Retrospective Study on the Safety of Daratumumab in Japanese Relapsed or Refractory Multiple Myeloma and Search for Risk Factors for Infusion Related Reaction

The introduction of carfilzomib in the treatment of relapsing and refractory multiple myeloma has allowed a significant increase in survival. The most frequent adverse effect of Carfilzomib treatment is arterial hypertension, even though the exact physiopathological mechanism are still unclear. MM patients, on the other hand, often present significant cardiovascular risk factors and comorbidities. Uncontrolled hypertension is frequently the cause of cardiovascular complications. It has been estimated that up to 50% of subjects in the general population are unaware of their hypertensive condition and only half of those who are aware of this risk factor present good control of blood pressure. Although the management of arterial hypertension is clearly important in reducing the risk of cardiovascular events, and is well described by the current guidelines, no clear indications are provided on how to approach and treat specifically MM patients undergoing treatment with proteasome inhibitors. The aim of our work is to summarize a practical approach to the stratification of cardiovascular risk of hypertensive in patients who are candidates for or actively treated with carfilzomib for refractory multiple myeloma (MMR). MM patients eligible for carfilzomib treatment should preliminary undergo a careful cardiovascular risk stratification. Perspective studies will help to better identify the specific risk factors that should be considered and treated in these patients.

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Retrospective Study Of Incidence Of Thromboses In Chinese Versus African Americans With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1121.1121 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1121-1121

Author(s):

Radha Raghupathy ◽

Sabarish Ayyappan ◽

Dhivya Prabhakar ◽

Frankie KF Mo ◽

Erica L. Campagnaro ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Lower Risk ◽

Conflicts Of Interest ◽

Significant Risk ◽

Chinese Patients ◽

Asian Patients ◽

Venous Thromboembolic Events ◽

The Difference

Abstract Background Risk of arterial (ATE) and venous thromboembolic events (VTE) is increased in multiple myeloma (MM). Immunomodulator therapy (Imid) concurrent with steroids further increases this risk. Retrospective single arm studies suggest that Asian patients with MM may have a lower risk of TE than in other ethnicities. We performed a retrospective study comparing Chinese (C) and African American (AA) patients in two centers, the Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong (PWH) and the University hospitals, Case Medical Center, Cleveland, Ohio (CMC), for ethnic differences in incidence of TE in MM. Methods 120 Chinese patients from PWH and 100 AA patients from CMC fulfilling IMWG consensus criteria for MM diagnosis between Jan 1st 2000 and Dec 31st 2011 were identified and selected for analysis. Data regarding demographics, comorbidities, myeloma characteristics, therapy and thrombotic complications were collected by electronic and paper chart review. Data collection was censored as of Dec 31st 2012. Results The Chinese cohort comprised more men, lower baseline incidence of diabetes (DM), hypertension (HTN) and non-myeloma related renal failure (CRF), advanced myeloma at diagnosis and more IgA subtype than AA. Over 90% of patients of both groups received chemotherapy. 72% of Chinese and 80% of AA received Imid based treatment. Lenalidomide with steroids was used more often in AA (36.8% AA vs 3.6%C, p<0.0001), Chinese received more thalidomide with steroids. (62.2% C vs 42.1%, p:0.004) Use of thromboprophylaxis (TP) is not routine in PWH, less Chinese were on TP during the disease course (11.7% vs 68%, p<0.0001) or during Imid based treatment. (16% vs 85%, p: 0.0001) Relative rates of aspirin, low molecular weight heparin and warfarin usage for TP were similar across both groups. Despite lower TP rates, a significantly lower rate of symptomatic VTE was observed in the Chinese. (3.3% vs 22%, p:0.001) The difference in VTE detection persisted on correction for number of imaging studies performed, 24 imaging tests in Chinese and 145 in AA. (16.7% vs 48.3%, p:0.004). Amongst the Chinese, all 4 events (100%) occurred on thalidomide dexamethasone (TD), 3 events (75%) in the absence of TP. In the AA, 21 of 26 events (81%) occurred on Imid based treatment. 12 events (46%) occurred in the absence of TP. On binary logistic regression using race, gender, prior venous thrombosis, any TP, TD and lenalidomide dexamethasone therapy as covariates, AA race (OR: 5.022, 95% CI:1.3- 19.4) and TD therapy (OR: 4.07, 1.26- 3.13) emerged as significant risk factors for VTE. Overall incidence of VTE on TD treatment was 4.5% in Chinese versus 22% in AA. (p:0.002) An increased number of arterial events were seen in the Chinese (9.2% vs 3% in AA) but the difference did not reach statistical significance. Of the 11 arterial events in Chinese, 5 (46%) occurred on Imid based therapy, 9 events (82%) were in the absence of TP. 7 were cardiac and 4 cerebrovascular. Of the 3 arterial events in AA, 1 (33.3%) occurred on Imids and all patients were receiving TP. 1 was cardiac, 1 abdominal and 1 upper limb. Conclusion Our study suggests that the Chinese have a lower risk of VTE than AA in the setting of MM. However , despite lower prevalence of most vascular risk factors in Chinese, ATE rates in Chinese were higher than AA, while not statistically significant. Larger studies are necessary to further elucidate these differences in thrombosis risk and to develop specific guidelines for TP in Asian patients with MM Disclosures: No relevant conflicts of interest to declare.

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IKZF1/3 Protein Expressions Are Associated with a Better Survival in Relapsed/Refractory Multiple Myeloma Patients Treated with Lenalidomide

Blood ◽

10.1182/blood.v128.22.4506.4506 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4506-4506

Author(s):

Maryam Pourabdollah ◽

Mohammad Bahmanyar ◽

Eshetu G Atenafu ◽

Donna Reece ◽

Hong Chang

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Bone Marrow ◽

Protein Expression ◽

Research Funding ◽

Nuclear Staining ◽

Cytoplasmic Staining ◽

Myeloma Cells ◽

Refractory Multiple Myeloma ◽

Sequence Of Events

Abstract It has been demonstrated that lenalidomide causes selective degradation of IKZF1 (Ikaros) and IKZF3 (Aiolos) which are two essential transcription factors for proliferation of multiple myeloma cells. Consequently, the drug sets up a molecular sequence of events that lead to programmed cell death in the tumoral cells. This anti-proliferative effect is mediated by down-regulation of c-Myc and interferon regulatory factor 4 (IRF4). However, it is not clear whether IKZF1/IKZF3 protein expression in myeloma cells is predictive of clinical outcome. Thus, we evaluated bone marrow samples of 50 relapsed/refractory multiple myeloma (MM) patients regarding IKZF1/3 protein expression before starting lenalidomide. There were 31 males and 19 females with median age of 59 years (range 41-75). They all had received lenalidomide-based therapy after relapse following autologous stem cell transplantation (ASCT), thalidomide, or bortezomib. The median follow-up was 86.4 months. By immunohistochemistry (IHC), CD138 positive myeloma cell aggregates were examined for IKZF1 and IKZF3 protein expression. We used H-score method (range 0-300) based on the intensity and percentage of the stained myeloma cells. Cases were considered positive for IKZF1 or IKZF3 if H-score is equal or over 150 or 200, respectively. IKZF1 showed nuclear staining but IKZF3 showed both nuclear and cytoplasmic staining. IKZF1 and IKZF3 were expressed in 72% and 58% of the bone marrow specimens, respectively. IKZF1 and IKZF3 expressions were strongly correlated (p<0.0001). Both IKZF1 & IKZF3 expressions were associated with longer progression free (p=0.0029 & p<0.0001, respectively) and overall survivals (p=0.0014 & p<0.0001, respectively). IKZF3 (p=0.0025) expression but not IKZF1 (p=0.094) was correlated with the clinical response to lenalidomide. There was no significant association between IKZF1/3 protein expression and other clinical or biological risk factors including age, gender, International staging system (ISS), hemoglobin, calcium, creatinine, bone lytic lesions, β2 micro-globulin, albumin or cytogenetic risk factors such as del (13q), del (17p), t(4;14), and amp (1q21). Our study demonstrates that expressions of the IKZF1/3 proteins detected by IHC are correlated with superior survival outcome in refractory MM patients treated with lenalidomide. IHC is routinely available, robust and inexpensive method. Thus, if confirmed in a larger prospective study, IKZF1/3 immunostaining can be readily adopted in clinical practice for prediction of drug response and clinical outcomes in MM patients receiving lenalidomide therapy. Disclosures Reece: Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Pomalidomide, cyclophosphamide, and dexamethasone for relapsed/refractory multiple myeloma patients in a real-life setting: a single-center retrospective study

Annals of Hematology ◽

10.1007/s00277-019-03649-3 ◽

2019 ◽

Vol 98 (6) ◽

pp. 1441-1447 ◽

Cited By ~ 5

Author(s):

Sabrina Trudel ◽

Benoît Tessoulin ◽

Maxime Jullien ◽

Nicolas Blin ◽

Thomas Gastinne ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Real Life ◽

Single Center ◽

Refractory Multiple Myeloma ◽

Real Life Setting

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Incidence and risk factors of hepatitis B virus reactivation in patients with multiple myeloma in an era with novel agents: a nationwide retrospective study in Japan

Blood Cancer Journal ◽

10.1038/s41408-017-0002-2 ◽

2017 ◽

Vol 7 (12) ◽

Cited By ~ 12

Author(s):

Yutaka Tsukune ◽

Makoto Sasaki ◽

Takeshi Odajima ◽

Kazutaka Sunami ◽

Tomomi Takei ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Novel Agents ◽

Virus Reactivation ◽

Hepatitis B Virus Reactivation ◽

B Virus

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Survival of Patients with Multiple Myeloma That Is Refractory to Both Bortezomib and Lenalidomide: A Retrospective Study

Blood ◽

10.1182/blood-2018-99-116170 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2020-2020

Author(s):

Kanji Miyazaki ◽

Kenshi Suzuki

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Autologous Transplantation ◽

Survival Rates ◽

Allogeneic Transplantation ◽

New Drugs ◽

Rank Test ◽

Refractory Multiple Myeloma ◽

Kaplan Meier ◽

Better Than

Abstract Introduction: Patients with multiple myeloma that is refractory to both bortezomib and lenalidomide show poor survival. This resistant myeloma is called double-refractory multiple myeloma. Several new drugs, such as pomalidomide, panobinostat, carfilzomib, ixazomib, elotuzumab, and daratumumab, have become available in recent years. These new drugs could prolong the survival of patients with double-refractory multiple myeloma in prospective clinical trials. The present study aimed to evaluate the survival of such patients and assess the effectiveness of the new drugs, autologous transplantation, and allogeneic transplantation in real clinical settings. Methods: This retrospective study reviewed the medical records of patients with multiple myeloma who received treatment between February 2002 and January 2018 at our institution. Patients with myeloma refractory to both bortezomib and lenalidomide were selected. Those with coexisting amyloidosis were excluded. The primary outcome was overall survival (OS). Survival analyses were performed using the Kaplan-Meier method, and survival rates were compared using the log-rank test. Results: The study included 103 patients. New drugs were used in 71 (68.9%) patients, and their OS was significantly better than that of the remaining 32 (31.1%) patients who did not receive those agents (median OS, not reached versus 5 months, p < 0.001) (Figure 1). Total 20 patients underwent autologous transplantation. Their OS was similar to that of those who did not undergo autologous transplantation (median OS, 21 months versus 17 months, p = 0.503). Total 10 patients underwent allogeneic transplantation. Their OS was similar to that of those who did not undergo allogeneic transplantation (median OS, 24 months versus 18 months, p = 0.517). In the 71 patients who were treated using new drugs, pomalidomide and panobinostat-based therapies were not associated with better survival, whereas carfilzomib, ixazomib, elotuzumab, and daratumumab-based therapies were associated with significantly better OS. Carfilzomib was administered to 45.1% (32/71) of patients, and their OS was significantly better than that of the remaining 54.9% (31/71) patients (median OS, not reached versus 19 months, p = 0.032). Although carfilzomib, lenalidomide, and dexamethasone (KRd) therapy was not associated with better OS among the 71 patients, carfilzomib and dexamethasone (Kd) therapy was associated with better OS (median OS, not reached versus 21 months, p = 0.040). Ixazomib was administered to 14.1% (10/71) of patients, and their OS was 100%, which was significantly better than that of the remaining 85.9% (61/71) of patients (median OS, 20 months, p = 0.037). Elotuzumab was administered in 15.5% (11/71) of patients, and their OS was also 100% and was significantly better than that in the remaining 84.5% (60/71) of patients (median OS, 20 months, p = 0.011). Daratumumab was administered in 25.4% (18/53) of patients, and their OS was significantly better than that of the remaining 74.6% of patients (median OS, not reached versus 20 months, p = 0.025). The OS of patients administered only 1 new drug was worse than that of patients administered 2 new drugs (median OS, 17 months versus not reached, p = 0.003). However, the OS of patients administered 2 new drugs was comparable with that of patients administered 3 or more new drugs (p = 0.477) (Figure 2). Conclusions: New drugs, particularly carfilzomib, ixazomib, elotuzumab, and daratumumab, are associated with improved survival in patients with multiple myeloma refractory to both bortezomib and lenalidomide. Autologous and allogeneic transplantation are not associated with improved survival. Figure 1. Figure 1. Disclosures Suzuki: SRL.Inc: Employment; Sanofi Aventis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients

Annals of Oncology ◽

10.1093/annonc/mdm370 ◽

2007 ◽

Vol 18 (12) ◽

pp. 2015-2019 ◽

Cited By ~ 103

Author(s):

F. Jadu ◽

L. Lee ◽

M. Pharoah ◽

D. Reece ◽

L. Wang

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Incidence Risk

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Osteonecrosis of the Jaw in Multiple Myeloma Patients: Incidence and Characteristics in Korean Patients.

Blood ◽

10.1182/blood.v114.22.4956.4956 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4956-4956 ◽

Cited By ~ 1

Author(s):

Hyo Jung Kim ◽

Hyeok Shim ◽

Eunkyung Park ◽

Min Kyoung Kim ◽

Seok Jin Kim ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Conflicts Of Interest ◽

Previous History ◽

Clinical Manifestations ◽

Osteonecrosis Of The Jaw ◽

Korean Patients ◽

Dental Procedures ◽

Exposed Bone

Abstract Abstract 4956 Introduction Osteonecrosis of the Jaw (ONJ) is a potentially serious complication of bisphosphonate (BP) therapy in multiple myeloma (MM). Despite of current update about bisphosphonate related ONJ (BRONJ), only a few Asian BRONJ cases were reported and incidence of BRONJ in Asian MM patients has not yet been definitively estimated. The purpose of this study was to determine incidence and characteristics of BRONJ in Korean MM patients who were receiving BP therapy. Patients and Methods We invited 9 hospitals of Korean Multiple Myeloma Working Group (KMMWP) to participate in a retrospective multicenter study on BRONJ in MM patients. To defined BRONJ incidence, we reviewed the data from 130 MM patients treated with BP in one hospital. We also reviewed the medical records of MM patients with BRONJ treated in 9 hospitals to know the patterns of disease. We analyzed patient and disease characteristics, type and number of BP infusions, previous history of dental procedures, locations of osteonecrosis, clinical symptoms, treatment and outcome. ONJ was defined as clinical evidence of exposed bone in the jaw, which has been present for more than 8 weeks. Results Nine of 130 MM patients (6.9%) treated with BP developed BRONJ in the hospital. Twenty-two patients with MM developed BRONJ after a median number of 17 BP infusions (range 6 - 50) in all 9 hospitals. None of the patients had been irradiated to the jaw. There were 14 male and 8 female patients. The median age was 62 years (range 46 – 75). Median time from MM diagnosis to BRONJ was 2.8 years (range 0.6 – 15.6). The MM isotype was IgG in 9, IgA in 8, IgM in 1, light chain in 3 and non-secretory myeloma in 1 patient. BP therapy included zoledronate (n = 2) or pamidronate (n = 4) and both drugs as sequential treatment (n = 16). Fifteen patients had recent problems in oral cavity (72.7%) and 14 had prior dental procedures (63.6%). The mandible was involved in 14 patients (63.6%), the maxilla in 7 (31.8%), and both the maxilla and mandible in 1 (4.5%). Patients usually presented with pain and soft tissue swelling. ONJ staging (Khan et al. Canadian consensus practice guidelines of Bisphosphonate associated ONJ. J Rheumatol 2008;35:1391-7) was used to define the severity, there were 5 patients in stage I, 14 in stage II and 1 in stage III. Because of the limitation of retrospective study, the stage of 2 patients could not be confirmed. Management of these established cases were discontinuation of BP and medical treatment including antibiotics and pain killer. Surgical debridement of necrotic bone was performed in 12 patients. From onset of exposed bone in jaw, patients were followed for median 11 months (range 4.2 - 42). Wounds of 10 patients were healed at median 175 days (range 60 – 404) after bone exposure. In 8 patients, lesions had persisted over 154 days (range 66 – 425). Evaluation was impossible for 4 patients due to loss of follow up. Four patients were dead because of disease progression (n = 3) or concomitant infection. BRONJ was healed in 2 of them. Conclusions To the best of our knowledge, this is the largest retrospective study ever reported about BRONJ in Asian MM patients. The incidence of BRONJ in Korean MM patients was 6.9% and this is similar with data in western countries. Clinical manifestations and outcome of BRONJ in Korean patients were not different from previously reported data, but no risk factors could be definitively identified with our retrospective analysis. In the name of KMMWP, prospective trials are ongoing to define incidence and risk factors of BRONJ in Korean MM patients. Disclosures No relevant conflicts of interest to declare.

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