Outcome with Lenalidomide Plus Dexamethasone Followed by Early Autologous Stem Cell Transplantation In the ECOG E4A03 Randomized Clinical Trial

Abstract Abstract 38 INTRODUCTION: Lenalidomide and bortezomib have moved into the management of newly diagnosed multiple myeloma leading to dramatically improved outcomes. As a consequence, the role of upfront autologous peripheral blood stem cell transplant (ASCT) has become more controversial. The ECOG E4A03 clinical trial randomized newly diagnosed MM patients to lenalidomide with high-dose dexamethasone (LD) vs lenalidomide with low-dose dexamethasone (Ld) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). Upon completing four cycles of therapy, pts had the option of ASCT or continuing on the assigned therapy. The purpose of this abstract is to determine the outcome of patients on this trial pursuing early ASCT according to various age-groups. MATERIALS and METHODS: This is a post hoc, retrospective analysis of overall survival within age subgroups stratified by early ASCT status. This is a landmark analysis including only pts surviving the first 4 cycles of therapy. RESULTS: In all three age-groups studied, 1, 2, and 3-year survival probability estimates with ASCT were excellent (Tables 1, 2, and 3). For patients under the age of 65 who survived the first 4 cycles of therapy, overall survival at 3-years was 94% with early ASCT, 78% in pts continuing protocol therapy. Although direct comparison with patients not going to early transplant is not possible because the assignment to early ASCT versus no early ASCT was not randomized, survival with ASCT at 3-years appeared higher. While we attempt to correct for age, the differences may be influenced by other factors such as performance status, comorbidities, response to therapy, etc. The presumption that treatment related mortality (TRM) should be more problematic for older pts undergoing ASCT is addressed by looking at the >65 and >70yo cohorts. In the >65 age group, one-year mortality is similar between the early ASCT population and the no early ASCT population. In the >70 age group, no adverse impact of early ASCT was seen in the first year on overall survival but the sample size is extremely small. In all age groups early ASCT seemed to mitigate some of the survival disadvantage associated with randomization to the LD arm. CONCLUSIONS: This analysis shows that the strategy of lenalidomide plus dexamethasone induction followed by early ASCT has a remarkably good outcome in terms of overall survival in all age groups studied and supports the continued role of early consolidative ASCT in newly diagnosed patients. The risk of early mortality was notably low in the first year in all age groups. The risk of early mortality seems to increase at 2 years for the LD pts not choosing early ASCT and at 3 years for the Ld pts not choosing early ASCT. Selection bias makes it difficult to compare results for pts that chose early ASCT directly to the patients who did not receive early ASCT in this trial. As such, these results emphasize the need for randomized trials investigating the timing of ASCT in myeloma in the era of novel therapy. Disclosures: Siegel: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for front line therapy. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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Variation in Health-Related Quality of Life by Age Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.2085.2085 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2085-2085

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Lymphocytic Leukemia ◽

Age Group ◽

Employment Equity ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Equity Ownership

Abstract Abstract 2085 Introduction. Although advanced patient age is commonly used as a factor in selecting therapy for patients with chronic lymphocytic leukemia (CLL), based on presumed associations with functional status, limited data exist regarding the relationships between age and physical, emotional, social, and functional well being. We examined the relationships between age and these domains of health-related quality of life (HRQOL) for CLL patients treated in US community practices. Methods. Baseline data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by patients in the clinic at enrollment. Patients completed 3 psychometrically validated instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BFI, EQ-5D and FACT-Leu scores were analyzed by age group (<65, 65–74, >74). Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Baseline HRQOL data were reported by 604 patients, enrolled from 161 centers. Patients were predominantly male (62%) and white (90%) with mean age at 69.9 (standard deviation [SD] 11.2) yrs. HRQOL scores by age group are presented: There were no significant differences between the age groups in fatigue as measured by the BFI, or differences in overall HRQOL as measured by the EQ-5D Visual Analogue Scale (VAS) or the FACT-G. Anxiety/depression and self care are EQ-5D domains that also did not vary by age. Although mobility was most impaired in the oldest age group compared to the two younger groups, usual activities and pain/discomfort were worse in both the younger and older cohorts compared to those 65–74 years of age. FACT-Leu results indicated that the social/family domain scores did not vary by age, but that physical, emotional, and functional domains did vary statistically with the oldest typically doing better than the 65–74 year olds, but not necessarily better than those <65. Conclusions. Initial results from the Connect CLL® Registry indicate that HRQOL does not worsen monotonically with older age. In this cohort, both the youngest and oldest age groups had worse HRQOL in certain domains, presenting an inverted v-shaped relationship. Future analyses should be conducted on: (1) how HRQOL may be affected over time with changes in disease; and, (2) how HRQOL may be influenced by alternative therapies. Results reported here should serve as a useful baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v124.21.2016.2016 ◽

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.

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A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4040.4040 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4040-4040 ◽

Cited By ~ 3

Author(s):

Kendra L. Sweet ◽

Rami S. Komrokji ◽

Eric Padron ◽

Christopher L Cubitt ◽

Leyla Khavarian ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Febrile Neutropenia ◽

Phase I ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

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Do Not Miss Karyotyping at Chronic Myeloid Leukemia Diagnosis: An Italian Campus CML Study on the Role of Complex Variant Translocations

Blood ◽

10.1182/blood-2020-139826 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Massimiliano Bonifacio ◽

Chiara Elena ◽

Mariella D'Adda ◽

Luigi Scaffidi ◽

Mairi Pucci ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Newly Diagnosed ◽

Advisory Committees ◽

Optimal Response ◽

Frontline Treatment ◽

Tki Treatment

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p<0.05 for all comparisons). Stable DMR was achieved by 39% of patients and 42% of them attempted a TFR. After a median follow-up of 91.3 months (range 1-236), 5-year FFS was 66% (95%CI: 53.4-76.4) and 84% (95%CI: 62.4-93.6) for imatinib and 2G-TKI treated patients, respectively (p=ns). The estimated 10-year OS for the entire cohort was 84.4% (95%CI: 73.6-91). The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding.

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First Results of Russian Multicenter Population Base Study of the Incidence of Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4431.4431 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4431-4431

Author(s):

Sergey M. Kulikov ◽

Olga Yu. Vinogradova ◽

Ekaterina Yu. Chelysheva ◽

Marya V. Galayko ◽

Irina A. Titshenko ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Symptoms ◽

Molecular Genetic ◽

Age Groups ◽

Chronic Phase ◽

Newly Diagnosed ◽

Advisory Committees ◽

First Results ◽

Collection Data

Abstract Abstract 4431 The European Treatment Outcome Study (EUTOS) is register based international investigation started in June 2007. [1] The aim is to study the epidemiology of CML and to gain insight into the ‘real world’ treatment of patients with CML. Population base section (EUTOS-PBS) is the prospective study directed mostly to epidemiology aims. Russian part of the EUTOS-PBS registry collect data of newly diagnosed patients lived in 7 large regions of about 10 millions of population totally. EUTOS-PBS inclusion criteria are following: newly diagnosed CML (Ph +/BCR-ABL) started form 1st October 2009, age: older than 18. Russian CML group includes additional protocol for collection data for patients with clinical symptoms of CML. These patients are included into the roster table and after laboratory confirmation are enrolled into the main phase of the study. Thus, 174 patients were included in pre-phase, 142 (82%) had the diagnosis of CML which was confirmed by cytogenetic/molecular-genetic tests (Ph +/BCR-ABL +), 32 (18%) was not confirmed as CML. Among them 87% (n = 20) - have other Ph–negative chronic myeloproliferative diseases, and also acute leukemia (n = 1), cancer (n = 1), chronic inflammatory processes (n = 1). 142 patients with CML are 73 men, 69 women have the age from 18 to 82 (Me 49) years. 136 (96%) of patients are in the chronic phase, 6 (4%) -in the phase of acceleration, nobody in a blast ñrisis. The standard frequency analysis with adjustment to the standard population of WHO was carried out to estimate distribution. The results was presented in the table 1. As shown registered morbidity in 6 regions is not varied so much: source incidence is 0,58 (0,44–0,69); standardized on WHO incidence is: 0,7 (0,57 – 0,85); per 100 thousands per year. Estimated registered morbidity of CML in Russian regions are in 1.5–2 times less, than published morbidity in western countries. The analysis of the incidence in age stratums (table 2) shows that there is no much growth of age morbidity as expected. It obviously points to low detectability of new CML incidents in senior age categories (are more senior 60 years). This fact is probably the main reason of low total registered morbidity. Tabl.1. Incidence rate of new CML cases in 6 regions of Russia Region population (mln.) N CML for 100000. in year Standard of WHO Mordovia Republic 0.87 14 0.69 0.85 Kirov region 1.46 18 0.53 0.6 Perm territory 2.77 45 0.68 0.8 Bryansk region 1.35 17 0.53 0.65 Irkutsk region 2.55 36 0.56 0.68 Zabaikal's territory 1.36 12 0.44 0.57 Total 10.13 142 0.58 0.7 Table 2.CML incidence in age groups Age groups Male Female Maleandfemale 18–29 0.65 0.57 0.61 30–39 0.86 0.39 0.62 40–49 0.50 0.57 0.54 Conclusion: The CML incidence in Russia regions is underestimated. The main reason is an insufficient CML diagnostic screening in the senior age groups of population. References. 1. http://www.eutos.org/content/registry/documents/documents/e940/infoboxContent941/CML-Registry_February09.pdf Disclosures: Vinogradova: BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Chelysheva:Novartis Pharma: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; MSD: Speakers Bureau. Senderova:Novartis: Consultancy. Turkina:Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Prognostic Role of IL-6 in POEMS Syndrome

Blood ◽

10.1182/blood-2021-149792 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2700-2700

Author(s):

Maryam Omar ◽

Rahma M Warsame ◽

Morie A. Gertz ◽

Francis K. Buadi ◽

Ronald Go ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Interleukin 6 ◽

Research Funding ◽

Statistical Significance ◽

Poems Syndrome ◽

Reference Ranges ◽

Time To Progression ◽

Advisory Committees

Abstract INTRODUCTION POEMS syndrome is a paraneoplastic disorder that results in multi-organ disease, and Vascular endothelial growth factor (VEGF) is associated with disease activity. There is evidence that the cytokine Interleukin- 6 (IL-6) stimulates VEGF production in several cancer cell lines. It has also been suggested that patients with POEMS syndrome experience symptoms improvement when IL-6 levels are low. Our study aims to understand the role of IL-6 and whether it is a contributor to disease activity in POEMS syndrome. METHODS We conducted a retrospective study of patients (pts) seen at Mayo Clinic within 1 year of diagnosis for POEMS syndrome with an IL-6 level within 3 months of diagnosis between 01/01/2011-05/31/2021 were included. Our database comprised 358 pts,7 were excluded because did not have official diagnosis of POEMS syndrome. Two hundred and ninety-nine pts did not have IL-6 testing within 90 days of diagnosis and were excluded. Clinical data was abstracted from our electronic medical record. Descriptive statistics were used for IL-6 levels. The majority of IL-6 laboratory testing for pts utilized the same reference range. A minority of pts had alternate reference ranges; thus, all IL-6 values and reference ranges were fold-corrected to have a unified reference to determine elevation in IL-6. High IL-6 was considered any value above the normal range, also analyzed pts in quartiles and deciles. Hematologic, VEGF and PET response criteria were utilized to group pts into responders or non-responders. Time to progression (TTP) and overall survival (OS) was calculated using the Kaplan Meier method. Differences between curves were by log rank. Statistical analysis was conducted via JMP software package (SAS, Cary, NC, USA). Univariate analysis was done to determine the prognostic value of IL-6. Statistical significance is considered with p-values <0.05. RESULTS 52 patients from among 352 met criteria and were included for analysis. Twenty-one patients (40%) had elevated IL-6 levels (IQR 5.67, 22.6) at the time of diagnosis. The fold elevation about normal was typically not very high, with a median of 3.1-fold elevation (IQR 1.3, 4.4; and range 1.0, 8.3). The percentage of males in the high IL-6 versus the normal Il-6 group were 90% versus 65%, p=0.03. Compared to normal IL-6, those with elevated IL-6 values had more instances of hepatomegaly (43% vs 16%, p=0.03), ascites (28% vs 6%, p=0 .04), abnormal DLCO (26% vs 3%, p=0.03), mixed bone lesions (57% vs 29%, p= 0.04), and lower serum albumin (range 2.3-3.5 vs 2.5-4.5 g/dL, p=0.0008).There was a trend for lower VEGF values among the high IL-6 group, but this did not meet statistical significance (median 250 vs 438 pg/mL). There was no significant difference in the time to progression between pts with high versus normal IL-6 levels (HR 1.36; p=0.456). Overall survival was significantly longer in pts with normal IL-6 compared to pts with high IL-6 levels (Median OS 67.4 vs 47.8 months, p=0.02). Forty-two pts were evaluated for VEGF response after treatment; there was a significant improvement in time to progression (85.5 vs 14.9 months, p=0.03) in pts who were VEGF responders. Among pts evaluable for a hematologic response (n=15), time to progression in pts with baseline high IL6 was longer in hematologic responders compared to non-responders (p=0.02). Conclusion Although OS was longer for pts with normal IL-6, elevated IL-6 at the time of diagnosis does not prevent pts from achieving disease remission. The study demonstrates that response to treatment rather than interleukin-6 levels in pts with POEMS syndrome is more prognostic. This study is an important initial step into understanding the utility of IL-6 in POEMS syndrome. Figure 1 Figure 1. Disclosures Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Kumar: Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dingli: GSK: Consultancy; Novartis: Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Apellis: Consultancy; Alexion: Consultancy. Lin: Janssen: Consultancy, Research Funding; Merck: Research Funding; Novartis: Consultancy; Legend: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Gamida Cell: Consultancy; Takeda: Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

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Long-Term Cardiac Effects of Successful Non-Myeloablative HLA-Matched Sibling Transplants in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-148173 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2898-2898

Author(s):

Vandana Sachdev ◽

My-Le Nguyen ◽

Wen Li ◽

Neal Jeffries ◽

Shalini S Ramachandra ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Left Ventricular ◽

Early Mortality ◽

Volume Index ◽

First Year ◽

Advisory Committees ◽

Lv Mass ◽

Second Year ◽

One Year

Abstract INTRODUCTION Cardiopulmonary complications lead to early mortality in adults with sickle cell disease (SCD). We previously showed in a small single-center study that cardiac morphology improves by one year after successful non-myeloablative hematopoietic stem cell transplantation (HSCT). Since cardiac outcomes following HSCT are not well-described, we sought to extend our results to a larger group of SCD patients from the National Institutes of Health (NIH) and University of Illinois Chicago (UIC). METHODS The majority of patients received alemtuzumab, 300cGy total body irradiation, and sirolimus; 21 also received pentostatin and cyclophosphamide preconditioning. An echocardiogram (echo) and routine laboratory testing were done at baseline before HSCT and at 1 and 2 year time points. Patients with an echo at least one year following HSCT were included. A generalized estimating equation regression model approach was used to evaluate echo and laboratory changes from baseline adjusting for age, gender, and site. A more stringent p-value threshold of 0.005 was used for significance given the large number of outcomes tested. The reported p values compare baseline vs 1 year and 1 year vs 2 year changes. RESULTS The study population consisted of 88 patients (69 NIH, 19 UIC) who had stable engraftment and were free of dialysis or chronic transfusion therapy. Mean + SD age of patients was 31.5 ± 10.5 years and 36 (41%) are female. Hemoglobin improved significantly in the first year (baseline 8.9 ± 1.5 g/dl, 1 year 12.9 ± 2.3, p < 0.0001), and continued to improve at 2 years (13.6 ± 2.0, p<0.0001). Laboratory results showed improvements in LDH, total bilirubin, and absolute reticulocyte count within the first year after HSCT (data not shown). Body surface area (BSA) was noted to increase significantly in the first year after HSCT (baseline 1.8 ± 0.2 m 2, 1 year 1.9 ± 0.2, p = 0.0002) and then stabilized in the second year (1.9 ± 0.3, p=0.9). Diastolic blood pressure was 66 ± 12 mmHg at baseline and closely followed the BSA, increasing in the first year (73 ± 11, p < 0.0001) and then remaining unchanged in the second year (74 ± 11, p=0.36). Systolic blood pressure (baseline 118 ± 15 mmHg) did not change significantly. The left ventricular size, as measured by the left ventricular end-diastolic volume index (LVEDVI) was elevated at baseline (82.6 ± 21.5 ml/m2), decreased dramatically at 1 year (69.0 ± 14.7, p < 0.0001), and continued to improve significantly at 2 years (63.1 ± 15.0, p < 0.0001, Figure). LV mass index, which is closely related to volume changes, did not change in the first year (baseline 84.9 ± 23.7 g/m 2, 1 year 85.1 ± 20.9, p= 0.72); however, it improved significantly by 2 years (79.2 ± 17.7, p=0.0003). The left atrial size, as measured by the left atrial volume index, also decreased in the first year (baseline 41.4 ± 12.8 ml/m2, 1 year 28.9 ± 8.7, p < 0.0001) with no change in the second year (27.9 ± 8.2, p=0.05). Diastolic filling parameters, which are independent risk markers of mortality, were seen to parallel the volume changes with baseline E/A ratio decreasing in the first year after HSCT (baseline 1.6 ± 0.6, 1 year 1.4 ± 0.4, p < 0.0001) and then remaining unchanged at 2 years (1.4 ± 0.5, p=0.09). Tricuspid regurgitation velocity (TRV), which is also a well-known early mortality risk marker in SCD, decreased significantly in the first year (baseline 2.5 ± 0.4 m/s, 1 year 2.4 ± 0.3, p = 0.002), and suggested a trend towards improvement at 2 years (2.3 ± 0.3, p=0.01). In 37 patients with a high-risk TRV ≥2.5 m/s, there was a significant decrease in the first year (baseline 2.9 ± 0.3, 1 year 2.5 ± 0.3, p < 0.0001) and then no change at 2 years (2.4 ± 0.3, p=0.05) CONCLUSION Our findings from two independent centers demonstrate significant improvements in cardiac size, mass, diastolic function, and TRV after non-myeloablative HSCT. Volume overload secondary to anemia is responsible for cardiac remodeling in SCD, and as the anemia resolves and high flow rates decrease following HSCT, many of the cardiac changes also reverse. LV volume decreased significantly in the first year, and these improvements, along with decreased LV mass index, continued in the second year. 55% of patients with a high-risk TRV normalized their TRV at 2 years. As diastolic dysfunction and TRV have both been associated with early mortality in adults with SCD, our results suggest that successful HSCT may impact survival. A larger multi-center study with longer follow-up is indicated. Figure 1 Figure 1. Disclosures Rondelli: Vertex: Membership on an entity's Board of Directors or advisory committees. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Determinants of Clinical Trial Participation and Impact on Survival Outcomes Among Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-131776 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5833-5833

Author(s):

Gabriella C Malave ◽

Prashant Kapoor ◽

Angela Dispenzieri ◽

Morie A. Gertz ◽

Martha Q. Lacy ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Trial Participation ◽

Newly Diagnosed ◽

Clinical Trial Participation ◽

Advisory Committees ◽

Baseline Characteristics

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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Characterization of Exceptional Responders to Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-119623 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4615-4615

Author(s):

Ashley Paquin ◽

Morie A. Gertz ◽

Hafsa Chaudhry ◽

Shaji K. Kumar ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Maintenance Therapy ◽

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Time Point

Abstract Aims: Autologous stem cell transplantation (ASCT) is an important component in the treatment of newly diagnosed multiple myeloma (MM). However, relapse following ASCT is considered almost inevitable, with a median time to progression (TTP) of approximately 23-26 months (without maintenance) and 40-46 months (with maintenance)(Attal MA et al. N Engl J Med 2012; 366:1782-1791; McCarthy PM et al. N Engl J Med 2012; 366:1770-1781). However, some patients can experience a prolonged period of remission with ASCT. The purpose of this study was to identify and characterize patients who have an exceptional response to upfront ASCT without maintenance therapy, and to determine the frequency of relapse in such patients. Methods: We searched the Mayo Clinic Multiple Myeloma bone marrow transplant database for patients who were diagnosed with MM between Aug 1, 1988 to Jan 3, 2006, and underwent ASCT within 12 months of initial diagnosis. For the purposes of this study, we defined exceptional responders as patients who were free of progression for 96 months or more, which is 2-3 fold more than the median TTP expected in this population. Since maintenance therapy was not standard of care at the time, only a small minority (6) of patients with prolonged TTP had received maintenance therapy; these patients were excluded since the study was focused on exceptional response with ASCT alone. One patient who had a tandem autologous transplant was excluded. Results: 509 patients underwent transplant during the study period. Of those, 46 (9%) met criteria for exceptional response. Twenty seven (59%) were female, 19 (41%) were male. Median age was 57.28 years, range, 31.9-73.0. Of 45 patients with response data available, the best response status was complete response or better in 32 patients (73.3%), VGPR in 4 patients (8.9%), and PR in 8 patients (17.7%). FISH data were available during the disease course for 41 patients. Of these, the majority, 28 patients (68.3%), had no abnormalities detected by the probes used; 3 patients (7.3%) had high risk cytogenetics (t(4;14) in 2 patients and t(14;16) in one patient) , 4 (9.8%) had trisomies; 6 patients had other isolated abnormalities. At last follow up, 23 patients have progressed (50%); 14 (30.4%) have died, including one who died without progression to MM. The median overall survival from time of diagnosis of the exceptional responders was 18.5 years, range 9.2-22 years. From the landmark time of 96 months, the median TTP was 6.2 years, range, 0.4-10.6 years (Figure 1); No plateau was seen in the TTP curve. From the landmark time of 96 months, the median OS was 10.5 years, range, 0.4-14 years. Conclusions: We conclude that approximately 10% of patients with newly diagnosed myeloma have an exceptional response to a single ASCT without maintenance therapy. These patients have a remarkable overall survival, both from diagnosis and from the landmark time point where they are classified as having achieved an exceptional response. Although TTP from the landmark time point is excellent, with median TTP of 6.2 years, there appears to be no plateau in the curve indicating ongoing risk of relapse despite a prolonged period of disease stability. Exceptional responders tended to have normal FISH studies (likely an indicator of responsive, low-tumor burden disease), and nearly 20% achieved this state despite not attaining a complete response. Figure. Figure. Disclosures Gertz: Research to Practice: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; janssen: Consultancy; Teva: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

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