vs 42.5 months (IQR: 36.8-54.6) for patients not eligible (HR 0.45, 95%CI 0.28-0.0.71; p<0.001). Double-ASCT did not improve significantly OS (75 vs 81.1 months ; p=0.41) and PFS1 (31.6 vs 47.8, p=0.30) compared with single-ASCT. Conclusion . This large multicenter real-world study confirms that patients with newly diagnosed MM carrying del(17p) and/or t(4;14) remain a therapeutic challenge with no significant overall survival improvement in the past decades despite the use of novel agents. The definition of high-risk MM patients is evolving with incorporation of new markers (i.e chromosome 1 abnormalities, PET-imaging). Minimal-residual disease achievement will also re-defined risk stratification. Nonetheless, the need for innovative approaches such as earlier strategies using new agents or immunotherapy (CAR-T cells, bispecific T-cell engager antibodies) may significantly improve outcomes. Figure captions Table 1. Clinical, biological characteristics, treatment and survival of the 246 included patients based on period of diagnosis. IQR: interquartile range; FISH: fluorescence in situ hybridization; ISS: international score system; LDH: lactate dehydrogenase; ASCT: autologous stem cell transplantation; len: lenalidomide; Poma: pomalidomide; Carfil: carfilzomib; Ixa: ixazomib; mAb: monoclonal antibodies; OS: overall survival Figure 1. Kaplan-Meier curves for overall survival for the 246 included patients based on period of diagnosis. Figure 1 Disclosures Moreau: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding.

Deletion of p53 as Detected by Fluorescence In Situ Hybridization Is Associated with Significant Shorter Event-Free Survival in Patients with Multiple Myeloma Who Are Receiving Allogeneic Blood Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4338-4338
Author(s):  
Georgia Schilling ◽  
Timon Hansen ◽  
Jose Antonio Perez-Simon ◽  
Rainer Schwerdtfeger ◽  
Martin Bornhaeuser ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
In Situ Hybridization ◽  
Stem Cell Transplantation ◽  
Fluorescence In Situ Hybridization ◽  
Cell Transplantation ◽  
Chromosome Band ◽  
Blood Stem Cell Transplantation

Abstract Deletion of chromosome band 17p13 (P53) is known to be an adverse prognostic factor for time to progression (TTP) and overall survival (OS) in myeloma patients receiving conventional or high-dose chemotherapy. In this retrospective multicenter study, we investigated the impact of P53 deletion as detected by fluorescence in situ hybridization combined with immunofluorescent cytoplasm immunoglobulin staining (cIg-FISH) on outcome after allogeneic blood stem cell transplantation (SCT) in 50 patients (pts) with advanced or relapsed multiple myeloma (MM). Median age was 51 years (34 – 67 ys.), 32 patients were male, 18 female. Thirty pts received a stem cell graft from an unrelated donor, and 20 pts from a HLA-identical sibling. P53 gene deletion was found in 5 out of 49 pts (10,2 %). Deletion 13 detected by cIg-FISH was found in 20 out of 47 pts (42%). There was a strong correlation between P53 deletion and deletion 13: four out of the five patients with P53 deletion also showed deletion in chromosome band 13q14. The estimated event-free (EFS) and overall survival (OS) at three years for the entire study population was 43% and 65%, respectively. For patients with del 13 only a trend for a worse 3 year EFS was seen (38% vs 42%, p=0.2), while pts with P53 deletion had a significant reduced EFS (0% vs 46%, p=0.0001). Three out of five pts with P53 deletion relapsed very early after allogeneic SCT (day 81, 108 and 287 respectively). These data suggest that P53 is a risk factor for patients with MM treated with allogeneic SCT which can not be overcome by this treatment strategy.

Carfilzomib Combined with Thalidomide and Dexamethasone (CTD) Is an Highly Effective Induction and Consolidation Treatment in Newly Diagnosed Patients with Multiple Myeloma (MM) Who Are Transplant Candidate

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 333-333 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Asselbergs ◽  
Sonja Zweegman ◽  
Bronno Van der Holt ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Objective Response ◽  
Hematological Toxicity ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Cell Harvest

Abstract Abstract 333 Background: Combinations of a proteasome inhibitor (PI) with an Imid plus dexamethason such as VRD or VTD have shown significant activity in newly diagnosed Multiple Myeloma. The use of these regimens is hampered by toxicity such as polyneuropathy and costs. Carfilzomib is a second generation PI that has shown activity as single agent and in combinations. Introduction: This investigator sponsored, dose escalation phase 2 trial was designed to investigate carfilzomib (C) combined with thalidomide (T) and dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Patients in cohort 1 received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, thalidomide 200 mg days 1 through 28 of a 28 day cycle and dexamethasone 40 mg on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 the dose of carfilzomib was 20 mg/m2 on days 1 & 2 followed by 36 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1,2, 8, 9, 15 & 16 of all subsequent 28-day cycles. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following single high-dose melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), consolidation therapy consisted of 4 cycles of carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), thalidomide 50 mg days 1–28 of a 28 day cycle and dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was at least very good partial response (VGPR) after 4 CTD cycles, secondary endpoints were complete response (CR) according to IMWG criteria, stringent CR (sCR), VGPR and an objective response (at least PR) pre-and post HDM, progression-free (PFS) and overall survival (OS). Results: 58 patients were included as of 1stAugust 2012. We here report on the first 40 registered patients, who were included in the first cohort and who are evaluable for response and toxicity. Median age was 58 yrs and ISS stages I/II/III were 40%/35%/25%, respectively. Of 40 patients, 35 (87%) completed 4 CTD induction cycles, 31 (77) competed HDM/ASCT. So far, 17 patients completed 4 consolidation cycles. 68 % of patients achieved an objective response within 1 cycle. Cytogenetic FISH data were available in 88%. Responses were achieved across ISS (I/II/III) or FISH subgroups, i.e. gain (1q) (n=4), t(4;14) (n=4), del(17p) (n=3), del(13q) (n=10) or normal. Stem cell harvest was successfully accomplished with > 3×10*6 CD34+ yield in 34/34 patients and HDM/ASCT was performed with complete hematologic recovery in 31/31 patients. Progression-free survival was 97% at 12 months, overall survival was 100% at a median follow-up of 10.4 months. This regimen was well tolerated. Non-hematological toxicity CTC grade 3+4 included tumor lysis syndrome (5%), DVT (10%), gastro-intestinal symptoms (5%), skin rash (8%). Peripheral polyneuropathy grade 2 or 3 was observed in 6 and 1 (17%) patients. No hematological toxicity was observed. Conclusion: Carfilzomib combined with thalidomide and dexamethasone is a rapidly effective induction regimen. With the same regimen used as consolidation, a significant upgrade of responses is observed. Disclosures: Sonneveld: Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; celgene: Honoraria, Research Funding. Lokhorst:Genmab: Consultancy.

Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 688-688 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Asselberg-Hacker ◽  
Sonja Zweegman ◽  
Bronno van der Holt ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Phase 2 Trial ◽  
Cell Harvest

Abstract Background A proteasome inhibitor (PI) combined with an immune-modulatory dexamethasone has significant activity in replapse and newly diagnosed Multiple Myeloma (MM). Carfilzomib is an effective 2nd generation PI. We report an update of a Phase 2 trial using Carfilzomib combined with Thalidomide and Dexamethasone in newly diagnosed MM. Introduction This investigator sponsored, dose escalation phase 2 trial was designed to investigate Carfilzomib © combined with Thalidomide (T) and Dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Fifty patients in cohort 1 received 4 cycles of Carfilzomib at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, Thalidomide 200 mg p.o. days 1 through 28 of a 28 day cycle and Dexamethasone 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 (20 patients) the dose of Carfilzomib was escalated from 27 mg/m2 to 36 mg/m2 in the same schedule. In cohort 3 (20 patients) the dose of Carfilzomib increased to 45 mg/m2 in the same schedule. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), followed by consolidation therapy: 4 cycles of Carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), Thalidomide 50 mg days 1-28 of a 28 day cycle and Dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was very good partial response (VGPR) after 4 CTD cycles: secondary endpoints were complete response (CR), stringent CR (sCR), VGPR and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results 90 patients were included as of 1st April 2013. We here report the response of cohorts 1+2 (n=70) with a median follow-up of 22 and 7 months respectively. Median age was 58 yrs and ISS stages I/II/III were 27%/40%/27%, respectively. Six (9%) patients had renal failure with serum creatinine > 2 mg/dL. Of 70 patients in cohorts 1 and 2, 8 patients stopped treatment during/after induction and 4 patients after HDM because of refusal (n=2), toxicity (n=4) non-eligibility (n=2) or progression (n=4). 39 patients completed protocol treatment with 19 still on treatment. Overall response rate on protocol treatment was 96%. After induction therapy response was 19% (CR/sCR), 60% (≥ VGPR) and 93% (≥ PR), respectively. The CR/sCR rate increased to 30% after HDM and to 49% after consolidation. CR/sCR rate was not different across ISS staged I/II/III. In addition, response was similar in poor risk FISH (gain 1q or t(4;14) or del17p: 26% of patients) and standard risk FISH (all other). Progression-free survival (PFS) f 70 patients is 74%, overall survival (OS) is 7%. Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 60/60 patients and HDM/ASCT was performed with complete hematologic recovery in 53/53 patients. This regimen was well tolerated. Safety analysis for all 3 cohorts showed non-hematological toxicity CTC Grade 3+4 in < 5%, mainly infections and skin lesions. Other toxicities were Grade 2 ≤ or less than 5% including cardiac symptoms. Purified myeloma plasma cells, obtained in 39 patients at diagnosis were used for gene expression profiling and exome sequencing. The prognostic impact of the EMC-92 gene classifier on outcome with CTd will be presented. Conclusion Carfilzomib combined with thalidomide and dexamethasone is a safe and rapidly effective regimen for newly diagnosed MM. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2016-2016
Author(s):  
Tomer M Mark ◽  
Peter Forsberg ◽  
Ihsane Ouansafi ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Determinants of Receipt of Stem Cell Transplant in Elderly Medicare Beneficiaries with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5927-5927
Author(s):  
Jean Yared ◽  
Daisuke Goto ◽  
Eberechukwu Onukwugha ◽  
Rahul Khairnar ◽  
Brian Seal ◽  
...  
Keyword(s):  
Older Adults ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Research Funding ◽  
Contextual Factors ◽  
Cell Transplant ◽  
Comorbid Conditions ◽  
The Past ◽  
Geographic Regions ◽  
Hispanic White

Abstract Introduction: Multiple myeloma (MM) is a disease of the elderly with a median age at diagnosis of 70 years. Autologous stem cell transplantation (ASCT) is a preferred treatment for younger patients but is also an option for older adults (i.e., patients >65 years) with good performance status. A previous SEER-Medicare study of MM patients diagnosed from 2000-2007 found that 5.8% underwent ASCT (Winn, et al. JNCI, 2015). The availability of ASCTs for older adults with MM has increased in the past decade due to improvement in supportive care and Medicare coverage approval. Apart from age and medical eligibility, several patient and contextual factors, such as comorbidity, may influence the receipt of ASCT in the MM population. There is limited information on the determinants of receipt of ASCT in older adults over the past decade in the US. Objective: To identify ASCT recipients among a cohort of elderly individuals with MM in order to determine characteristics associated with receiving ASCT. Specifically, this study identifies patient and contextual factors associated with the receipt of ASCT. Methods: This retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER) registry and linked Medicare claims (SEER-Medicare) data. We identified individuals aged 66 and above, with an incident diagnosis of MM between 2007 and 2011 as well as claims data from 2006 to 2012. We required continuous enrollment in Medicare Parts A and B 12 months prior to and including the month of diagnosis and six months post-diagnosis. We required continuous Part D enrollment two months pre- and six months post-diagnosis. Patients were followed until death or censoring due to non-continuous Parts A and B enrollment after six months. ICD-9 and HCPCS codes were used to identify ASCT. Charlson Comorbidity Index (CCI) was used to measure the number of comorbid conditions at the time of MM diagnosis using claims one year prior to diagnosis. Student's t-test and Chi-square test of proportions were used to compare those who received ASCT to those who did not based on patient-level factors (i.e., age, gender, race, comorbidity status), geographic regions (i.e., Northeast, Midwest, West and South), and over time (diagnosed in 2007-2009 vs. diagnosed in 2010 to 2011). We also measured the time to ASCT for those who underwent ASCT. Results: Among 3,318 individuals with MM who met our inclusion criteria, 226 (6.8%) underwent ASCT during the follow-up period. ASCT recipients were younger, more likely to be male, white non-Hispanic, and have fewer comorbid conditions (Table 1). The median time from MM diagnosis to ASCT was 278 days. The rate of ASCT among recipients aged 66-69 was 23.2%, 7.3% among recipients aged 70-74, and 0.84% among those aged 75+ (p<0.001). The rate of ASCT was higher among males (8.5%) than females (5.2%) (p<0.001). Rates of ASCT were higher among those who were non-Hispanic white (8.1%), compared to those who were non-Hispanic black (3.5%) or of another race/ethnicity (4.1%) (p<0.001). Among those with CCI=0, 9.9% underwent ASCT, while 7.2% of those with CCI=1 underwent ASCT and 2.7% of those with CCI>1 underwent ASCT (p<0.001). Rates of ASCT were similar across the geographic regions (p=0.15). Of those who were diagnosed in 2007-2009, 6.0% received transplant, while 7.8% of those who were diagnosed in 2010-2011 received transplant (p=0.04). Conclusion: ASCT is performed in less than 1 in 10 patients aged 66 and older. A greater proportion of ASCT recipients were non-Hispanic white, male, diagnosed at a younger age, and had a lower comorbidity burden compared to non-transplant patients. Comparing the pre-2007 estimate from the aforementioned study to our early (2007-09) and late (2010-11) period estimates, our results illustrate an upward trend in ASCT over the past decade. We were unable to identify smoldering MM patients who would not be candidates for ASCT. This may bias our estimates downward. The aforementioned previous study found that 62% of recipients were 66-69, 32% of recipients were 70-74, while 6% were 75+ (Winn, et al. JNCI, 2015). These rates did not differ greatly from our findings indicating that the age distribution of ASCT recipients has remained stable over a 10 year period of observation. Future studies should investigate the implications of these differences for post-transplant outcomes among older MM patients. Disclosures Goto: Novartis AG: Research Funding. Onukwugha:Takeda: Research Funding; IMPAQ International: Honoraria; Bayer Healthcare: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Romanus:Takeda: Employment. Yong:Takeda: Employment. Slejko:Takeda: Research Funding; PhRMA: Research Funding; National Pharmaceutical Council: Research Funding.

scholarly journals Comparison of Denosumab Versus Intravenous (IV) Bisphosphonate Use for Hypercalcemia in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-16
Author(s):  
Matthew M Lei ◽  
Erica Tavares ◽  
Uvette Lou ◽  
Evan Buzgo ◽  
Noopur S. Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Dysfunction ◽  
Board Of Directors ◽  
Research Funding ◽  
Additional Dose ◽  
Newly Diagnosed ◽  
Median Dose ◽  
Publicly Traded ◽  
Advisory Committees ◽  
The Past

Background Hypercalcemia (HC) is a frequent complication of multiple myeloma (MM) occurring in 20-30% of patients. This is often associated with renal dysfunction and both features are important myeloma defining events resulting in significant morbidity and mortality. Denosumab, a fully human monoclonal antibody that inhibits RANKL, has been evaluated in the prevention of skeletal related events in patients with newly diagnosed MM, as well as the treatment of bisphosphonate-refractory HC of malignancy (HCM). Cases of denosumab for HCM in MM patients with renal dysfunction have been described. Both denosumab and IV bisphosphonates (IVB) represent treatment options for HC in MM. We describe a comparison of patients with MM with HC who received denosumab vs IVBs. Methods We retrospectively identified patients age ≥18 with a diagnosis of MM with HC (corrected serum calcium level [CSC] &gt;10.5 mg/dL). Patients were included if they received either denosumab or IVB (zoledronic acid [ZA] or pamidronate), between April 2016 and June 2020. The primary endpoint was complete response (CR), defined as normalization of CSC to less than 10.5 mg/dL. Secondary endpoints included HC relapse (CSC &gt;10.5 mg/dL) and safety. Hypocalcemia was graded per CTCAE v5. Acute kidney injury (AKI) was defined using KGIDO criteria. Patients were followed-up for 56 days. Bivariate analyses were performed. Results A total of 40 patients were included with 18 in the denosumab group and 22 in the IVB group, of whom 15 (68%) received ZA and 7 (32%) received pamidronate. Baseline characteristics are described in Table 1. Patients with newly diagnosed MM composed 33% and 55% of the denosumab and IVB groups, respectively. All patients in the denosumab group received 120 mg except one who received 60 mg, while in the IVB group, dose reductions occurred in 5/15 patients who received ZA (median dose, 4 mg; range, 3.3-4) and 4/7 patients who received pamidronate (median dose, 60 mg; range, 30-90). Most patients received HC treatment as an inpatient (58% inpatient vs. 42% outpatient). A minority of patients had received IVBs in the past 90 days. The mean CSC was 12.5 mg/dL (standard deviation [SD], 1.40) and 13.3 mg/dL (SD, 2.39) in the denosumab and IVB groups, respectively. Baseline serum creatinine (SCr) was higher and creatinine clearance (CrCl) was lower in the denosumab group (median SCr, 2.06 vs. 1.24 mg/dL, p=0.048; median CrCl, 33 vs. 48 mL/min, p=0.048). The CR rate by day 3-4 was 92% and 94% in the denosumab and IVB groups, respectively (p=NS). HC relapse occurred in 2 (12%) and 6 (29%) patients in the denosumab and IVB groups, respectively (p=0.257). Incidence of grade 1 hypocalcemia was similar between groups; however, incidence of grade ≥2 hypocalcemia was higher in the denosumab group. Incidence of new AKI was 28% (5/18) in the denosumab group 23% (5/22) in the IVB group (p=0.71). No patients in the denosumab group received an additional dose of denosumab within 14 days of initial dose. Three patients in the IVB group received an additional dose of an IVB within 14 days of initial dose. One patient, who was in the denosumab group, had refractory hypercalcemia and had not achieved CR at day 56. Conclusions We describe our experience with denosumab and IVB for the management of HC in patients with MM. The CR rate at 3-4 days was similar with either agent in our MM only population that was not bisphosphonate refractory. A higher incidence of grade 2 hypocalcemia was noted in the denosumab group. Conclusions on renal safety are limited by the small sample size and that patients in the denosumab group had a higher SCr on presentation. Denosumab and IVB represent acceptable agents for the management of HC in MM patients with further investigation necessary in those with renal dysfunction. Disclosures Lei: Fresenius Kabi USA: Consultancy; Trapelo Health: Consultancy; Bluebird Bio: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Clovis Oncology: Current equity holder in publicly-traded company; Blueprint Medicines: Divested equity in a private or publicly-traded company in the past 24 months. Lou:Fresenius Kabi USA: Consultancy. Raje:Bluebird, Bio: Consultancy, Research Funding; Takeda: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Astrazeneca: Consultancy. Yee:Karyopharm: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Denosumab is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. We describe the use of denosumab for hypercalcemia of malignancy in a multiple myeloma only patient population that is not bisphosphonate refractory. The use of denosumab for these patients was part of normal clinical practice in adherence to institutional policies and guidelines.

scholarly journals A Multi-Center Phase 1b, Open-Label, Dose-Finding Pilot Study to Evaluate the Combination of Carfilzomib and Cyclophosphamide with Dexamethasone (CCyD) Prior to Autologous Stem Cell Transplant (ASCT) in Patients with Transplant Eligible Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4739-4739 ◽  
Author(s):  
William I. Bensinger ◽  
Robert Vescio ◽  
Cristina Gasparetto ◽  
Elber S. Camacho ◽  
Rajneesh Nath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Dose Finding ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Advisory Committees

Abstract Background: Carfilzomib is an epoxy ketone, second generation proteasome inhibitor approved for the treatment of relapsed and refractory multiple myeloma. It has shown very high activity when combined with lenalidomide and dexamethasone for the treatment of newly diagnosed patients with multiple myeloma. This is the first reported trial of carfilzomib, cyclophosphamide, and dexamethasone (CCyD) in newly-diagnosed, transplant eligible patients. Methods: This study was a multi-center Phase Ib, open-label, dose-finding study in newly diagnosed transplant eligible multiple myeloma patients (pts) studying the combination of CCyD as induction therapy prior to autologous stem cell transplant (ASCT). Pts could receive a minimum of 4 cycles and up to 6 cycles prior to ASCT. Pts were enrolled into a dose-escalation treatment cohort. A standard 3+3 dose escalation schedule was used with cohorts of carfilzomib 36 (initial), 45 and 56 mg/m2 (administered over 30 minutes on days 1, 2, 8, 9, 15 and 16) combined with 300 mg/m2 of oral cyclophosphamide weekly on days 1, 8, 15 and 40 mg of oral dexamethasone once weekly. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the IMWG criteria. Prior therapy was limited to up to 160 mg of dexamethasone or limited field radiation. Results: 28 patients were enrolled from 5 centers. Of 28 patients enrolled, 3 did not complete 4 cycles of therapy (1 proceeded to ASCT after Cycle 3) and are not evaluable for response (pts came off secondary to AE of pulmonary HTN unrelated, secondary to SAE of CHF possibly related, due to PI discretion related to maximum benefit achieved), 8 patients did not undergo ASCT (1 had PD after Cycle 5), 8 patients proceeded to ASCT (1 the aforementioned patient after Cycle 3), 6 patients have completed induction and are still pre-transplant and 4 patients are still on treatment. The median age was 64 years (range 44–74), 57% were male. Cytogenetic abnormalities included 13 patients with del(13), 4 with del(17p), 2 with t(14;16) and 1 with hypodiploidy for a total of 16 patients with high-risk cytogenetics. In the dose-escalation portion of the study, the maximum administered dose tested was 56 mg/m2 carfilzomib. There was one DLT in cycle 1, of Grade 3 dyspnea, at the 56 mg/m2 level. Drug-related AEs occurring in >20% of patients included fatigue (23%) and thrombocytopenia (31%). Thirty-one percent experienced at least one Grade ≥3 AE with dyspnea and nausea as the most common. There were no deaths on study with a median follow-up of 4.9m (range: 1.1 to 13.1m). One pt came off study after Cycle 5 for PD as evidenced by new plasmacytomas. Six patients received 36-45 mg/m2 carfilzomib on the dose escalation portion of this study and 22 patients received the maximum administered dose of carfilzomib at 56 mg/m2. One patient yet to be enrolled to obtain 20 efficacy evaluable pts at the maximum dose. Twenty-three patients were response evaluable. Median of 5.7 cycles of therapy with 2 CR, 9 VGPR, 10 PR, 1 MR and 1 PD for ≥ PR rate of 91%. Of the 12 response-evaluable patients with high risk cytogenetics, 92% were ≥ PR; of the 11 standard risk patients, 91% were ≥ PR. Of 9 patients who underwent stem cell mobilization, all collected adequate stem cells and median number of stem cells collected was 12.58 (5.07-25.31) x106 CD34+ cells/kg. Conclusions: The combination of CCyD given to untreated, symptomatic patients with myeloma was well tolerated and highly active with an 87% RR and a 48% ≥ VGPR after 4 to 6 cycles. This study compares favorably with other regimens used for induction prior to transplant for the management of newly diagnosed multiple myeloma. Disclosures Bensinger: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Vescio:Onyx Pharmaceuticals: Honoraria, Speakers Bureau. Gasparetto:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nath:Celgene: Consultancy. Shah:Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Durie:Onyx Pharmaceuticals: IRC Other; Millennium Pharmaceuticals: IRC, IRC Other.

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