Real-World Clinical Outcomes By Cytogenetic Risk Category in Relapsed or Refractory Multiple Myeloma: Evidence from a Cohort Review in France

Abstract INTRODUCTION: Multiple Myeloma (MM) is an incurable hematologic cancer characterized by multiple recurrences. With each recurrence, patients have a lower probability of response and duration of response is shorter. Therefore, there is an unmet need to improve outcomes in relapsed/refractory multiple myeloma (RRMM). There is a shortage of data describing clinical features and outcomes in these patients in real-world practice, particularly with regard to differences in outcomes by baseline cytogenetic risk. To help address this information gap, this study analyzed data from a cohort of RRMM patients in France. METHODS: A retrospective observational review of medical records was conducted in a cohort of 200 patients with RRMM in France. Patients were selected (based on randomly generated first letter of last name) from the caseloads of 40 hematology/oncology providers across France practicing mainly in academic hospitals. Inclusion criteria were: ≥18 years of age at initial MM diagnosis; first determined to have RRMM between January 1, 2009 and December 31, 2011, where RRMM was defined by (1) first-line (induction) regimen of chemotherapy with or without stem cell transplant (SCT) and with or without other post-induction/SCT therapy and (2) disease progression while on or at any time after completion of first-line therapy. Patients could be alive or deceased at the time of record abstraction. Baseline cytogenetic risk was defined as follows: high-risk: cytogenetic abnormalities del(17p), t(4:14), or t(14;16); unknown/unassessed risk: patients for whom cytogenetics were unavailable; or standard-risk: all patients with known cytogenetics not classified as high-risk. Patients were assessed for treatment response, overall survival (OS) and progression-free survival (PFS) from date of first relapse (study index date). All analyses were descriptive. Survival was assessed using the Kaplan-Meier (K-M) method. RESULTS: Demographic and clinical characteristics of the study sample are presented in Table 1. A total of 55 high-risk and 113 standard-risk patients were identified; risk category was unknown or unassessed for 32 patients. Among all patients, mean (SD) age at RRMM diagnosis was 66.3 (8.9) years and 62% of the sample was male. Lenalidomide + dexamethasone was the most common second-line systemic regimen initiated (50% of high-risk patients, 59.5% of standard-risk patients receiving second-line treatment). A total of 114 patients (57%) initiated a third-line treatment. Despite clinical response in second-line treatment occurring sooner in high-risk patients (median: 106 days) than in standard-risk patients (median: 237 days), physician-assessed overall response rate (ORR) was lower in high-risk patients (63%: 17% complete response, 46% partial response) than standard-risk patients (91%: 26% complete response, 65% partial response) across all second-line treatments combined (Table 2).. For third-line treatment, ORR was lower in high-risk patients (54%: 12% complete response, 42% partial response) than standard-risk patients (74%: 9% complete response, 65% partial response). Among patients who initiated a second-line treatment (n = 192), 47.4% were deceased at the time of data collection. From second-line initiation, K-M estimates of 1- to 5-year OS and PFS were substantially lower for high-risk patients versus standard-risk. Specifically, the proportions of patients still alive 1, 3, and 5 years after second-line treatment initiation were 73%, 51%, and 36%, respectively, for high-risk patients and 94%, 73%, and 61% for standard-risk patients. The proportions of patients without disease progression at 1, 3, and 5 years after second-line initiation were 48%, 13.5%, and 5% for high-risk patients and 82%, 42%, and 14% for standard-risk patients. CONCLUSIONS: The importance of cytogenetic risk classification as a prognostic factor in RRMM was apparent in this retrospective review, in which patients with high-risk cytogenetics had less favorable outcomes in terms of ORR, OS, and PFS than standard-risk patients. Decreased response rate and lower PFS and OS was documented among patients with high-risk cytogenetics, which is in contrast to shorter time needed to achieve best clinical response in this subgroup. Results from this real-world study provide further confirmation of the unmet medical need presented by RRMM, especially for patients with high-risk cytogenetics. Disclosures Lin: Takeda: Employment. Davis:Takeda: Research Funding. Kaye:Takeda: Research Funding. Luptakova:Takeda Oncology: Employment. Gao:Takeda: Employment. Nagar:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

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Real-World Treatment Patterns and Health Care Resource Utilization in Relapsed or Refractory Multiple Myeloma: Evidence from a Cohort Review in France

Blood ◽

10.1182/blood.v128.22.5945.5945 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5945-5945 ◽

Cited By ~ 1

Author(s):

Huamao Mark Lin ◽

Keith L Davis ◽

James A. Kaye ◽

Katarina Luptakova ◽

Lu Gao ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Research Funding ◽

Line Treatment ◽

Second Line ◽

Risk Patients ◽

First Relapse ◽

Third Line ◽

Standard Risk ◽

Third Line Treatment

Abstract INTRODUCTION: Despite the introduction of numerous novel agents and treatment strategies leading to improved response rates and overall survival, virtually all patients with multiple myeloma (MM) eventually relapse. While relapsed and/or refractory multiple myeloma (RRMM) remains an area of unmet need, little data have been generated describing typical treatment patterns and resource utilization in these patients. To help address this information gap, we analyzed data from a cohort of RRMM patients in France. METHODS: A retrospective medical record review was conducted in 200 patients with RRMM in France. Patients were selected (based on randomly generated first letter of last name) from the caseloads of 40 hematology/oncology providers across France practicing mainly in academic hospitals. Inclusion criteria were: ≥18 years of age at initial MM diagnosis; first determined to have RRMM between January 1, 2009 and December 31, 2011, where RRMM was defined by (1) first-line (induction) regimen of chemotherapy with or without stem cell transplant (SCT) and with or without other post-induction/SCT therapy and (2) disease progression while on or at any time after completion of first-line therapy. Baseline cytogenetic risk was defined as follows: high-risk: cytogenetic abnormalities del(17p), t(4:14), or t(14;16); unknown/unassessed risk: patients for whom cytogenetics were unavailable or unassessed; or standard-risk: all patients with known cytogenetics not classified as high-risk. Patients were retrospectively assessed on second- and third-line treatment regimens received, treatment duration and reasons for discontinuation, and subsequent health care utilization from date of first relapse (study index date). All analyses were descriptive. RESULTS: Demographic and clinical characteristics are presented in Table 1. Altogether 55 high-risk and 113 standard-risk patients were selected; risk category was unknown for 32 patients. Among the 200 patients studied, 192 (96%) received ≥1 additional line of systemic chemotherapy after first relapse; 114 patients (57%) received ≥2 additional lines of systemic therapy (i.e., at least second- and third-line therapy). The most common second-line regimen was lenalidomide + dexamethasone (54%), followed by bortezomib + dexamethasone with or without a third agent (23%). Median duration of second-line treatment was 9 cycles over 9.4 months. Most patients (92%) discontinued second-line treatment, most commonly due to disease progression (37%), to reaching complete clinical response with no additional benefit expected (33%), to lack/loss of response (13%), or to toxicities/adverse events (8%). Among the 114 patients receiving a third-line treatment, regimens were more varied; bortezomib + dexamethasone with or without other third agents was the most common third-line regimen (27%). Median third-line duration (across all regimens) was 6 cycles over 5.9 months. The leading reason for third-line treatment discontinuation was disease progression (42%), followed by attainment of complete response with no addition benefit expected (21%). During the follow-up period from RRMM diagnosis until death or last medical record, 35% of patients had ≥1 hospitalization, with high-risk patients having a higher hospitalization incidence than standard-risk patients (34 vs. 15 admissions per 100 person-years; p<0.05); a similar disparity was observed for emergency department utilization (25 vs. 15 visits per 100 person-years; p<0.05). Leading clinical burdens included bone pain (58%), fatigue/weakness (75%), impairment of daily activities (59%), anemia (55%), thrombocytopenia (44%), and neutropenia (40%). CONCLUSIONS: Lenalidomide + dexamethasone was the most commonly observed second-line regimen in this medical record review. Second-line treatment duration was generally less than a year, which indicates an unmet need in these patients, particularly in light of the primary reasons cited for unplanned discontinuation (disease progression, loss of response, no perceived additional benefit, and toxicities). Hospitalizations and emergency department visits were common among these patients after first relapse, indicating a potentially high cost burden of disease, particularly for patients with high-risk cytogenetic abnormalities in whom health care utilization was generally higher than for patients with standard-risk disease. Disclosures Lin: Takeda: Employment. Davis:Takeda: Research Funding. Kaye:Takeda: Research Funding. Luptakova:Takeda Oncology: Employment. Gao:Takeda: Employment. Nagar:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

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Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽

10.1182/blood-2018-99-113481 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1000-1000 ◽

Cited By ~ 1

Author(s):

Robert James Hayashi ◽

Stuart S. Winter ◽

Kimberly P. Dunsmore ◽

Meenakshi Devidas ◽

Brent Wood ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Partial Response ◽

Board Of Directors ◽

Complete Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

To Receive ◽

Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Final Analysis of MELISSE, a Large Multicentric Observational Study to Determine Risk Factors of Venous Thromboembolism in Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Blood ◽

10.1182/blood.v118.21.1235.1235 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1235-1235 ◽

Cited By ~ 1

Author(s):

Xavier Leleu ◽

Laurent Daley ◽

Philippe Rodon ◽

Cyrille Hulin ◽

Charles Dauriac ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

High Risk ◽

Incidence Rate ◽

Research Funding ◽

Final Analysis ◽

Vte Prophylaxis ◽

High Risk Patients ◽

Increased Risk ◽

Risk Patients

Abstract Abstract 1235 Background. Immunomodulator drugs (IMiDs) are associated with an increased risk of thromboembolic events (TE). Multiple Myeloma patients (MM) that can not benefit from novel agents, including IMiDs, only have 9 months survival. IMiDs must be stopped when TE occurs with the consequence of potential shortened life expectancy. MELISSE was designed to prospectively evaluate the incidence and risk factors of venous TE (VTE) associated with IMiDs in MM. We have presented the interim analysis of MELISSE at ASH 2010. A reduced incidence rate of early VTE was observed when a prophylaxis for VTE was started as compared to patients that had no prophylaxis. Interestingly, we also reported that most of the patients had received aspirin, while aspirin is not considered to exert any venous prophylactic effect. LMWH was primarily proposed to patients with high risk of TE according to physician's evaluation. We present the final analysis of MELISSE with updated results at 1 year. Method. A total of 524 MM treated with IMiDs-based therapy were included in 52 IFM centers. VTE prophylaxis was recommended prior to start IMiDs, the choice of which was left at the discretion of the investigator. Patients gave written informed consent according to the declaration of Helsinki. The physicians were to record the risk of VTE occurrence, categorized as low, moderate and high, based on guidelines and their own appreciation of the risk. Occurrence of any VTE was to be recorded along with the management of the event and the patient's outcome. The data were collected at entry in the study, and then after 4 and 12 months. Results. The median age was 70 years old, with 64.67% of patients >65 years old. Overall 36.0% had thalidomide-based and 64.0% had lenalidomide-based therapy, with 180 patients in first line and the remaining patients in 2nd and 3rd lines of therapy. The observed repartition of TE risk factors was as expected in a European population with myeloma. The risk of VTE was assessed as high in 14.2% patient and small or intermediate otherwise. Interestingly, approximately 70% of patients rated as low and intermediate risk received aspirin as a routine prophylaxis for VTE as compared to 20% in high risk patients. LMWH was primarily given to high risk patients, 45.8%. Surprisingly, 16.0% of patients had no VTE prophylaxis. Investigators recorded 29 (5.5% annual incidence rate) TE at 12 months, including 12 associated with PE. The incidence rate of TE was similar within the first 4 months (early occurrence, 3.5%) versus after 4 months (late, 2.5%). We have not identified any risk factor that would explain early versus late occurrence of VTE. Interestingly, the incidence of VTE was higher in patients that had no prophylaxis treatment, 8.5%, as compared to 4.4% and 5.9% in the LMWH and aspirin groups, respectively. There was no PE recorded in patients that were on LMWH prophylaxis. The VTE was equally breakdown across the 3 groups of risk factors. The bleeding adverse events were reported for 27 patients, mainly patients with aspirin. We isolated a model with 3 variables that independently predicted a higher risk to develop VTE in the multivariate model, and that comprised the male gender [OR 4.31 (95% CI 1.60 – 13.90)], the smoking habit [6.76 (1.73–22.42)] and the association to EPO [2.66 (1.04–6.58)]. Aspirin showed no significance, but with a p value at 0.55. The multivariate analysis is limited as certain subgroups with high risk factors might have received the optimal VTE prophylaxis, such as patients with bed rest and patients with prior history of VTE. These 2 groups rarely had aspirin. Survival data will be updated and presented at ASH 2011. Conclusion. This study further demonstrates that TE prophylaxis is required for MM treated with IMiDs-based therapy. There is a slight increase risk of VTE/PE with the use of aspirin as compared to LMWH, but a significant increase in bleeding events. Although we have identified risk factors of VTE in MM treated with IMiDs, for the first time, we could not identified VTE risk factors to guide investigators between LMWH and aspirin-based prophylaxis. The optimal dose and duration of LMWH remains to be determined. Disclosures: Leleu: LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Daley:LeoPharma: Employment. Hulin:Janssen: Honoraria; Celgene: Honoraria. Lamblin:LeoPharma: Employment. Natta:LeoPharma: Employment.

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Demographics and Outcomes of Multiple Myeloma Patients Undergoing Modern Modality Treatments Proceeding to ASCT: A Retrospective Study

Blood ◽

10.1182/blood-2021-154070 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4743-4743

Author(s):

Shubham Adroja ◽

Arslan Babar ◽

Muhammad Ali ◽

Gauranga Mahalwar ◽

Taeyeong Ko ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Categorical Variables ◽

Risk Category ◽

Line Treatment ◽

Second Line ◽

Significant Difference ◽

Before And After ◽

Risk Categories

Abstract Introduction: Multiple myeloma accounts for 1% of all cancers and approximately 10% of all hematologic malignancies. With the advent of novel therapies for multiple myeloma and emerging data from randomized trials, there has been a substantial improvement and favorable outcomes in survival. Here, we report demographics and outcomes in a cohort of patients who underwent Autologous Stem Cell Transplant (ASCT) over the past year. Methods: In this retrospective, cohort study, we assessed all MM patients who received ASCT from January 1, 2020, to January 15, 2021, at Cleveland Clinic, and followed until July 31, 2021. Baseline demographics, ECOG performance status, ISS stage, cytogenetic risk category, therapy received before ASCT, maintenance therapy, time to first relapse/progression, time to next treatment (TTNT; 2nd line of treatment onwards) with treatment response (defined per IMWG response criteria) before and after ASCT were obtained by review of electronic medical records. All patients received HDCT Melphalan 140 mg/m2 or 200 mg/m2 prior to ASCT. Continuous variables were presented as median and interquartile range, while categorical variables were presented as numbers and percentages. Categorical variables were compared using the chi-square test. Results: Of 81 MM patients who underwent ASCT, 59% were males, 84% were white, with a median age of 62 (IQR: 57-67) at the time of diagnosis. 42 (52%) and 24 (30%) patients belonged to the standard and high-risk category. Amongst high-risk cytogenetic abnormalities, +1q was the most common (72%) followed by del(17p) (28%). Baseline characteristics of patients are included in Table 1.1. Lenalidomide, bortezomib, and dexamethasone (VRd) regimen was the most common (75%) first-line induction regimen used, followed by Daratumumab-based regimens (20%). 10 (12%) patients required second-line treatment, and 6 (7%) patients required more than 2 lines of treatments prior to transplant. The median time to transplant was 6.5 months. The overall response rate (ORR) prior to transplant was 99% (21% complete (CR), 40% very good partial (VGPR), and 38% partial (PR)). The ORR post-ASCT was 78% (CR 27%, VGPR 37%, PR 14%). There was no significant difference in response between risk categories after transplant (P=0.72). At 1-year follow-up, 10 (12%) patients had relapsed and 7 (9%) patients had progression of the disease. 3 (4%) patients died of progressive MM, one of which had progressed to plasma cell leukemia. Response to treatment before and after the ASCT are summarized in Table 1.2 and Figure 1. The time to second-line treatment among patients with relapse/progression was 7 months [IQR: 3.75-10.25]. Conclusion: Here we report the demographics and outcomes of patients with MM undergoing modern modality treatments and ASCT, at our center over the last year. The median time to transplant was 6.5 months after induction therapy, and the ORR post-ASCT was 78%. No significant difference in response was observed between high and standard risk categories. No transplant-related mortality was observed as well. Figure 1 Figure 1. Disclosures Anwer: Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding.

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Is There an Unequal Benefit of Autologous Stem Cell Transplant in Different Cytogenetic Groups of High Risk Patients with Multiple Myeloma: The University of Miami Experience

Blood ◽

10.1182/blood-2020-143266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Fahmin Basher ◽

Sandra Sanchez ◽

Jonathan H. Schatz ◽

James E. Hoffman ◽

Lazaros J. Lekakis

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Retrospective Analysis ◽

Comprehensive Cancer Center ◽

High Risk Patients ◽

Risk Patients ◽

University Of Miami ◽

The University ◽

Standard Risk

BACKGROUND: Stratification using cytogenetics (CG), either metaphase karyotyping or fluorescence in situ hybridization (FISH) is used to identify patients (pts) with multiple myeloma (MM) who are at higher risk of relapse and tend to have poorer survival. It is largely unknown if autologous stem cell transplantation (auto-HCT) after high dose melphalan (200 mg/m2) is able to modify the survival of some of these high-risk MM pts and to make it comparable to standard risk. METHODS: Pts were classified as high risk (HR) if either conventional cytogenetics or FISH demonstrated at least one of the following 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16), realizing that the inclusion of 13q- by FISH alone and 1p- in the HR MM definition is controversial. Pts with normal chromosomes or those with trisomies and hyperdiploidy were considered standard-risk (SR). We compared progression-free survival (PFS) and overall survival (OS) via a retrospective analysis of pts at the University of Miami Sylvester Comprehensive Cancer Center who underwent auto-HCT between January 2014 and December 2017 for MM. Survival analyses were performed using the log-rank test, with significance at p-value < 0.05. RESULTS: Male pts comprised 56% of the population, and 40% of pts were of Hispanic ethnicity. Of 205 pts undergoing auto-HCT, 108 (53%) had at least one HR cytogenetic abnormality. Interestingly, the depth of response to pre-transplant induction was higher in pts classified as HR, with 71% (77 of 108) achieving at least a very good partial response (VGPR), while 24% (23 of 96) SR pts achieved VGPR. While OS remained largely unaffected in HR pts (34.0 m vs. 35.1 m, p = 0.27); HR pts had an inferior PFS compared to SR pts (21.9 m vs. 25.7 m, p = 0.041). The presence of trisomies did not negate the poorer PFS of HR pts. When we evaluated specific HR CG abnormalities, OS and PFS in patients with 1q+ or t(4;14) were surprisingly comparable to SR pts, indicating a significant benefit from auto-HCT. On the other hand, OS was significantly decreased in pts with 1p- when compared to standard risk (16.5 m vs. 35.1 m, p = 0.004) or other high-risk patients (16.5 m vs. 35.4 m, p = 0.01), implying that 1p- group derive no benefit from auto-HCT. Similarly, OS was shorter in pts with t(14;16) (16.5 m vs. 34.4 m, p = 0.025) and with 17p- (26.6 m vs. 35.1 m, p=0.01), however the PFS was not affected in these populations. In pts with 13q-, PFS was significantly shorter (20.3 m vs. 25.7 m, p=0.023) compared to SR pts without affecting OS. CONCLUSION: At our center in a retrospective analysis of 205 pts: a) patients with HR MM responded better and faster than SR pts to induction, b) those with 1p- did not derive any benefit from transplant and c) pts with 17p- and t(14;16) had some short term benefit (similar PFS to SR group) but at the end their OS remained inferior. Nevertheless, we consider a very important finding the fact that, by having auto-HCT, pts with 1q+ and t(4;14), equalized their PFS and OS to those of SR pts. Based on these findings, patients with 1q+ and t(4;14) should still have a transplant in CR1 even after optimal induction. Whether 17p- and t(14;16) pts can extend PFS benefit after transplant into OS benefit with maintenance regimens stronger than lenalidomide alone remains to be determined. Disclosures Hoffman: Celgene: Honoraria, Speakers Bureau; Loxo: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding.

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28-Day Metronomic Therapy for Relapsed Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142210 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-13

Author(s):

Tarek H Mouhieddine ◽

Julia Hieulle ◽

Erin Moshier ◽

Josh R. Richter ◽

Hearn Jay Cho ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

High Risk ◽

Partial Response ◽

Clinical Benefit ◽

Research Funding ◽

Complete Response ◽

Chemotherapeutic Agents ◽

Metronomic Therapy ◽

Grade 3

Background: The advent of novel therapies has led to tremendous progress in the treatment of multiple myeloma (MM). However, management of patients with high-risk disease who have failed approved agents and have rapidly progressive disease with cytopenias continues to be challenging. While palliative care is an option, many patients hope to qualify for a clinical trial option. Here we report results of a 28-day metronomic therapy (METRO-28) consisting of continuous administration of very low doses of classical chemotherapeutic agents. Sixteen-day cycles of metronomic therapy were previously shown to have a favorable response with acceptable toxicity profiles in MM patients (Papanikolaou et al. Haematologica 2013). Aim: To investigate the efficacy and toxicity in patients with high-risk relapsed refractory MM (RRMM) ineligible for clinical trial options receiving 1 cycle of METRO-28. Method: We retrospectively analyzed the clinical outcomes of 106 RRMM, treated with 1 cycle of 28-day metronomic chemotherapy at the Tisch Cancer Institute - The Mount Sinai Hospital. METRO-28 consists of 6 agents: dexamethasone 8 mg on days 1 through 4, 7 through 10, 13 through 16, 19 through 22 and 25 through 28; bortezomib 1 mg/m2 on days 1, 4, 7, 10, 13, 16, 19, 22, 25, 28; cisplatin 1 mg/m2 daily; doxorubicin 1 mg/m2 daily; thalidomide 100 mg daily; and vincristine flat dose 0.06 mg daily. METRO-28 was administered through a central line in either the inpatient or outpatient setting. Result: Our cohort of 106 RRMM patients has a median age of 65 years (range: 35-85) and at a median of 59 months from time of diagnosis; 42% were females. They had a median of 7 prior lines of therapy (range: 1 - 25); with 73% triple- and 58% penta-refractory cases. Prior autologous transplantation was utilized in 69% of patients including tandem transplants in 30%. Moreover, 78% of patients carried high-risk cytogenetic features, including 1q21 duplication/amplification (89%), 17p deletion (49%), t(4;14) (17%), t(14;16) (17%) or t(14;20) (3%). At the time of METRO-28 initiation, patients were cytopenic with grade 3 and 4 anemia (21%), neutropenia (8%) and thrombocytopenia (23%). Profound cytopenias in some patients led to early discontinuation of treatment; forty-three patients (41%) received the full 28-day course of METRO-28, while 11%, 17%, 20% and 11% were treated for <1 week, <2 weeks, <3 weeks or <4 weeks, respectively. Grade 3-4 cytopenia increased: anemia 66%, leucopenia 61%, neutropenia 55% and thrombocytopenia 76%. On an intent to treat basis (106 patients), the deepest response included 2% stringent complete response (sCR), 7% near complete response (nCR), 7% very good partial response (VGPR), 28% partial response (PR), 11% minimal response (MR) and 12% stable disease (SD). Only 43 patients (41%) completed all 4 weeks of METRO-28 and had a 72% overall response rate (ORR) and 88% clinical benefit rate (CBR). Seventy-four percent of these patients were able to move on to new therapies, including novel agents and clinical trials. Their overall survival (OS) was 11.8 months (range: 6.1-NE) as opposed to an OS of 4.2 months (range: 3.4-7.2) for patients with <4 weeks of METRO-28. Sixty-three patients had their treatment interrupted: 34 due to disease progression or absence of response, 18 due to bacterial or viral infections and 11 due to hematologic toxicity. Conclusion: Giving 1 cycle of METRO-28 is better tolerated in patients with good hematologic reserve and offers an opportunity for a clinical benefit and a bridge to a subsequent treatment option for these advanced refractory myeloma patients. Disclosures Richter: Takeda: Consultancy; Janssen: Speakers Bureau; Sanofi: Consultancy; AstraZeneca: Consultancy; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; Secura Bio: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Speakers Bureau. Parekh:Foundation Medicine: Consultancy; Celgene: Research Funding; Karyopharm: Research Funding. Chari:Adaptive Biotechnology: Honoraria; The Binding Site: Honoraria; Array BioPharma: Honoraria; Novartis: Honoraria; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Antengene: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Seattle Genetics: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jagannath:Legend Biotech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy.

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Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance

Blood ◽

10.1182/blood-2011-04-345801 ◽

2011 ◽

Vol 118 (17) ◽

pp. 4547-4553 ◽

Cited By ~ 46

Author(s):

María-Victoria Mateos ◽

Norma C. Gutiérrez ◽

María-Luisa Martín-Ramos ◽

Bruno Paiva ◽

María-Angeles Montalbán ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Dna Ploidy ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Free Survival ◽

Cytogenetic Abnormalities ◽

High Risk Patients ◽

Risk Patients ◽

Standard Risk

Abstract Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.

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Real-World Treatment Patterns, Outcomes, and Healthcare Resource Utilization in Relapsed or Refractory Multiple Myeloma: Evidence from a Medical Record Review in France

Advances in Hematology ◽

10.1155/2019/4625787 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Huamao Mark Lin ◽

Keith L. Davis ◽

James A. Kaye ◽

Katarina Luptakova ◽

Saurabh P. Nagar ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Medical Record ◽

Real World ◽

Treatment Patterns ◽

Medical Record Review ◽

Second Line ◽

Risk Patients ◽

Record Review ◽

Standard Risk

Background. Limited data are available from real-world practices in Europe describing prevailing treatment patterns and outcomes in relapsed/refractory multiple myeloma (RRMM), particularly by cytogenetic risk. Methods. A retrospective medical record review was conducted in 200 RRMM patients in France. From first relapse, patients were assessed on second-/third-line treatments, progression-free survival (PFS), overall survival (OS), and healthcare utilization. Results. Fifty-five high risk and 113 standard risk patients were identified. Overall, 192 patients (96%) received second-line therapy after relapse. Lenalidomide-based regimens were most common (>50%) in second line. Hospitalization incidence in high risk patients was approximately twice that of standard risk patients. From Kaplan-Meier estimation, median (95% CI) second-line PFS was 21.4 (17.5, 25.0) months (by high versus standard risk: 10.6 [6.4, 17.0] versus 28.7 [22.1, 37.3] months). Among second-line recipients, 47.4% were deceased at data collection. Median second-line OS was 59.4 (38.8, NE) months (by high versus standard risk: 36.5 [17.4, 50.6] versus 73.6 [66.5, NE] months). Conclusions. The prognostic importance of cytogenetic risk in RRMM was apparent, whereby high (versus standard) risk patients had decidedly shorter PFS and OS. Frequent hospitalizations indicated potentially high costs associated with RRMM, particularly for high risk patients. These findings may inform economic evaluations of RRMM therapies.

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Multiple Myeloma in the Time of COVID-19

Acta Haematologica ◽

10.1159/000507690 ◽

2020 ◽

Vol 143 (5) ◽

pp. 410-416 ◽

Cited By ~ 25

Author(s):

Abdullah S. Al Saleh ◽

Taimur Sher ◽

Morie A. Gertz

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

High Risk Patients ◽

High Risk Disease ◽

Risk Patients ◽

Smoldering Myeloma ◽

Standard Risk ◽

High Risk Screening

We provide our recommendations (not evidence based) for managing multiple myeloma patients during the pandemic of COVID-19. We do not recommend therapy for smoldering myeloma patients (standard or high risk). Screening for COVID-19 should be done in all patients before therapy. For standard-risk patients, we recommend the following: ixazomib, lenalidomide, and dexamethasone (IRd) (preferred), cyclophosphamide lenalidomide and dexamethasone (CRd), daratumumab lenalidomide and dexamethasone (DRd), lenalidomide, bortezomib, and dexamethasone (RVd), or cyclophosphamide, bortezomib, and dexamethasone (CyBorD). For high-risk patients we recommend carfilzomib, lenalidomide, and dexamethasone (KRd) (preferred) or RVd. Decreasing the dose of dexamethasone to 20 mg and giving bortezomib subcutaneously once a week is recommended. We recommend delaying autologous stem cell transplant (ASCT), unless the patient has high-risk disease that is not responding well, or if the patient has plasma cell leukemia (PCL). Testing for COVID-19 should be done before ASCT. If a patient achieves a very good partial response or better, doses and frequency of drug administration can be modified. After 10–12 cycles, lenalidomide maintenance is recommended for standard-risk patients and bortezomib or ixazomib are recommended for high-risk patients. Daratumumab-based regimens are recommended for relapsed patients. Routine ASCT is not recommended for relapse during the epidemic unless the patient has an aggressive relapse or secondary PCL. Patients on current maintenance should continue their therapy.

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Long-Term Carfilzomib for High-Risk Patients with Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies

Blood ◽

10.1182/blood-2018-99-112075 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3240-3240

Author(s):

Roberto Mina ◽

Alessandra Larocca ◽

Maria Teresa Petrucci ◽

Gianluca Gaidano ◽

Stelvio Ballanti ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Advisory Board ◽

Induction Phase ◽

Advisory Committees ◽

High Risk Patients ◽

Risk Patients ◽

Standard Risk

Abstract INTRODUCTION: High-risk cytogenetic abnormalities, such as del(17p), t(4;14), and/or t(14;16), are associated to an unfavorable prognosis. Several trials investigating current approved regimens have shown that high-risk multiple myeloma (MM) patients have shorter progression-free survival (PFS) and overall survival (OS) as compared to standard-risk patients. Carfilzomib, a second generation proteasome inhibitor, demonstrated to be able to improve the survival of high-risk MM patients in the relapse setting. Here we present a pooled analysis of two phase 1/2 studies to investigate the role of carfilzomib in high-risk, newly diagnosed (ND) MM patients. METHODS: Transplant ineligible patients with NDMM enrolled in the IST-CAR 561 and IST-CAR 506 studies were pooled together and analyzed. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly (IST-CAR 561) or 36 mg/m2 twice weekly (IST-CAR 506), combined with weekly cyclophosphamide (300 mg/m2) and dexamethasone (40 mg) (CCyd). After the induction phase, patients proceeded to maintenance with single-agent carfilzomib until progressive disease or intolerable toxicity. The primary objective was to compare response to treatment, PFS, PFS-2 and OS in standard versus high-risk FISH, defined by the presence of del(17p), t(4;14), and/or t(14;16). A 15% cut-off point was used for detection of translocation [t(4;14) and t(14;16)] and 10% for detection of del(17p). RESULTS: 121 NDMM patients were enrolled in the IST-CAR 561 (n=63) and in the IST-CAR 506 (n=58) study. Cytogenetic data were available in 94 patients: 37 (31%) had high-risk chromosomal abnormalities by FISH, including 10% of patients with t(4;14), 3% with t(14;16) and 18% with del(17p), while 57 patients (47%) were classified as standard-risk. After the induction phase, no difference in terms of overall response rate (ORR; 86% vs. 92%; p=0.52) and at least near complete response (39% vs. 41%; p=1) was observed between standard and high-risk patients. After a median follow-up of 39 months, median PFS from enrollment was NR in standard-risk patients and 27.8 months in high-risk ones (HR: 0.76; p=0.38) (Figure 1); at 3 years, 52% and 43% of patients, respectively, were alive and free from progression. The PFS benefit for the comparison between standard and high-risk patients was more pronounced in patients who received once weekly carfilzomib at 70 mg/m2, (median: NR vs. 39.6 months; HR: 0.78, p=0.63) as compared to those treated with twice weekly carfilzomib at 36 mg/m2 (median: NR vs. 24.2 months; HR: 0.52, p=0.12). Median PFS-2 from enrollment was NR in standard-risk patients and 44.1 months in high-risk ones (HR: 0.66; p=0.26), without significant differences in the once weekly (median, NR vs. 39.6; p=0.27) and the twice weekly group (median; NR vs. 44.1; p=0.63). Median OS from enrollment was NR in standard-risk patients and 47.5 months in high-risk ones (HR:0.71; p=0.36) (Figure 1). In patients who received once weekly carfilzomib, median OS was NR and 47.5 months (HR:0.66, p=0.48) in standard and high-risk patients, respectively, while median OS in the twice weekly group was NR in standard-risk patients and 44.1 months (HR:0.73; p=0.55) in high-risk ones. CONCLUSION: In transplant ineligible patients with NDMM, carfilzomib combined with cyclophosphamide and dexamethasone as initial treatment mitigated the poor prognosis of high-risk FISH in terms of PFS, PFS-2 and OS. The median PFS of high-risk patients treated with CCyd compares favorably with those reported with current standard of care. As compared to twice weekly carfilzomib at 36 mg/m2, once weekly carfilzomib, at the dose of 70 mg/m2, confirmed to be effective in high-risk patients. These data support the use of carfilzomib for the treatment of high-risk NDMM patients. Figure 1. Figure 1. Disclosures Larocca: Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Petrucci:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Gaidano:AbbVie: Other: Advisory Board; Janssen: Other: Advisory Board, Speakers Bureau. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita di Toritto:Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Amgen: Other: Advisory Board; Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding; Takeda: Other: Advisory Board. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

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