Treatments and Outcomes of Patients with Multiple Myeloma (MM) Older Than 75 Years of Age: A Single Institution Experience

Abstract Abstract 4756 Background: Considerable advances in the treatment of myeloma patients have culminated in the approval of novel agents (thalidomide, bortezomib, lenalidomide) with survival benefits noted for each. The outcomes of patients younger than 65 years have been shown to be improved with the availability of novel therapies. However, older adults, who comprise the majority of patients with myeloma, have not experienced the same improvement in outcomes as noted in epidemiologic studies (Brenner et al. Hematologica 2009. 94(2): 270 and Schaapveld et al, Eur J Cancer. 2009. 46(1):160.). We postulated that lack of access to novel agents, difference in disease biology, or competing causes of mortality might explain this finding. Method: We conducted a retrospective review of electronic medical records for patients 75 years of age or older at the time of diagnosis with symptomatic myeloma after 2004 (to allow for the availability of novel agents). Demographic information including comorbid conditions, disease characteristics (including risk features and cytogenetics), treatment information as well as survival data was collected. Risk stratification (standard or high risk) was based on the Mayo criteria (Steward et al. Leukemia 2007; 21: 529). Result: 72 patients (median age 78 years, range 75–89, 58% were older than 80 years) with symptomatic myeloma were the subjects of this study. Seventy-two percent were males and 28%, 15%, 60% and 29% had a history of cardiac dysfunction (defined as CAD or CHF), diabetes, hypertension and another malignancy (excluding non melanoma skin cancer) respectively. While 31 patients had missing information to determine the International Staging System; 29%, 32% and 39% had ISS stages 1, 2, and 3, respectively (similar to what is expected in younger cohorts). Moreover, using the Mayo risk model, 31% of patients had high risk disease. The median number of systemic therapies received was 2 (range 0–6). First line therapy did not include a novel agent in 29% of patients (who received alkylating agents 12%, anthracyclines 4%, corticosteroids alone 13%) and at the time of relapse, all but 4 patients had received a novel agent. First line therapy consisted of lenalidomide based regimens (30%), bortezomib based regimens (12%), thalidomide based regimens (28%) and a combination of novel agents (1%). The median overall survival for the entire cohort was 46 months (95% CI: 36.4–56.2 months). Conclusion: Older adults (greater than 75 years of age) with multiple myeloma continue to experience a shortened survival despite the use of novel agents and without a discernable higher incidence of high risk disease suggesting competing causes of mortality and tolerance to therapy may significantly limit the benefit of novel therapies in this age group. To address these limitations, we have initiated a clinical trial evaluating a sequential response adapted lenalidomide based therapy for older adults with newly diagnosed myeloma in order to minimize treatment related toxicities. Disclosures: Alsina: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Baz:celgene: Consultancy, Research Funding; millenium: Research Funding; orthobiotec: Research Funding.

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Outcomes of Plasma Cell Leukemia Patients in the Era of Next-Generation Novel Agents: A Single-Center Retrospective Cohort Study

Blood ◽

10.1182/blood-2020-141525 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Alex Ge ◽

Chiung-Yu Huang ◽

Thomas Martin ◽

Jeffrey L. Wolf ◽

Nina Shah ◽

...

Keyword(s):

Plasma Cell ◽

Research Funding ◽

Progression Free Survival ◽

Novel Agents ◽

Next Generation ◽

First Line ◽

Advisory Committees ◽

Free Survival ◽

First Line Therapy ◽

Line Therapy

Introduction Primary plasma cell leukemia (pPCL) is a rare and aggressive disease comprising 1-5% of all plasma cell dyscrasias. Although historically pPCL has been defined by circulating plasma cells (CPCs) ≥ 20% and 2.0 × 109/L, many series require only one of these two criteria for diagnosis. Over time there has been a pressing need to change the definition further in order to capture patients at an earlier stage of the disease. Recent studies have shown that multiple myeloma (MM) patients who have CPCs ≥ 5% but < 20% at diagnosis have similarly poor outcomes. These thresholds for defining pPCL have not been studied in the current era of novel agents. While bortezomib-based regimens have been shown to extend pPCL patient survival, studies with next-generation agents such as carfilzomib (CFZ), pomalidomide, and daratumumab (DARA) are still scarce. Methods We performed a single-center, retrospective study of patients who at diagnosis had pPCL (defined as CPCs ≥ 20% or 2.0 × 109/L) or had MM with < 20% CPCs (MM-CPC). Patients were treated at our institution between 1/1/2000-7/17/2020. Overall response rates were determined according to International Myeloma Working Group criteria. Overall survival (OS) was defined as the length of time between initiation of first line therapy and death. Progression-free survival (PFS) was defined as the length of time between initiation of first line therapy and first progression. OS and PFS were compared using log-rank tests. Results Of the 54 patients identified, 38 had pPCL and 16 had MM-CPC. The median age at diagnosis of the pPCL and MM-CPC groups were 59.2 (range 43-94) and 59.8 years (range 29-79), respectively, with a similar percentage of females, 47.4% vs. 37.5%. Both groups were similarly distributed by year of diagnosis; 76.3% and 62.5% of pPCL and MM-CPC patients were diagnosed between 2012-2020, respectively. The pPCL cohort had median CPCs of 40% (15-98) while the MM-CPC cohort had median CPCs of 4% (1-15). Median CPCs at diagnosis was 3.36 (0.44-179) × 109/L in the pPCL group compared to 0.33 (0.04-1.79) × 109/L in the MM-CPC group. Most patients for both groups were ISS stage III at diagnosis (57.9% in pPCL cohort, 56.2% in MM-CPC cohort). R-ISS assessment was not feasible due to missing data. A greater proportion of patients in the pPCL group (44.7%) had complex cytogenetics at diagnosis compared to the MM-CPC group (25.0%). All patients were exposed to at least one novel agent over the entire disease course. Of these patients, 50 (92.6%) were exposed to bortezomib, 45 (83.3%) to lenalidomide, 33 (61.1%) to CFZ, 22 (40.7%) to DARA, 13 (24.1%) to pomalidomide, and 4 (7.4%) to venetoclax. Twenty-four patients (44.4%) received an autologous stem cell transplant (ASCT). At the best response to treatment, 76.7%, 62.8% and 37.9% of patients achieved a partial response or greater to first, second and third line therapy, respectively. The median OS of the pPCL and MM-CPC groups was 34.5 and 35.5 months (p = 0.97) (Figure 1A), while the median PFS was 13.9 and 10.9 months (p = 0.52) (Figure 1B), respectively. The median follow-up was 28.1 months. No differences were observed for patients with CPCs < 20% compared to patients with CPCs ≥ 20% (p = 0.98). There was trend towards a better survival for patients with CPCs < 2 × 109/L compared to CPCs ≥ 2 × 109/L (p = 0.35). Since we did not observe any meaningful difference in OS or PFS between the pPCL and MM-CPC groups, we combined these groups for further survival analysis. Patients exposed to either DARA or CFZ (n = 37) had a median OS of 59.2 months, while patients exposed to neither drug (n = 17) had a median OS of 11.7 months (p = 0.02) (Figure 1C). ASCT was associated with a prolonged median OS (66.8 months vs. 17.2 months, p = 0.0001) (Figure 1D), while a complex karyotype at diagnosis was associated with a poorer median OS (17.4 months vs. 66.8 months, p = 0.01). Conclusions In the era of next-generation novel agents, overall and progression-free survival of pPCL and MM-CPC patients are similar. Patients exposed to DARA or CFZ have an improved survival compared to those who did not receive these drugs. ASCT is also associated with a superior survival over those who did not receive a transplant. Further studies are needed to evaluate the efficacy of these next-generation drugs in this patient population. Disclosures Martin: Janssen: Research Funding; Seattle Genetics: Research Funding; AMGEN: Research Funding; GSK: Consultancy; Sanofi: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Wong:Sanofi: Membership on an entity's Board of Directors or advisory committees; Fortis: Research Funding; Roche: Research Funding; Janssen: Research Funding; Amgen: Consultancy; GSK: Research Funding; Bristol Myers Squibb: Research Funding.

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Natural History of Skeletal Related Events in Patients with Multiple Myeloma Who Received First- and Second- Line Therapy with Novel Agents: Results from a Single Center Analysis in 620 Patients

Blood ◽

10.1182/blood-2019-123606 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4326-4326

Author(s):

Evangelos Terpos ◽

Nikolaos Kanellias ◽

Eftathios Kastritis ◽

Maria Gavriatopoulou ◽

Vassilis Koutoulidis ◽

...

Keyword(s):

Research Funding ◽

Novel Agents ◽

Long Bone ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Skeletal Related Events ◽

First Relapse

Introduction: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Although the incidence of SREs at diagnosis is well-documented, there is limited information for the natural history of SREs during treatment with novel agents. Thus, we evaluated the SRE rate in MM patients who received frontline and second line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies and explored possible correlations with disease or genetic features and type of treatment. Methods: MM patients who received frontline therapy in our center (Department of Clinical Therapeutics, University of Athens, Greece), between 2007-2017, were included in this analysis. Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and then at the time of relapse or whenever clinically indicated. Magnetic Resonance Imaging (MRI) of the spine and pelvis at diagnosis was recorded when available. SNPs in genes that are involved in bone destruction in osteoporosis were also evaluated: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). Results: In total, 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. At diagnosis, osteolytic disease was present in 408 (66%) patients. MRI was available in 390 patients: 149 (38%) patients had focal, 139 (36%) diffuse, 81 (21%) normal and 21 (5%) variegated pattern of marrow involvement. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures (183 with vertebral fractures, 18 with rib fractures and 15 with long bone fractures; 32 patients had both vertebral and long bone or rib fractures), while 34 (5.5%) patients needed surgery to bone, 45 (7.2%) radiotherapy and 31 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (76.4% vs. 12.4%, p<0.0001) or abnormal MRI pattern (49% vs. 11.3%, p<0.0001) at diagnosis. No correlation was found between the presence of SREs at diagnosis and a specific SNP of those studied. Frontline therapy with IMiD-based regimens was given in 38% of patients; 27% patients received bortezomib-based regimens and 28% both IMiD and bortezomib-based therapies (VTD or VRD); 7% received only conventional chemo. Bisphosphonates (BPs) were given to 465 patients (75%) at diagnosis; the vast majority (91%) received zoledronic acid. The remaining 155 patients did not receive upfront BPs, mainly due to renal insufficiency. During first line treatment, 39 (6.3%) patients developed a SRE: 25/341 (7.3%) on bortezomib- (including combos with an IMiD) and 14/235 (6%) on IMiD-based regimens. At the time of first relapse, 4.5% of patients presented with new fractures and 12% required local radiotherapy to bone (SRE rate: 16.5%). The rate of SREs at first progression was much higher in patients who did not receive upfront BPs (92.3% vs. 7.7%). There was no difference in the incidence of SREs at first relapse between patients who received PI- vs. non-PI-based regimens as first line therapy (54.2% vs. 45.8%, p=0.544). During second line therapy, 12.2% of patients developed a SRE, with no difference regarding the second line therapy (PI- or IMiD-based regimens). In total, 126 (20.3%) patients developed at least one SRE, during the course of the first and second line of therapy; this was more common in those who presented with an SRE at diagnosis (33% vs 12%; p<0.03). Conclusions: Our data, which constitutes one of the few systematic reports on the incidence and characteristics of SREs in the era of novel agents, indicate that SREs remain a significant complication in MM. Despite high response rates after first line therapy and the broad use of BPs, more than 20% of patients develop a new SRE during the first and second line treatment or at the time of first relapse. Importantly, patients who do not receive BPs due to renal impairment develop very frequently SREs, suggesting an unmet need in this setting. More effective frontline therapies or more potent bone-targeted agents (denosumab or anti-sclerostin drugs) may manage to further reduce the SREs rate in MM patients, especially in those who cannot receive BPs. Disclosures Terpos: Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Kastritis:Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding.

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Role of Neutrophil Lymphocyte Ratio [NLR] As a Biomarker of Frailty and Predictor of Survival Among Older Adults with Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2020-143290 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-6

Author(s):

Smith Giri ◽

Susan Bal ◽

Kelly N. Godby ◽

Joshua Richman ◽

Adam J Olszewski ◽

...

Keyword(s):

Older Adults ◽

Overall Survival ◽

Research Funding ◽

First Line ◽

Targeted Interventions ◽

First Line Therapy ◽

Systems Research ◽

Line Therapy ◽

Race Ethnicity ◽

The Impact

Introduction: NLR combines a marker of inflammation (neutrophilia) and immune senescence (lymphopenia) to reflect aging related alterations in the immune systems. Prior studies have shown that NLR can serve as a marker of frailty and predict survival among older adults with solid tumors and lymphomas, its role among older adults with MM remains unclear. Methods: We used the Flatiron Health electronic health record-derived de-identified database to source older adults (age ≥60y) with incident MM diagnosed between 1/1/2011 and 2/1/2020. We limited our study cohort with known first line therapy and absolute neutrophil and lymphocyte count (cells//µL) up to 90 days before the start of treatment. We constructed a modified frailty index (Facon et al Leukemia 2020) at MM diagnosis combining age, comorbidity and ECOG performance status, captured within 90 days from the start of first line therapy categorizing patients into frail vs nonfrail. We examined the association between NLR (stratified into quartiles, Q1-Q4) and frailty using logistic regression model adjusted for age, sex and race/ethnicity. We used Kaplan Meier methods and multivariable Cox regression to assess the impact of NLR on overall survival adjusting for age, sex, race/ethnicity, international staging system (ISS) stage, high-risk cytogenetics (HRCA; del17p, t4;14 or t14;16), and first-line therapy. Results: Of 2792 eligible patients, the median age at MM diagnosis was 73y (IQR: 67-78y), with 53% males and 61% non-Hispanic whites. Of these, 56% had IgG isotype, 22% ISS stage-III and 13% had HRCA. The median NLR was 2.29 (IQR: 1.5 to 3.59). Of the 1,743 evaluable for frailty, 1042 patients (59.8%) were frail. Overall, 45% received proteasome inhibitor (PI) + Immunomodulatory agent (Imid) based first line therapy and 19% received autologous stem cell transplantation. Patients in the highest NLR quartile were at a 2.1-fold higher odds of being frail (95% CI 1.52-2.86; p <0.001) when compared with those in the lowest NLR quartile (after adjusting for age, sex and race/ethnicity). NLR was poorly correlated with age (Pearson's r= 0.02). Patients in the highest NLR quartile had an inferior overall survival vs those in the lowest quartile (median OS/3y-OS in Q4 3.3y/53% vs 4.7y/69% in Q1; log-rank p <0.01). Similar results were seen when limiting to patients receiving first line PI & Imid triplet and PI or Imid based doublet regimens (Fig 1). In a multivariable analysis, patients in the highest NLR quartile had a 1.5 times increased hazards of death (95% CI 1.28-1.85, p <0.001) when compared with those in the lowest NLR quartile, after adjusting for potential confounders (Table 1). Conclusion: NLR is an easily available laboratory biomarker associated with frailty as well as inferior overall survival among older adults with MM. Future studies should explore its value as a screening tool to identify frail older adults with MM and guide appropriate treatment selection and targeted interventions to prevent excess toxicities and improve outcomes. Table 1 Disclosures Giri: Pack Health: Research Funding; Carevive Systems: Research Funding; Carevive Systems: Honoraria. Olszewski:Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Costa:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Genentech: Consultancy.

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Good Tolerance of Lenalidomide Maintenance Therapy in Patients with High Risk Profile Chronic Lymphocytic Leukemia (CLL) after Frontline Chemoimmunotherapy: Preliminary Safety Overview of the CLLM1 Trial of the German CLL Study Group (GCLLSG)

Blood ◽

10.1182/blood.v124.21.4699.4699 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4699-4699 ◽

Cited By ~ 1

Author(s):

Barbara Eichhorst ◽

Jasmin Bahlo ◽

Anna Maria Fink ◽

Michael Pfreundschuh ◽

Holger Hebart ◽

...

Keyword(s):

High Risk ◽

Adverse Events ◽

Maintenance Therapy ◽

Research Funding ◽

B Cell Lymphoma ◽

First Line ◽

Skin Reactions ◽

First Line Therapy ◽

Line Therapy ◽

Grade 3

Abstract Introduction: CLL patients (pts) with persistence of minimal residual disease (MRD) after frontline chemoimmunotherapy or an unfavourable genetic profile have a high risk of early relapse and a short survival (Fink et al., Leukemia 2013). Therefore, the GCLLSG designed the CLLM1 trial, a phase 3, randomized, double-blinded, placebo-controlled study to investigate the efficacy and safety of lenalidomide maintenance therapy for high–risk (HR) CLL following first-line chemoimmunotherapy. HR is defined by the presence of MRD at levels of ≥10-2 or the combination of MRD levels of ≥10-4 to <10-2 with an unmutated IGHV status, or del(17p) or TP53 mutations. Methods and patients: Prior to randomization pts underwent central screening procedures including the assessment of all risk factors and eligibility in particular response to first-line therapy. MRD levels were centrally analyzed. Pts were randomly assigned to receive either placebo or lenalidomide 5 mg p.o. daily for the first 28-day cycle, 10 mg p.o. daily for cycle 2-6, and the target dose of 15 mg for cycle 7-12. Further escalations up to 25 mg were allowed in MRD-positive pts if the study drug was well tolerated. Pts were treated until progression. Between July 2012 and June 2014 535 pts were registered from 130 sites in five countries (Austria, Germany, Italy, Netherlands and Spain). 126 (23.6%) of the pts were excluded before proceeding to MRD-analysis after first-line therapy due to misdiagnosis of other B-cell lymphoma (N=18), withdrawal of consent (N=44), comorbidities (N=5), hepatitis B infections (N=2) or other reasons (N=57). A total of 239 pts completed the screening. 186 (77.8%) achieved MRD negativity and were therefore ineligible for the study, and 8 (3.3%) pts are awaiting randomization. Pts remained blinded for this analysis. Results: To date, 45 HR pts were randomized. First-line therapy according to investigator’s choice included FCR in 17 (37.8%), BR in 27 (60.0%) and FC in 1 (2.2%) of 45 pts. Before first-line therapy, 9 of 45 (20.0%) pts had Binet A, 19 (43.2%) Binet B and 16 (36.4%) Binet C stage of disease, respectively. The median age was 66 years (range 44-80), median CIRS score was 2 (range 0-6). 33 of 45 pts (73.3%) showed MRD levels between ≥10-4 to <10-2 combined with by high risk genetics, and 12 (26.7%) showed MRD levels ≥10-2. 43 (95.1%) pts had unmutated IGVH genes. Del(17p) was detected in 4 (8.9%) and TP53 mutation in 6 (13.3%) pts, while 2 (4.4%) pts carried both abnormalities. At the time point of analysis 195 treatment cycles [60.2% of 324 expected cycles] were documented in 26 of 45 (57.8%) randomized pts. The median number of administered cycles was 6.5 (range 1-20). 115 of 195 treatment cycles (59.0%) were administered without the occurrence of any adverse event (AE). In 80 treatment cycles (41.0%) at least one AE was documented. 133 adverse events (AEs) of all CTC grades (1 to 4) occurred in 19 of 26 pts (73.1%). Eleven pts (42.3%) experienced at least one AE of CTC grade 3 or 4. The most common AEs were related to haematological parameters [9 (34.6%) pts, 7 (26.9%) with CTC grade 3/4], infections [8 (30.7%), all CTC grade 1/2], gastrointestinal [9 (34.6%), all CTC grade 1/2], respiratory/thoracic/mediastinal [4 (15.4%), all CTC grade 1/2] and skin disorders [9 (34.6%), 2 (7.6%) with CTC grade 3]. AEs led to the discontinuation of study treatment in 3 pts (11.5%) including fatigue [N=1, CTC grade 3] and allergic dermatitis [N=2, both CTC grade 3]. In total 13 of 45 pts (28.9%) treated in both arms have discontinued the study caused by withdrawal of consent (N=5) disease progression (N=4), toxicity (N=3) and technical reasons (N=1). To date, no treatment-related death has been reported in both treatment arms. Seven SAEs have been reported so far, three of them related to treatment including septic arthritis due to staphylococcal infection, autoimmune haemolytic anemia and cholecystitis, the latter resulted in study discontinuation. Conclusion: So far, maintenance therapy with lenalidomide or placebo appears to be a safe treatment option as the majority of adverse events reported during the maintenance therapy were mild or moderate (CTC grade 1/2). Severe adverse events (CTC grade 3/4) were observed solely with skin reactions and cytopenia. Reasons for discontinuation were mostly non-serious events including skin reactions and fatigue. Later analyses will clarify the impact of lenalidomide maintenance on relapse-free survival in high-risk CLL. Disclosures Eichhorst: Roche: Research Funding; Mundipharma: Research Funding. Off Label Use: Lenalidomide is not approved for maintenance treatment in CLL. Fink:Celgene: Other. Maschmeyer:Celgene: Consultancy. Westermann:Celgene: Other. Zey:Celgene: Other. Fischer:Roche: Other. Wendtner:Celgene: Consultancy, Honoraria, Research Funding. Ghia:Merck: Consultancy; GSK, Roche Italia: Consultancy; Gilead, Pharmacyclics, Boehringer Ingelheim, Celgene, Roche Italia: Membership on an entity's Board of Directors or advisory committees. Bosch:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Döhner:Celgene: Research Funding. Stilgenbauer:Celgene: Consultancy, Honoraria, Research Funding. Boettcher:Roche: Honoraria, Research Funding; Celgene: Research Funding. Hallek:Celgene: Consultancy, Honoraria, Research Funding.

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Bortezomib in first-line therapy is associated with falls in older adults with multiple myeloma

Journal of Geriatric Oncology ◽

10.1016/j.jgo.2021.02.009 ◽

2021 ◽

Author(s):

Kelly L. Schoenbeck ◽

Mark A. Fiala ◽

Tanya M. Wildes

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Falls In Older Adults

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Analysis of Falls in Older Adults with Multiple Myeloma Undergoing First-Line Therapy

Blood ◽

10.1182/blood-2019-129611 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5886-5886

Author(s):

Kelly L. Schoenbeck ◽

Tanya M. Wildes ◽

Mark A. Fiala

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Peripheral Neuropathy ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Increased Risk ◽

Risk Of Falls ◽

Falls In Older Adults ◽

First Line Treatment

Background: Patients with multiple myeloma are frequently treated with bortezomib, a proteasome inhibitor, which is associated with treatment-related peripheral neuropathy. Older adults are at increased risk of falls compared to the general population, often leading to associated morbidity and mortality. While an association between peripheral neuropathy and falls in older adults is well-established, the relationship between bortezomib and falls in older multiple myeloma patients is unknown. Our primary aim was to determine if older patients with multiple myeloma treated with bortezomib as first-line therapy had an increased incidence of falls within the first 12 months after starting treatment. Our secondary aim was to assess the overall survival of patients who fell compared to those who did not among patients who lived more than 12 months after initiating treatment. Methods: We analyzed the SEER-Medicare database for all patients 65 years old or older diagnosed with multiple myeloma between 2007 and 2013 and were enrolled in fee-for-service Medicare part A, B and D plans. The patients' corresponding Medicare claims data were analyzed through 2014 for myeloma treatments, fall claims, and covariates of interest. The primary outcome was accidental falls (E880-E888) occurring between 14 days to 12 months after starting multiple myeloma treatment. First-line therapy was defined as any anti-myeloma treatment administered within 14 days of starting multiple myeloma treatment, with bortezomib treatment being the focal independent variable. Cox regression was performed to determine the relative risk of having a fall after controlling for other covariates. Patients who started bortezomib after first-line therapy were censored at time of bortezomib commencement. The survival analysis included only patients who survived more than 12 months of starting treatment to allow landmark analysis of falls in the first year. Results: Of 4,084 older adults with new multiple myeloma diagnoses undergoing first-line therapy, the median age was 75 (range 65-97) with 51% males. Bortezomib was used in first-line therapy for 2,052 (50%) patients, of which 157 (8%) patients experienced a fall within 12 months after starting treatment compared to 102 (5%) of patients not receiving bortezomib (p < 0.001). Bortezomib was associated with a 28% increase risk of falls (HR 1.29; 95% CI 1.00-1.65; p = 0.047). In multivariate analysis, bortezomib was not associated with an increased incidence of falls after controlling for age, gender, race, proxies for Charlson Comorbidity Index (CCI) and poor performance status, pre-existing peripheral neuropathy, falls within the 12 months prior to starting first-line myeloma treatment, depression, polypharmacy, and first-line treatment with lenalidomide (Table 1). Advancing age, history of fall(s), depression, and polypharmacy (defined as more than 10 unique prescription medications at initiation of first-line treatment), were all associated with an increased risk of falls, consistent with prior literature. In a landmark analysis of those who survived 12 months following the start of treatment, a fall was associated with a 26% increased risk of hazard for death (aHR 1.26; 95% CI 1.02-1.56; p = 0.033) after controlling for other covariates. The median OS of those with a fall was 35.7 months (95% CI 29.1-48.4) compared to 49.1 months (95% CI 47.1-52.8) for those without (p < 0.0001). Conclusion: In older adults with multiple myeloma, treatment with bortezomib was not associated with increased risk of a patient having a diagnostic code for falls. However, experiencing a fall within the year after starting treatment was associated with decreased overall survival. Limitations of the study include that the incidence of falls is likely underestimated in billing data, given prior data from our group showing a rate of self-reported falls of 26% in the year after diagnosis. Additional research, including prospective trials involving fall assessments, should be considered in older patients with multiple myeloma. Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Fiala:Incyte: Research Funding.

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Mo1310 OVER-THE-SCOPE CLIP AS FIRST-LINE THERAPY IN THE MANAGEMENT OF HIGH RISK BLEEDING PEPTIC-ULCERS: A CASE-MATCH CONTROL STUDY

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2019.03.789 ◽

2019 ◽

Vol 89 (6) ◽

pp. AB484

Author(s):

Carlos Robles-Medranda ◽

Juan M. Alcívar-Vásquez ◽

Roberto Oleas ◽

Jorge Baquerizo-Burgos ◽

Juan I. Olmos ◽

...

Keyword(s):

High Risk ◽

Peptic Ulcers ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Bleeding Peptic Ulcers ◽

Over The Scope Clip ◽

Control Study

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First-Line Therapy with Donor Derived HCMV-Specific T Cells Reduce Persistent HCMV Infection after Allogenic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-113923 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 727-727

Author(s):

Xiangyu Zhao ◽

Xuying Pei ◽

Xiaojun Huang ◽

Ying-Jun Chang ◽

Lanping Xu ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

High Risk ◽

Hcmv Infection ◽

Antiviral Agents ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Risk Patients ◽

One Year

Abstract Background: Human cytomegalovirus (HCMV) infection, especially persistent HCMV infection, is an important cause of morbidity and mortality after allogenic stem cell transplantation (allo-SCT). Antiviral agents remain the mainstay of treatment and are recommend as the first-line therapy for HCMV. However, drugs are associated with significant toxicity, and their efficacy is limited in the absence of cell-mediated immunity. In recent years, adoptive immunotherapy with HCMV-specific T cells (CTLs) has been developed as an alternative option for HCMV, and data from previous studies have indicated that infusion of CTLs at early-stage of HCMV infection may have better benefits compared to salavage therapy. However, because CTLs remains time consuming and cost-intensive, so far there have no reports of first-line therapy with CTLs for HCMV infection, and the mechanisms driving the sustained antiviral immunity induced by adoptive T cells transfer remain undetermined. Our previous study had demonstrated that patients with acute graft-versus-host disease (aGVHD) were at high risk to develop persistent HCMV infection. Therefore, in the current study, we selected patients who developed aGVHD before HCMV reactivated and started CTLs generation in advance. This risk-stratified measure successfully selected patients who had high risk resisting to conventional anti-HCMV therapy , and spared low risk patients as well, making it feasible and financially viable to use CTLs as a first-line therapy. Aims: To provide robust support for the safety and efficacy of CTLs given as a first-line therapy for HCMV infection after allo-SCT, and gain some insight into the underlying mechanisms. Methods: Firstly, using humanized HCMV infected mice model, we explored where the adoptive transferred CTLs cells trafficked, evaluated the antiviral efficacy of CTLs and investigated the recovery of HCMV-specific immunity after T cell transfer. Secondly, we conducted a prospective clinical trial enrolled 35 allo-SCT patients who diagnosed with acute GVHD and had high risk developing persistent HCMV infection, intervened with antiviral agents combined with CTLs as first-line therapy and evaluated the long-term safety and durability of antiviral responses. As controls, we selected a cohort of 70 high-risk patients as well as another cohort of 70 low-risk patients who only received antiviral agents as first-line therapy without CTLs. We also evaluated the immune response after infusion and analyzed the association between immune recovery and HCMV clearance. Results: i) In humanized HCMV infection mice, adoptive infused CTLs had the ability to homing to organs, and effectively combated systemic HCMV infection by promoting the restoring of stem cell derived endogenous HCMV-specific immunity. ii) In clinical trial, first-line therapy with CTLs significantly reduced the rate (2.86% vs. 20.00%, P=0.018) and the cumulative incidence (HR=7.60, 95%CI=1.22-10.15, P=0.020) of persistent HCMV infection, and showed a lower one-year treatment related mortality (TRM) (HR=6.83, 95%CI=1.16-8.90, P=0.030) and a better one-year overall survival (OS) (HR=6.35, 95%CI=1.05-9.00, P=0.040) compared to high-risk control cohort. The cumulative incidence of persistent HCMV infection, one-year TRM and OS in CTL cohort were comparable to those in low-risk control cohort. Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance. Conclusion: In this study, we firstly demonstrated the safety and efficacy of CTLs administration as a first-line therapy for HCMV infection in humanized HCMV infection mice, and in a large clinical cohort study. The data provided robust support for the benefits of donor derived CTLs in treating HCMV infection as a first-line therapy, and suggested that infused CTLs might probably stimulate the recovery of donor derived HCMV-specific immunity. This trial was registered at www.clinicaltrials.gov as #NCT02985775. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Outcomes of Primary Systemic Light Chain (AL) Amyloidosis in Patients Treated Upfront with Novel Agents and the Importance of Risk Adapted Treatment Strategies

Blood ◽

10.1182/blood.v120.21.1786.1786 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1786-1786

Author(s):

Efstathios Kastritis ◽

Maria Roussou ◽

Maria Gavriatopoulou ◽

Magdalini Migkou ◽

Alexandra Gkougkoutsi ◽

...

Keyword(s):

Cardiac Biomarkers ◽

Novel Agents ◽

Al Amyloidosis ◽

First Line ◽

Hematologic Response ◽

First Line Therapy ◽

Line Therapy ◽

Initiation Of Therapy ◽

Intent To Treat ◽

Stage 1

Abstract Abstract 1786 Novel antimyeloma agents (thalidomide, lenalidomide and bortezomib) may induce high rates of hematologic responses in patients with AL amyloidosis in whom they are increasingly used. Due to the multisystemic involvement many patients with AL are frail and vulnerable to treatment related toxicity and often succumb to their disease early after initiation of therapy, mainly due to complications associated with cardiac amyloidosis. In order to investigate the outcomes of AL patients in the era of novel agents and explore strategies to reduce complications and early mortality, we analyzed 81 consecutive patients in a single center (Department of Clinical Therapeutics, University of Athens, Greece). All patients were assessed and followed rigorously and received similar supportive care according to our institution's practice. Bortezomib (B) was given as first line or salvage therapy after 1/9/2005 and lenalidomide (L) was given as primary therapy or salvage after 1/1/2008. Beginning on 1/1/2011, we follow a risk-adapted strategy, in which previously untreated patients with AL received bortezomib at a dose and schedule adjusted according to performance status (PS), levels of cardiac biomarkers and age (BDa). Patients were divided in those who started therapy from 2005 to 31/12/2007 (23 patients), those who received therapy between 1/1/2008 to 31/12/2010 (36 patients) and those who started therapy after 1/1/2011 (22 patients): 54% received first line therapy with B, 40% with L and 6% received conventional therapy upfront (mostly melphalan with dexamethasone; all received novel agents at later stages of their disease). Most patients (57%) were males; the median age was 67 years (range 42–82 years); 55% had a PS ≥2; the heart was involved in 68% of patients, the kidneys in 70%, the liver in 9%, and the peripheral nerve in 25%. Median eGFR was 70 ml/min and 4% required dialysis at diagnosis. Median NTproBNP was 2318 ng/l (range 36–75000 ng/l) and according to cardiac biomarkers, 26% were Mayo stage 1, 42% stage 2 and 32% stage 3. There were no significant differences in the demographic and disease characteristics between the three groups but 80% of patients, who started therapy from 2005 to 31/12/2007, received upfront BD, 80% of patients, who started therapy from 1/1/2008 to 31/12/2010, received upfront L and 82% of patients after 1/1/2011 received upfront BDa. On intent to treat, 65% of patients achieved hematologic response to first line therapy, including 20% hemCRs. Hematologic response rates were not different between the three groups (p=0.118); however, hemCRs were more frequent in patients treated before 31/12/2007 and after 1/1/2011 (30% and 27% vs. 9% in those treated from 1/2008-12/2010). The respective hemCR rates for patients treated with B vs. L were 32% vs. 6% (p=0.025). On intent to treat, organ responses were achieved by 28% of patients. Hematologic or organ progression or death has occurred in 60.5% of patients; the median PFS was 10 months and the 1-year PFS rate was 50%, 27% and 59% for patients treated in the three consecutive time periods, respectively (p=0.011). For patients treated upfront with B- vs. L-based regimens the respective 1-year PFS rate was 51% vs. 31% (p=0.054). After progression to first line therapy, 21 (26%) patients received second line therapy: 17 received B and 4 L. The median survival of all patients was 34 months; the 1-year survival rate for patients with Mayo stage 1 disease was 94%, for stage 2 was 56% and for stage 3 was 28% (p<0.001); 18 (22%) patients died within the first 3 months from initiation of therapy (all except one had cardiac involvement). The respective early death rates were 17%, 34% and 4% for patients treated in the three time periods, respectively (p=0.024) and were 22% and 25% for B- and L-based regimens (p=0.443), indicating that the reduction of early deaths was mainly due to the risk-adapted treatment strategy after 1/2011. In conclusion, our data indicate that novel agents, and especially bortezomib, resulted in significant response rates in patients with AL amyloidosis; however, 22% of AL patients die within 3 months form initiation of therapy due cardiac amyloidosis-associated complications. A risk-adapted treatment strategy with bortezomib dose and schedule adjusted according to individual patient characteristics may reduce early mortality and allow patients to achieve a hematologic response. Updated results will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Salvage Therapies in Patients with High-Risk Relapse After Fludarabine, Cyclophosphamide, Rituximab (FCR) for Chronic Lymphocytic Leukemia: The French CLL Intergroup Experience

Blood ◽

10.1182/blood.v120.21.1796.1796 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1796-1796

Author(s):

Luc-Matthieu Fornecker ◽

Therese Aurran-Schleinitz ◽

Anne-Sophie Michallet ◽

Bruno Cazin ◽

Jehan Dupuis ◽

...

Keyword(s):

High Risk ◽

Second Line ◽

Complex Karyotype ◽

First Line ◽

Second Line Therapy ◽

High Risk Patients ◽

First Line Therapy ◽

Line Therapy ◽

Ultra High Risk ◽

Risk Patients

Abstract Abstract 1796 Introduction: FCR chemoimmunotherapy is recommended as first line therapy for fit cll patients. Since the 2007 EBMT guidelines based on the previously published trials using FCR, the definition of high risk CLL has evolved, to include biologic parameters (TP53 disruption by deletion/mutation, high b2-microglobulin level, IgVH unmutated, complex karyotype), refractoriness (progression during fluda-based regimen or within 6mo of completion), and also remission duration (high risk if PFS after FCR <24mo, ultra-high risk if TTNT <24–36mo with TP53 del/mut). However, few data are available regarding the characteristiscs, response rate and outcome of CLL patients treated in second line after FCR first line. Patients and methods: In this multicentric retrospective study, we collected data from 117 patients who relapsed after FCR first line therapy and received second-line therapy (according to NCI2008 guidelines). Results: At the time of initial FCR therapy: patients characteristics were as follows: Binet B/C 87.2%, unmutated IgVH 52.2%, del11q 25.6% (n=30/81 with FISH available), del17p 6.8% (n=8/87 with FISH available), bulk>5cm 22%, complex karyotype 21% (n=12/57 with karyotype available). FCR yielded 93% ORR, with 66% clinical CR, 27% PR, and 7% failed to respond. Median PFS and TTNT were 27mo and 32.5mo, respectively. At the time of relapse: patients characteristics were as follows: del11q 16.4% (n=19/65 with FISH available), del17p 19% (n=22/77), bulk>5cm 26%, complex karyotype 44% (n=24/54 with karyotype available). According to FCR remission duration, 11.1% of patients were considered as truly FCR-refractory, 47% had PFS<24mo, 34.2% had TTNT<24mo. TTNT<24mo after FCR was correlated to age>65y, del17p (20% vs 0%) and complex karyotype (38% vs11%), but not with gender, IgVH status, del11q, or bulk>5cm. Based on FCR-refractoriness, or TTNT<24mo and/or del17p, 53 patients were considered as ultra-high risk (45.3%). Various regimen were used for second-line treatment after FCR: R-bendamustine (n=47, 40.2%), alemtuzumab-based therapy (single agent or with chemo/dexa, n=22, 18.8%), R-CHOP (n=15, 12.8%), FCR (n=14, 12%), and other miscellaneous regimens (as follows: R-alkylator (n=6, 5.1%), R-DHAP (n=4, 3.4%), R-methylprednisolone (n=3, 2.6%), or investigational drugs (n=6, 5.1%)). Thus, 74.3% of patients received a second course including rituximab-based chemotherapy. Overall response rate was 78.4%, with 13.8% clinical CR, 64.6% PR, and 21.6% failure/stable disease. 14 pts (12%) underwent stem cell transplantations, 8 had maintenance therapy ongoing (ofatumumab, alemtuzumab, or lenalidomide). With regards to factors defining high-risk relapse, distribution of salvage therapies was as follows: As expected, a second course of FCR was seldom used in high-risk patients. Among ultra-high risk patients, 30.3% received R-benda, 11.3% Alem-based Rx, 32% R-CHOP and 18% the miscellaneous regimens described above. After second-line therapy, median PFS was 12 months, median TTNT was 14mo, and median OS was 36mo (20 deaths). On univariate analysis, complex karyotype (p=0.04) but not del17p (p=0.1), PFS<24mo (p=0.028) and TTNT<24mo (p=0.04) correlated with OS. Regarding treatment, OS was significantly improved in R-bendamustine-treated patients, as compared to alem-based or CHOP regimen (p=0.01). Most importantly, patients who received an allogeneic transplant benefited from significantly prolonged OS (at 4y, 70% vs 40%, p=0.03). Of note, only one patient treated with R-benda received allotransplant. Conclusions: This study shows that there are no consensus for second line therapy after FCR. Second line trials after FCR therapy are warranted. Definition of high-risk subsets of patients at relapse after FCR is of upmost importance in the management of CLL, to compare second-line strategies. Our data suggest that R-bendamustine is an efficient regimen even in high-risk patients (complex karyotype, PFS<24mo, TTNT<24mo). These data are important since this immunochemotherapy is now used as the backbone for combination with new compounds (ibrutinib, GS1101, GDC-199). Disclosures: Aurran-Schleinitz: Roche: Honoraria. Leblond:Roche: Advisory Board Other, Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen-Cilag: Honoraria.

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