Clinical findings in 25 patients with sinonasal or nasopharyngeal extramedullary plasmacytoma in a four-decade single-centre series.
Vento Seija Inkeri,Vähämurto Pauli,Silventoinen Kaija,Karjalainen-Lindsberg Marja-Liisa,Mannisto Susanna,Leppä Sirpa,Mäkitie Antti Aarni
OBJECTIVES:Extramedullary plasmacytoma in the sinonasal tract or nasopharynx is rare. The aim of the study was to review data on symptoms, clinical findings, treatment and follow-up of plasmacytomas in the sinonasal and nasopharyngeal regions in order to delineate the main clinical characteristics and the optimal management. METHOD:Twenty-five patients with sinonasal or nasopharyngeal plasmacytoma, diagnosed and treated at the Helsinki University Hospital during a 39-year period from 1975 to 2013 were retrospectively reviewed. RESULTS:There were 18 males and 7 females with a median age of 66 years (range, 36-80). Sixty-eight percent received only radiotherapy or (chemo)radiotherapy. Forty-seven percent of them had a complete response to primary radiotherapy and one patient had a complete response after receiving additional brachytherapy. Four patients were treated primarily with surgery only. Two of them had a local recurrence, but were then successfully treated with radiotherapy. Altogether, four patients received a combination of surgery and (chemo)radiotherapy. Forty-four percent were alive with no evidence of disease after a median follow-up time of 78 months. Forty percent died of their disease and 16% died of other causes. CONCLUSIONS:Our study supports radiotherapy as a treatment of choice, but for small tumours surgery alone or in combination with radiotherapy may also be considered.
A multicenter phase 2 study of pomalidomide plus dexamethasone in patients with relapsed and refractory multiple myeloma: the Japanese MM-011 trial.
Ichinohe Tatsuo,Kuroda Yoshiaki,Okamoto Shinichiro,Matsue Kosei,Iida Shinsuke,Sunami Kazutaka,Komeno Takuya,Suzuki Kenshi,Ando Kiyoshi,Taniwaki Masafumi,Tobinai Kensei,Chou Takaaki,Kaneko Hitomi,Iwasaki Hiromi,Uemura Chie,Tamakoshi Hiromi,Zaki Mohamed H,Doerr Thomas,Hagiwara Shotaro
Experimental hematology & oncology
BACKGROUND:The immunomodulatory agent pomalidomide in combination with low-dose dexamethasone has demonstrated efficacy and safety for the treatment of relapsed and refractory multiple myeloma (RRMM) in phase 2 and 3 trials. However, these trials enrolled very few Asian patients. METHODS:This phase 2 study investigated pomalidomide plus low-dose dexamethasone in 36 Japanese patients with RRMM after ≥2 prior therapies. RESULTS:Patients enrolled in the study had a relatively high disease burden (81 % Durie-Salmon stage II or III) and were heavily pretreated (median, 6.5 prior antimyeloma regimens). The overall response rate was 42 % (1 patient with complete response and 14 with partial response), with an additional 44 % (16 patients) achieving stable disease (SD). Response rates in patients aged ≤65 years and >65 years were 47 and 35 %, respectively. None of the five patients with extramedullary disease achieved a response, with three of them maintaining SD of short duration. Median progression-free survival was 10.1 months after a 7.7-month median follow-up, and the median overall survival was not reached. The most frequent grade ≥3 adverse events (AEs) were neutropenia (64 %), anemia (42 %), and thrombocytopenia (31 %). The most frequent nonhematologic grade ≥3 AEs were pneumonia and decreased appetite (8 % each). Adverse events in patients aged >65 years were similar to those in patients aged ≤65 years, except for a higher rate of grade ≥3 pneumonia. CONCLUSIONS:Collectively, the results of this study demonstrate that pomalidomide plus low-dose dexamethasone is an effective and safe treatment for Japanese patients with RRMM, although careful attention needs to be paid to serious infections. TRIAL REGISTRATION:Clinicaltrials.gov NCT02011113.
Successful retreatment with lenalidomide for relapsed and refractory multiple myeloma previously treated with bortezomib, lenalidomide and pomalidomide.
Oka Satoko,Ono Kazuo,Nohgawa Masaharu
Journal of clinical pharmacy and therapeutics
WHAT IS KNOWN AND OBJECTIVES:Optimal strategies for treating patients with very advanced relapsed and refractory multiple myeloma (RRMM) have not been clarified. CASE SUMMARY:A 80-year-old patient with RRMM experienced extramedullary relapse following treatment with bortezomib, lenalidomide and pomalidomide. However, he achieved very good partial remission after retreatment with lenalidomide. WHAT IS NEW AND CONCLUSION:This report illustrates that patients with very advanced RRMM can still respond to prior therapy even after being exposed and refractory to several agents. Considering the depth or duration of response to prior treatment, "retreatment" may improve the outcome of frail RRMM.
[Clinical features and outcome analyses of newly-diagnosed multiple myeloma with extramedullary involvements].
Zhang Yi-zhuo,Zhi Ya-qin,Wang Ya-fei,Yu Yong,Zhao Zhi-gang,Wang Xiao-fang,Zhai Qiong-li,Sun Bao-cun
Zhonghua yi xue za zhi
OBJECTIVE:To explore the clinical features and prognostic factors of newly-diagnosed multiple myeloma (MM) with extramedullary (EM) involvements. METHODS:The clinical features, efficacies, survival rates and prognostic factors were retrospectively analyzed in 46 MM patients with EM (group A) from January 2000 to October 2011. And another 53 MM patients without EM (group B) were selected as the controls. RESULTS:The median age of Group A was 58 years. Compared with group B, the incidence of EM was associated with a higher level of β2-microglobulin (β2-MG) and extensive bone disease. The most common location of EM was soft tissues. And the total effective rates of groups A and B were 58.5% (24/41) and 78.8% (41/52) respectively. The difference was statistically significant (P = 0.042). The median follow-up time was 28(2-88) months. The estimated overall survival (OS) of the patients with EM was significantly shorter than those without EM (42.6 vs 53.9 months, P = 0.009). Log-rank univariate analysis showed that the number of osteolytic lesions ≥ 3, β2-MG ≥ 5.5 mg/L, hemoglobin ≤ 110 g/L and albumin ≤ 30 g/L were poor prognostic factors in MM patients with EM. Multivariate analysis with Cox model showed only the number of osteolytic lesions ≥ 3 (OR = 2.327, 95%CI: 1.282 - 4.224) and β2-MG ≥ 5.5 mg/L (OR = 2.677, 95%CI: 1.092 - 6.566) were statistically significant. CONCLUSIONS:Multiple EM lesions may be involved in MM patients. For the patients with EM, the response to conventional chemotherapy is poor and the prognosis is unfavorable, especially for those with a high level of β2-MG or the number of osteolytic lesions ≥ 3.
[Clinical characteristics and therapeutic efficacy of immunoglobin D multiple myeloma].
Liu Yan,Ke Xiao-Yan,Wang Jing,Jing Hong-Mei,Wang Ji-Jun,Dong Fei,Wan Wen-Li,Zhang Wei
Zhongguo shi yan xue ye xue za zhi
This study was aimed to evaluate the clinical characteristics of immunoglobin D multiple myeloma (IgD MM) and its curative efficacy. The clinical data of 15 cases of newly diagnosed IgD MM from April 1993 to June 2013 were analyzed retrospectively. Among 15 cases received induction treatment, the traditional chemotherapy was carried out in 9 cases, bortezomib-based therapy was performed in 6 cases. The diagnostic criteria and disease response criteria of MM were based on International Myeloma Working Group (IMWG) criteria,survival time was analyzed by using Kaplan-Meier method, the median age of patients was 57 years (range 40-72), the ratio of male to female was 2:1, the MM patients in Durie-Salmon stage III accounted for 100% (15/15) , the MM patients with λ light chain accounts for 80% (12/15) , with bone lesion 86.7% (13/15), with pleural effusion 26.7% (4/15) , with renal impairment (RI) 86.7% (13/15) ,with anemia 93.3% (14/15) , with serum album<35 g/L 26.7% (4/15). The median creatinine clearance rate (Ccr) of patients was 23.1 (6-44) ml/min, and median hemoglobin level was 82 (43-131) g/L. The results showed that in followed-up 11 cases, 8 cases died, 3 cases survived; the average duration of follow-up for these cases was 20 (0.5-138) months, the median progression-free survival time (PFS) was 7 (95%CI4.6-9.4) months, and the median overall survival (OS) time was 15 (95%CI6.6-27.4 ) months. Compared traditional chemotherapy with bortezomib regimen therapy,median OS time was 17 (95%CI6.1-28.0) months vs 15 (95%CI 0.0-33.3) months (P = 0.90) . Assessable curative effect of 14 cases was as follows: CR 33.3% (5/15); VGPR 13.3% (2/15); PR 20% (3/15); SD 20% (3/15); PD 6.7% (1/15). It is concluded that IgD MM is a rare type of MM and has a poor prognosis. Bortezomib may be beneficial for some patients with extramedullary infiltration. Autologous hematopoietic stem cell transplantation may improve survival time.
[Effects of ifosfamide in combination with pegylated liposomal doxorubicin and dexamethasone in the treatment of relapsed/refractory multiple myeloma].
An N,Shen M,Li X,Huang Z X,Chen S L
Zhonghua yi xue za zhi
To investigate the efficacy and adverse effects of ifosfamide in combination with pegylated liposomal doxorubicin and dexamethasone (CDD) in treating patients with relapsed/refractory multiple myeloma (MM). The clinical data of 30 relapsed/refractory MM patients treated with CDD regimen in Department of Hematology and Oncology of Beijing Chaoyang Hospital from November 2012 to November 2015 were retrospectively analyzed. The CDD treatment included ifosfamide 0.5-1.0 g/d on d1-4, pegylated liposomal doxorubicin 40-60 mg/d on d1, and dexamethasone 10-20 mg/d on d1-4. One cycle consisted of 21 or 28 days. Efficacy analysis was performed after every two cycles. (1)The overall response rate (ORR) was 50.0% and the complete remission and near complete remission (CR+ nCR) rate was 10.0%. (2)The ORR of the 23 patients without extramedullary plasmacytoma(EMP)was 43.5% and the CR+ nCR rate was 8.7%. The ORR of the 7 patients with EMP was 5/7 and the CR+ nCR rate was 1/7. There were no statistically significant differences in ORR and CR+ nCR rate between the two groups (both >0.05). (3)Except for the 5 patients with disease progression, the median progression-free survival (PFS) of the other 25 patients was 8.0 (3.0-25.0) months. The median PFS of the patients without EMP was 8.5 (3.0-25.0) months, that of the patients with EMP was 6.0 (2.0-21.0) months, with no statistically significant difference (>0.05). The adverse effects included constipation, infection, hyperglycemia, and hemocytopenia, which were controlled by symptomatic treatment and did not affect the chemotherapy. CDD regimen can be used for the treatment of relapsed/refractory MM, especially in patients with EMP, with good efficacy and tolerance.
Successful treatment of extramedullary tumors with low-dose thalidomide in patients with multiple myeloma.
Yasuda Hajime,Ando Jun,Sato Eriko,Inagaki Naoko,Aritaka Nanae,Komatsu Norio,Hirano Takao
Internal medicine (Tokyo, Japan)
Extramedullary tumor (EMT) is a poor prognostic factor of multiple myeloma (MM). The majority of patients report poor efficacy of thalidomide in MM with EMT, and bortezomib is the preferred choice of treatment. We report two cases of MM with EMTs in which thalidomide was highly beneficial. Case 1 has been in remission for ten months with 100 mg every other day of thalidomide monotherapy, which is the lowest dose to be reported in a successfully treated case of MM with EMT. Case 2 eventually became refractory, but low dose thalidomide gave excellent disease control over a period of eleven weeks, despite the EMT being in a highly aggravated state. Some reports have speculated that EMT cases with preceding bone marrow transplantation (BMT) are an exception and have a good response to thalidomide, but the present two cases have no history of BMT. In conclusion, low dose thalidomide can be effective in MM with EMT and should be considered as a treatment option, especially in the elderly.
Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma.
Short K Detweiler,Rajkumar S V,Larson D,Buadi F,Hayman S,Dispenzieri A,Gertz M,Kumar S,Mikhael J,Roy V,Kyle R A,Lacy M Q
We studied 174 consecutive patients with relapsed refractory multiple myeloma (MM) enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone at Mayo Clinic. Extramedullary disease (EMD) was present at the time of trial entry in 7.5% (13 of 174 patients). The rate of EMD in the first 3 years following diagnosis of MM was 3%. The response of EMD to pomalidomide plus low-dose dexamethasone included two complete and two partial responses among the 13 patients (response rate, 31%). Overall survival measured from trial entry was significantly shorter for patients with treatment-emergent EMD compared with those who did not have EMD, (median 16 months versus not reached, P=0.002).
Successful treatment with lenalidomide of secondary multiple myeloma with extramedullary liver plasmacytoma in a renal transplant recipient: A case report and review of the literature.
Xie Xiaobao,Wu Wei,Zhu Yuandong,Liu Deliang,Dong Weimin,Li Haiqian,Li Qing,Gu Weiying
Multiple myeloma (MM) represents a rare form of post-transplantation lymphoproliferative disorder, and the presence of plasma cells in the liver is generally associated with aggressive forms of MM. In the present study, an unusual case of extramedullary plasmacytoma, affecting the liver and vertebrae of a recipient of a renal transplant, is reported. The patient had been previously treated with bortezomib for an MM following renal transplantation, as diagnosed by percutaneous needle biopsy of the hepatic lesion. He was then treated with 5 cycles of RCD regimen (lenalidomide, 25 mg, days 1-21; cyclophosphamide. 50-100 mg, days 1-21; and dexamethasone, 20 mg, days 1, 8, 15 and 22). The patient achieved partial clinical remission without any severe therapy-associated toxicity effects, indicating that lenalidomide is an effective and safe treatment for extramedullary liver plasmacytoma in renal recipients. In conclusion, the present case study indicated that the RCD regimen was effective and safe in the treatment of relapsed and refractory MM.
[Clinical analysis of multiple myeloma with extramedullary plasmacytomas].
Li Xin,Sun Wan-jun,Chen Shi-lun,Zhong Yu-ping,An Na,Hu Ying,Zhang Jia-jia,Liu Xiao-hui
Zhonghua yi xue za zhi
OBJECTIVE:To explore the clinical features, treatment and prognosis of multiple myeloma (MM) with extramedullary plasmacytomas (EM). METHODS:A total of 43 patients were enrolled and divided into 2 groups. Group-1 had 12 patients of EM occurring after the diagnosis of MM while Group-2 included 31 EM patients at the initial diagnosis of MM. RESULTS:The male-to-female proportion was 23:20 and there was a median age of 53 years. The distribution of different isotypes was IgG (n = 15), IgA (n = 9), IgD (n = 2), κ light chain (n = 6), λ light chain (n = 6), biclonal myeloma (n = 3) and nonsecretory myeloma (n = 2). The sites of complicating plasmacytoma included skin, muscle and spinal canal. Nine patients received bortezomib plus DECP (cisplatin, etoposide, cyclophosphamide and prednisone) and 2 patients underwent traditional chemotherapy in Group-1. The outcomes were as follows: complete remission (CR, n = 2), partial remission (PR, n = 4) and death (n = 5). And 11 patients received traditional chemotherapy in Group-2, 7 attained PR and 4 died. Twenty patients received bortezomib plus other chemotherapeutic drugs in Group-2. The outcomes were as follows: CR (n = 12), PR (n = 7) and death (n = 1). The median overall survival (OS) was 36 months (range: 10 - 120) in Group-1 and 23 months (range: 5 - 52) in Group-2 respectively. In Group-1, the estimated 3- and 5-year OS were 54.21% and 27.10% respectively. And in Group-2, the estimated 3- and 4-year OS were 39.83% and 13.28% respectively. CONCLUSIONS:The EM patients show aggressive, complicated and diverse clinical courses and the unusual manifestation of multiple organ involvement by plasma cells. Traditional chemotherapy has a poor efficacy and the prognosis is unfavorable, especially for EM with concurrent MM. The combined treatment of bortezomib with second-line chemotherapy may achieve curative effects.
Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis.
Pick Marjorie,Vainstein Vladimir,Goldschmidt Neta,Lavie David,Libster Diana,Gural Alexander,Grisariu Sigal,Avni Batia,Ben Yehuda Dina,Gatt Moshe E
European journal of haematology
OBJECTIVE:Daratumumab is a promising new antimyeloma agent. We report a single center "real-world" series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab. METHODS:Forty-one patients were included: 7 second-line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL. RESULTS:Second-line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression-free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti-CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab. CONCLUSIONS:Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.
[Successful Treatment with Pomalidomide, Bortezomib, and Dexamethasone in a Patient with Frail Refractory and Relapsed Multiple Myeloma with Extramedullary Disease].
Oka Satoko,Takeuchi Suguru,Shiragami Hiroshi,Shimazu Yayoi,Shimazu Yutaka,Nougawa Masaharu
Gan to kagaku ryoho. Cancer & chemotherapy
An 85-year-old female was diagnosed with multiple myeloma(MM)(IgG-l)with t(4 ;14)(p16;q32)in 200X. She received bortezomib with dexamethasone(Vd)therapy and lenalidomide with dexamethasone(Ld)therapy, and she subsequently maintained a very good partial response(VGPR). On day 731, she experienced relapse and was treated with 2 courses of elotuzumab with Ld therapy. However, on day 794, she experienced relapse with plasmacytoma, and was treated with 2 courses of pomalidomide and low-dose dexamethasone(Pd), 2 courses of cyclophosphamide with Pd(PCd), and bortezomib with Pd(PVd)therapies. After 3 courses of PVd therapy, she achieved PR. She has continued to receive 11 courses of PVd therapy and has not suffered any adverse events(BGrade 3). These findings suggest that PVd therapy is a relatively safe and highly efficacious treatment for frail patients with relapsed and refractory MM who have previously received both lenalidomide and bortezomib. Further studies are needed to establish treatment efficacy and safety in frail patients with relapsed and refractory MM with extramedullary disease.
Extramedullary progression of multiple myeloma despite concomitant medullary response to multiple combination therapies and autologous transplant: a case report.
Kumar Anup Kasi Loknath,Dakhil Christopher,Teeka Satyan Megha,Haideri Nisreen
Journal of medical case reports
INTRODUCTION:Extramedullary myeloma that occurs during the clinical course of multiple myeloma is rare but is an independent poor prognostic factor with mortality of 73% and median survival of 12 months despite aggressive therapies including novel agents. The clinicopathological aspects, biology and management of extramedullary myelomas are poorly understood. Our case highlights the pathobiological aspects of this important but rare entity, and the repercussions of modern therapies. CASE PRESENTATION:A 60-year-old Caucasian man initially presented with an anterior rib fracture. Subsequent workup revealed stage IIIB immunoglobulin G lambda multiple myeloma. A bone marrow biopsy showed sheets of plasma cells, harboring unfavorable cytogenetics including deletion of 17p and t(4;14). He achieved near complete remission and resolution of karyotypic abnormalities with three cycles of induction doxorubicin, thalidomide, and dexamethasone (clinical trial). This was followed by high-dose melphalan and autologous stem cell transplant. He relapsed 1 year later. His bone marrow at that time showed only a few scattered polyclonal plasma cells. He received three cycles of bortezomib and tanespimycin (clinical trial) and achieved very good partial response. He again relapsed 1 year later with multiple large peripheral soft tissue masses and lymph nodes. Biopsies of the peripheral lesions were consistent with extramedullary myeloma, but repeat bone marrow biopsy continued to show no evidence of intramedullary disease. CONCLUSIONS:This is one of the few cases reported that illustrates the differential response of extramedullary compared to intramedullary myeloma to multiple standard combination therapies including novel therapeutics and transplant, resulting in a very short survival. Several mechanisms for intra-to-extra medullary migration and hence the differential treatment response have been hypothesized. Physicians should be aware of this problem during treatment with immunomodulatory drugs and proteasome inhibitors not only in relapsed but also in front-line setting. In such cases, there is a potential role for evolving targeted therapeutics as we continue to better understand the tumor biology.
Treatment of relapsed multiple myeloma complicated by cardiac extramedullary plasmacytoma with D-PACE chemotherapy.
Toocheck Corey,Pinkhas Daniel
BMJ case reports
Cardiac extramedullary plasmacytomas (EMPs) are rare and may be a seen as a complication of multiple myeloma (MM) or in isolation. Here, we describe a case of cardiac EMP that presented clinically as a congestive heart failure exacerbation in a patient with relapsed and refractory IgG lambda MM. We highlight radiographic imaging in conjunction with laboratory biomarkers at presentation and in response to D-PACE (dexamethasone, cisplatin (Platinol), doxorubicin (Adriamycin), cyclophosphamide and etoposide) systemic chemotherapy.
[Successful treatment with a combination of elotuzumab, lenalidomide and dexamethasone of extramedullary disease in a patient with refractory multiple myeloma].
Kashima Emiko,Fujieda Atsushi,Nato Yuma,Ino Kazuko,Tawara Isao,Masuya Masahiro,Katayama Naoyuki
[Rinsho ketsueki] The Japanese journal of clinical hematology
A 56-year-old man diagnosed with multiple myeloma was treated with CBD (cyclophosphamide, bortezomib, and dexamethasone; DEX), which was discontinued because of bortezomib-associated adverse events. Thereafter, he was treated with Ld (lenalidomide; LEN+DEX) followed by high-dose chemotherapy with autologous stem cell rescue, resulting in a complete response. Ld as maintenance therapy was discontinued because of immune thrombocytopenia, resulting in disease progression. Although treatment was switched to Pd (pomalidomide+DEX), DLd (daratumumab+LEN+DEX), and IRd (ixazomib+LEN+DEX); the patient's M protein level continued to increase and the extramedullary disease expanded despite radiotherapy. He was treated with E-Ld (elotuzumab+LEN+DEX) after 3 cycles of short VAD (vincristine, doxorubicin, and DEX). The extramedullary disease disappeared after 8 cycles of E-Ld. To the best of our knowledge, this is the first report showing the effectiveness of E-Ld treatment for extramedullary disease of a heavily treated patient for multiple myeloma. We believe that the clinical course of this patient provides useful insights about the antimyeloma mechanism of elotuzumab.
CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma.
Lapa Constantin,Herrmann Ken,Schirbel Andreas,Hänscheid Heribert,Lückerath Katharina,Schottelius Margret,Kircher Malte,Werner Rudolf A,Schreder Martin,Samnick Samuel,Kropf Saskia,Knop Stefan,Buck Andreas K,Einsele Hermann,Wester Hans-Juergen,Kortüm K Martin
C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.
[Clinical Analysis of Maintenance Therapy with Thalidomine and Bortezomib for Multiple Myeloma].
Xu Yan-Jie,Xia Bing,Wang Lu,Wang Chao-Yu,Zhao Hai-Feng,Yang Hong-Liang,Wang Xiao-Fang,Wang Ya-Fei,Yu Yong,Zhang Yi-Zhuo
Zhongguo shi yan xue ye xue za zhi
OBJECTIVE:To evaluate the therapeutic effect and adverse reactions of the maintenance therapies with Thalidomine or Bortezomib in the patients with newly diagnosed multiple myeloma (MM), so as to provide a reference for clinical treatment. METHODS:A retrospective analysis was conducted to compare the progression-free survival (PFS), overall survival (OS) and adverse reaction rate of 23 MM patients received the maintenance therapies of Bortezomib and of 68 MM patients received maintenance therapy of Thalidomine. RESULTS:The maintenance therapy with Bortezomib could extend the PFS of MM patients as compared with Thalidomine (PFS rate of patients on the maintenance therapy of Bortezomib in 12th, and 24th month was 100%, 88.89%, and that of Thalidomine-treated group was 72.31%, 47.54%). What's more, some specific patients could get better 2-year PFS rate in Bortezomib group than that in Thalidomine group, such as older than 65 years old, after autologous hematopoietic stem cell transplantation(ASCT), having genetic changes, extramedullary lesions, poor renal function, low serum free light chain ratio, high β2-MG, anemia, high LDH, VGPR of induction and consolidation therapy. The OS rate of Bortezomib on 18th, 24th and 30th month was 100%, 88.89%, 80% verus 91.52%,83.63%,72.90% of the group with thalidemide at the same time. As for 2-year OS rate, the Bortezomib group was higher than Thalidomine without statistical differences. However, the patients such as older than 65 years old, poor renal function and with extramedullary lesions, would also get higher 2-year OS rate from Bortezomi. Bortezomib and thalidomide could cause bone marrow suppression, peripheral neuritis and other adverse reactions. CONCLUSION:The efficacy of maintenance therapy with Bortezomib is superior to thalidomide. As a conclusion, bortezomib is a better option for maintenance therapy of MM patient.
First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.
Herrmann Ken,Schottelius Margret,Lapa Constantin,Osl Theresa,Poschenrieder Andreas,Hänscheid Heribert,Lückerath Katharina,Schreder Martin,Bluemel Christina,Knott Markus,Keller Ulrich,Schirbel Andreas,Samnick Samuel,Lassmann Michael,Kropf Saskia,Buck Andreas K,Einsele Hermann,Wester Hans-Juergen,Knop Stefan
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
UNLABELLED:Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand ((68)Ga-pentixafor) for diagnostic receptor targeting, (177)Lu- and (90)Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. METHODS:CXCR4 target expression was demonstrated by baseline (68)Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic (177)Lu-pentixather dosimetry was performed before (177)Lu-pentixather or (90)Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone marrow rescue. RESULTS:A remarkable therapeutic effect was visualized in 2 patients, who showed a significant reduction in (18)F-FDG uptake. CONCLUSION:CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced multiple myeloma.
[Research Progress on Multiple Myeloma with Extramedullary Disease].
Wang Lu,Zhang Yi-Zhuo
Zhongguo shi yan xue ye xue za zhi
Multiple myeloma (MM) is a malignancy of terminally differentiated monoclonal B cells, which is characterized by the presentation of malignant plasma cell within the bone marrow and the secretion of monoclonal immunoglobulin. Extramedullary disease (EMD) may be found either at diagnosis or during therapy of these patients. For the patients with EMD, the response to conventional chemotherapy is poor and the prognosis is unfavorable. This review mainly discusses the research progress in the pathogenesis, the clinical feature, the therapy and the prognosis of MM with EMD.
Multiple myeloma with extramedullary disease: impact of autologous stem cell transplantation on outcome.
Kumar L,Gogi R,Patel A K,Mookerjee A,Sahoo R K,Malik P S,Sharma A,Thulkar S,Kumar R,Biswas A,Sharma O D,Gupta R
Bone marrow transplantation
Impact of extramedullary plasmacytomas on outcomes according to treatment approach in newly diagnosed symptomatic multiple myeloma.
Lee Sung-Eun,Kim Jung-Ho,Jeon Young-Woo,Yoon Jae-Ho,Shin Seung-Hwan,Eom Ki-Seong,Kim Yoo-Jin,Kim Hee-Je,Lee Seok,Cho Seok-Goo,Lee Jong Wook,Min Woo-Sung,Park Chong-Won,Min Chang-Ki
Annals of hematology
The prognostic impact of extramedullary plasmacytomas (EMPs) on newly diagnosed symptomatic multiple myeloma (MM) was evaluated in the context of treatment approach including autologous stem cell transplantation (ASCT) and chemotherapy alone. A total of 275 consecutive patients with newly diagnosed MM were included, and 54 patients (19.6 %) had EMPs at diagnosis. Patients with initial EMPs were more likely to have myeloma bone disease but favorable laboratory parameters in hemoglobin and β2-microglobulin. Patients were treated with different schemas based on transplant eligibility (154 in ASCT-eligible vs. 121 in ASCT-ineligible). After a median follow-up of 24.6 months (range, 0.2-56.3 months) in survivors, patients with initial EMPs had significantly worse progression-free survival (PFS) (P = 0.035) and overall survival (OS) (P = 0.006) compared to those without initial EMPs. In the multivariate analyses, the presence of initial EMPs was an independent prognostic factor for PFS (relative risk (RR) of 2.24, P = 0.024) and OS (RR of 2.47, P = 0.027) in the transplant-ineligible patients, whereas it did not significantly influence PFS (P = 0.341) or OS (P = 0.499) in the transplant-eligible patients. However, the adverse impact of EMPs observed in transplant-ineligible patients was attenuated among the patients treated with bortezomib. These data suggest that ASCT can overcome the negative impact of EMPs and highlight the potential efficacy of bortezomib on EMPs in the non-transplant setting.
Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation.
Mey Ulrich J M,Renner Christoph,von Moos Roger
BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches. We here present the first report on the combination of vemurafenib and cobimetinib in a young patient with highly resistant and rapidly progressing multiple myeloma harboring the BRAF V600E mutation who achieved a rapid and sustained response to this combination therapy.
A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial.
Yan Zhiling,Cao Jiang,Cheng Hai,Qiao Jianlin,Zhang Huanxin,Wang Ying,Shi Ming,Lan Jianping,Fei Xiaoming,Jin Lai,Jing Guangjun,Sang Wei,Zhu Feng,Chen Wei,Wu Qingyun,Yao Yao,Wang Gang,Zhao Jing,Zheng Junnian,Li Zhenyu,Xu Kailin
The Lancet. Haematology
BACKGROUND:Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has been shown to have activity in patients with relapsed or refractory multiple myeloma. Reports have suggested that a small subgroup of less differentiated myeloma clones express CD19 and anti-CD19 CAR T-cell therapy has shown activity in some of these patients. We aimed to assess the activity and safety of a combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma. METHODS:We did a single-centre, single-arm, phase 2 trial at the Affiliated Hospital of Xuzhou Medical University in China. Patients were eligible if they were aged 18-69 years, had histologically confirmed multiple myeloma, a Karnofsky Performance Score of 50 points or more, and met the International Myeloma Working Group diagnostic criteria for relapsed or refractory disease. Fludarabine (three daily doses of 30mg/m) and cyclophosphamide (one daily dose of 750 mg/m) were used to deplete lymphocytes before infusion of humanised anti-CD19 CAR T cells (1 × 10 cells per kg) and murine anti-BCMA CAR T cells (1 × 10 cells per kg). The primary outcome was the proportion of patients who achieved an overall response. Responses were assessed according to the International Myeloma Working Group criteria. This study is registered with the Chinese Clinical Trial Registration Center, number ChiCTR-OIC-17011272. FINDINGS:From May 1, 2017, to Jan 20, 2019, 22 patients were enrolled and 21 received an infusion of CAR T cells and were evaluable for safety and activity analyses. At a median follow-up of 179 days (IQR 72-295), 20 (95%) of 21 patients had an overall response, including nine (43%) stringent complete responses, three (14%) complete responses, five (24%) very good partial responses, and three (14%) partial responses. The most common adverse events included cytokine release syndrome (19 [90%] of 21), including 18 patients (86%) with grade 1-2 cytokine release syndrome. The most common serious adverse events were haematological toxicities, which occurred in 20 (95%) of 21 patients. Common grade 3 or higher adverse events included neutropenia (18 [86%]), anaemia (13 [62%]), and thrombocytopenia (13 [62%]). One patient died due to cerebral hemorrhage, which was considered related to sustained thrombocytopenia. No deaths were judged to be treatment-related. INTERPRETATION:Our results confirm that combined infusion of humanised anti-CD19 and anti-BCMA CAR T cells is feasible in patients with relapsed or refractory multiple myeloma, and the preliminary activity observed warrants further investigation in randomised trials. This dual CAR-T cell combinations might be a promising treatment option for relapsed or refractory multiple myeloma. FUNDING:National Natural Science Foundation of China, Natural Science Foundation, Key Research and Development Plan of Jiangsu.
The lymphoma-like polychemotherapy regimen "Dexa-BEAM" in advanced and extramedullary multiple myeloma.
Rasche Leo,Strifler Susanne,Duell Johannes,Rosenwald Andreas,Buck Andreas,Maeder Uwe,Einsele Hermann,Knop Stefan
Annals of hematology
Extramedullary disease (EMD) in multiple myeloma (MM) is characterised by an aggressive biology and an adverse prognosis especially when occurring at relapse. Due to the high proliferation found in EMD lesions, we analysed outcome data of patients treated with a lymphoma-type therapy not based on novel compounds, the Dexa-BEAM protocol. Retrospective analysis of MM patients having received Dexa-BEAM (including dexamethasone, carmustine, cytarabine, etoposide and melphalan) at our institution from January 2007 to November 2012. In all, 18 patients were identified, 11 of whom had EMD. Objective response (≥PR) to Dexa-BEAM was achieved in more than half of the patients with EMD (6/11); consecutive high-dose consolidation strategy with autologous or allogeneic stem cell transplantation improved upon the depth of remission in two thirds of EMD patients (4/6) with ongoing remissions in three patients. In contrast, all patients without consolidation relapsed. Progression-free survival after Dexa-BEAM was short in both patient groups with intramedullary or extramedullary myeloma with a median of 3 and 4 months, respectively. Toxicity was relevant with one treatment-related death and grades 3 and 4 toxicities in all 18 patients. Dexa-BEAM is an effective induction regimen in medically fit patients with extramedullary manifestations to regain disease control prior to an intended autologous or allogeneic transplantation.
Carfilzomib and dexamethasone for extramedullary myeloma with pleuropericardial involvement.
Español Ignacio,Romera Marta,Gutiérrez-Meca María Dolores,García Maria Del Carmen,Tejedor Aurelia,Martínez Antonio,Ibáñez Jerónima,De Arriba Felipe,Minguela Alfredo,Iturbe Teodoro,López Maria Dolores
Clinical case reports
The dismal outcome of pleuropericardial extramedullary multiple myeloma (EMM) reflects both the selection of resistant disease and absence of useful drugs. Carfilzomib and dexamethasone should be explored in advanced EMM patients, even for bortezomib-resistant patients, as may provide much longer overall survival than previously reported treatments.
Expression of CD99 in Multiple Myeloma: A Clinicopathologic and Immunohistochemical Study of 170 Cases.
Shin Su-Jin,Lee Hyangsin,Jung Geunyoung,Gil Minchan,Park Hosub,Park Young Soo,Yoon Dok Hyun,Suh Cheolwon,Park Chan-Jeoung,Huh Jooryung,Park Chan-Sik
Korean journal of pathology
BACKGROUND:Multiple myeloma (MM) is a heterogeneous and ultimately fatal disease. Risk stratification using prognostic biomarkers is crucial to individualize treatments. We sought to investigate the role of CD99, a transmembrane protein highly expressed in many hematopoietic cells including subpopulations of normal and neoplastic plasma cells, for MM risk stratification. METHODS:CD99 expression was measured in paraffin samples of bone marrow and extramedullary biopsies of 170 patients with MM. Patients were divided into those with high score (moderately and strongly positive) and low score (negative and weakly positive), with all staining being cytoplasmic and/or membranous. RESULTS:High anti-CD99 immunostaining was observed in 72 of 136 (52.9%) bone marrow biopsies and 24 of 87 (27.6%) extramedullary biopsies in MM. High CD99 expression of extramedullary specimens was associated with significantly longer overall survival (OS; p=.016). High CD99 expression of extramedullary specimens was also associated with better prognosis in the nonautologous stem cell transplantation group of MM patients (p=.044). In multivariate analysis, International Staging System stage was an independent prognostic factor, whereas CD99 expression was no longer statistically significant. CONCLUSIONS:Expression of CD99 in extramedullary specimens was correlated with longer OS, suggesting that CD99 may be a helpful immunohistochemical marker for risk stratification.
Clinical effects of CD45 on the prognosis of extramedullary myeloma relapse.
Oka Satoko,Ono Kazuo,Nohgawa Masaharu
Journal of clinical pharmacy and therapeutics
WHAT IS KNOWN AND OBJECTIVES:The incidence of extramedullary relapse (EMR) arising during the clinical course of multiple myeloma (MM) has increased in recent years. Therefore, we herein investigated the effects of immunophenotyping on the prognosis of MM patients with EMR. METHODS:We conducted a retrospective review on data collected from MM patients with EMR between January 2007 and December 2018 at the Japanese Red Cross Society Wakayama Medical Center. Patient characteristics at the diagnosis of EMR, the prognostic significance of immunophenotyping and other factors were evaluated. RESULTS AND DISCUSSION:Extramedullary relapse was detected in 55 of 231 patients (23.8%). At the diagnosis of EMR, CD45, the leucocyte common antigen, was detected in 54.5% of cases. CD45 negativity in bone marrow correlated with thrombocytopenia and higher serum LDH levels. Moreover, high-risk cytogenetics was more frequently observed in CD45- than in CD45+ patients. A univariate analysis showed that overall survival (OS) was significantly shorter in CD45- than in CD45+ patients. Thrombocytopenia, higher serum LDH levels and high-risk cytogenesis were also associated with shorter OS. A multivariate analysis confirmed that CD45 negativity, higher serum LDH levels and high-risk cytogenesis were independent adverse prognostic factors for OS. A Kaplan-Meier analysis revealed the potential of CD45- as a prognostic factor in patients with EMR and that it correlated with shorter survival. WHAT IS NEW AND CONCLUSION:The present results showed that the expression of CD45 in the neoplastic plasma cells of MM patients with EMR was associated with patient prognosis independent of other prognostic factors. The establishment of a treatment strategy for EMR patients with CD45- MM cells is needed to improve poor outcomes.
Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs.
Montefusco Vittorio,Gay Francesca,Spada Stefano,De Paoli Lorenzo,Di Raimondo Francesco,Ribolla Rossella,Musolino Caterina,Patriarca Francesca,Musto Pellegrino,Galieni Piero,Ballanti Stelvio,Nozzoli Chiara,Cascavilla Nicola,Ben-Yehuda Dina,Nagler Arnon,Hajek Roman,Offidani Massimo,Liberati Anna Marina,Sonneveld Pieter,Cavo Michele,Corradini Paolo,Boccadoro Mario
Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, =0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, <0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115).
Efficacy of Carfilzomib, Lenalidomide, and Dexamethasone for Extramedullary Intracranial Localization of Multiple Myeloma.
Mele Giuseppe,Pastore Domenico
Case reports in hematology
EMD of myeloma usually occurs several years after diagnosis and is associated with a very poor OS of <6 months due to the fact that there are no efficient treatment options. In rrMM with EMDs, the most effective treatment is a lymphoma-like polychemotherapy regimen such as PACE, Dexa-BEAM, and HyperCVAD followed by ASCT or allogeneic SCT. RT of soft-tissue plasmacytoma is the further treatment choice and results in a high rate of local control and a prolonged disease-free survival. We report the case of a 41-year-old man affected by ultra-high-risk symptomatic IgA MM with extramedullary intracranial soft-tissue relapsed after VTD-PACE followed by ASCT. The salvage program with KRd regimen determines a second biochemical and haematological remission and a gradual reduction in size of the extramedullary intracranial soft-tissue even in the absence of local aggressive radiotherapy, suggesting that carfilzomib and lenalidomide together could be effective also in this critical situation.
Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations.
Varga Cindy,Xie Wanling,Laubach Jacob,Ghobrial Irene M,O'Donnell Elizabeth K,Weinstock Matthew,Paba-Prada Claudia,Warren Diane,Maglio Michelle E,Schlossman Robert,Munshi Nikhil C,Raje Noopur,Weller Edie,Anderson Kenneth C,Mitsiades Constantine S,Richardson Paul G
British journal of haematology
Proteasome inhibitors (PI) and immunomodulatory agents (IMIDs) have improved the overall survival (OS) of patients with multiple myeloma (MM), but concerns have been raised about increased incidence of extramedullary disease (EMD) after the combined use of PIs and IMIDs for upfront therapy. We evaluated whether the addition of lenalidomide to bortezomib-based front-line regimens precipitated earlier development of EMD. We reviewed the charts of 117 MM patients (median follow-up from diagnosis 6·1 years; range 0·1-10·2 years) enrolled in eight clinical trials of first-line treatment with bortezomib-based regimens, with or without lenalidomide. We assessed development of EMD as extraosseous (distant from bone) or osseous (originating from bone) plasmacytomas. The primary endpoint was time from diagnosis until development of EMD, based on imaging, biopsy and/or physical examination. Any form of EMD at progression was observed in 40 (34·2%) patients, including 21 (18%) osseous, 8 (7%) extraosseous and 11 (9%) both osseous and extraosseous. Median OS was 0·9 years (range 0·1-4·8 years) after extraosseous EMD development. Sensitivity analyses with follow-up times truncated at 5 years detected no statistically significant difference in rates of any EMD form between the two groups (P > 0·2 for each comparison). Therefore, we observed no evidence that bortezomib-lenalidomide-based front-line therapy precipitates earlier EMD.
[Clinical observation of DECP combination chemotherapy for relapsing and refractory multiple myeloma patients with extramedullary plasmacytomas].
Li Xin,Sun Wanjun,Jin Fengyan,Chen Shilun,Zhong Yuping,Hu Ying,Zhang Jiajia,An Na,Shen Man,Huang Zhongxia
Zhonghua yi xue za zhi
OBJECTIVE:To explore the clinical effect and toxicity of (cisplatin, etoposide, ifosfamide & dexamethasone) DECP combination chemotherapy in the treatment of relapsing and refractory multiple myeloma (MM) with extramedullary plasmacytomas. METHODS:A total of 20 relapsed and refractory MM patients with extramedullary plasmacytomas treated with DECP regimen from May 2005 to May 2013 were analyzed retrospectively. DECP protocols included cisplatin 20 mg/m(2), Day 1-3; etoposide 100 mg/d,Day 1-3; ifosfamide 500 mg·m(-2)·d(-1), Day 1-4; dexamethasone 20 mg/d, Day 1-4. Efficacy was evaluated after 2 therapeutic cycles. RESULTS:After 2 therapeutic cycles, the objective response rate (ORR) was 55% (11/20). After 3 therapeutic cycles, the ORR was 7/12.Seven patients completed 4 cycles with an ORR of 4/7. Two patients had finished 6 cycles and continued to maintain partial remission. The most common adverse events included gastrointestinal reaction and myelosuppression. The median follow-up time was 30 (12-80) months. The median time of overall survival (OS) was 30 (9-121) months. The 1-year OS was 73%, 2-year OS 28% and 3-year OS 21%. CONCLUSION:The DECP chemotherapy is both effective and safe in the treatment of relapsed and refractory MM patients with extramedullary plasmacytomas.
Pomalidomide-dexamethasone for treatment of soft-tissue plasmacytomas in patients with relapsed / refractory multiple myeloma.
Jiménez-Segura Raquel,Granell Miquel,Gironella Mercè,Abella Eugenia,García-Guiñón Antoni,Oriol Albert,Cabezudo Elena,Clapés Victoria,Soler Joan Alfons,Escoda Lourdes,López-Pardo Jordi,Fernández de Larrea Carlos,Cibeira Maria Teresa,Tovar Natalia,Isola Ignacio,Bladé Joan,Rosiñol Laura,
European journal of haematology
OBJECTIVE:The presence of plasmacytomas (Ps) in patients with multiple myeloma (MM) is associated with a poor outcome, both in patients treated conventionally and in patients treated with novel agents. Two types of plasmacytomas have being recognized: paraskeletal plasmacytomas (PPs) and extramedullary plasmacytomas (EMPs), being the incidence of EMPs lower but with worse prognosis. Our aim has been to analyze the efficacy of the pomalidomide-dexamethasone combination in this patient profile. METHOD:In the present study, the efficacy of pomalidomide and dexamethasone in 21 patients from nine hospitals of Catalonia (Spain), with relapsed or refractory MM and Ps, was analyzed. For this purpose, we describe the evolution of paraprotein in serum and urine and the size of plasmacytomas during treatment with pomalidomide-dexamethasone. RESULTS:While 34% of the patients achieved a paraprotein response, only two patients with PPs (9%) responded (RC and PR). There were no responses among patients with EMPs. The median progression-free survival from the start of treatment with pomalidomide/dexamethasone was only 1.7 months and the median overall survival of 4.5 months. CONCLUSION:In conclusion, pomalidomide and dexamethasone has limited efficacy in patients with advanced MM and soft-tissue plasmacytomas.
A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement.
Rasche Leo,Menoret Emmanuelle,Dubljevic Valentina,Menu Eline,Vanderkerken Karin,Lapa Constantin,Steinbrunn Torsten,Chatterjee Manik,Knop Stefan,Düll Johannes,Greenwood Deanne L,Hensel Frank,Rosenwald Andreas,Einsele Hermann,Brändlein Stephanie
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. EXPERIMENTAL DESIGN:GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. RESULTS:Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions. CONCLUSIONS:PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. ©2016 AACR.
Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach.
Bladé Joan,Fernández de Larrea Carlos,Rosiñol Laura,Cibeira María Teresa,Jiménez Raquel,Powles Ray
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
We provide an overview on soft-tissue extramedullary plasmacytomas (EMPs) in multiple myeloma (MM). We reviewed the incidence of EMPs in MM, myeloma bone marrow homing, possible mechanisms of extramedullary spread, and prognosis and response to therapy. The incidence of EMPs is 7% to 18% at MM diagnosis and up to 20% at relapse. The current notion that EMPs are more frequent after treatment with novel agents remains to be proven, especially considering that different patterns of disease recurrence can emerge as patients live longer in the era of novel drugs. Bone marrow genetic abnormalities are not associated with extramedullary spread per se, which also suggests that microenvironmental interactions are key. Possible mechanisms of extramedullary spread include decreased adhesion molecule expression and downregulation of chemokine receptors. EMPs usually show plasmablastic morphology with negative CD56 expression. High-dose therapy with autologous stem-cell transplantation (ASCT) can overcome the negative prognostic impact of extramedullary disease in younger selected patients. EMPs do not typically respond to thalidomide alone, but in contrast, responses to bortezomib have been reported. The incidence of EMPs in patients with MM is high and is associated with poor outcome in patients treated conventionally. A potential first-line treatment option seems to be a bortezomib-containing regimen followed by ASCT, whenever possible. Experimental studies on the mechanisms of myeloma cell adhesion, myeloma growth at extramedullary sites, and drug sensitivity are priorities for this area of continuing therapeutic challenge.
Tandem Autologous Stem Cell Transplantation Improves Outcomes in Newly Diagnosed Multiple Myeloma with Extramedullary Disease and High-Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.
Gagelmann Nico,Eikema Diderik-Jan,Koster Linda,Caillot Denis,Pioltelli Pietro,Lleonart Juan Bargay,Reményi Péter,Blaise Didier,Schaap Nicolaas,Trneny Marek,Passweg Jakob,Porras Rocio Parody,Cahn Jean Yves,Musso Maurizio,Poiré Xavier,Fenk Roland,Itälä-Remes Maija,Pavone Vincenzo,Fouillard Loic,Maertens Johan,Bron Dominique,Pouli Anastasia,Schroyens Wilfried,Schönland Stefan,Garderet Laurent,Yakoub-Agha Ibrahim,Kröger Nicolaus
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous-allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; P = .02 and P = .03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.
Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review.
Parrondo Ricardo D,Roy Vivek,Sher Taimur,Alegria Victoria,Chanan-Khan Asher A,Ailawadhi Sikander
Case reports in hematology
Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.
[Pomalidomide/cyclophosphamide/dexamethasone combination therapy for relapsed/refractory multiple myeloma accompanied by extramedullary lesions].
Hagihara Masao,Ide Shiro,Ohara Shin,Uchida Tomoyuki,Inoue Morihiro,Hua Jian
[Rinsho ketsueki] The Japanese journal of clinical hematology
We retrospectively evaluated the efficacy of pomalidomide/cyclophosphamide/dexamethasone (PCd) treatment in seven patients with extramedullary disease (EMD). Three of the seven patients achieved VGPR (very good partial response) with PCd therapy. We handled a patient complicated with secondary plasma cell leukemia, which was completely cured with PCd regimen and succeeded to autologous stem cell transplantation. In addition, there were no severe infections during the treatment period. This is the first report demonstrating the efficiency and tolerability of PCd treatment for EMD.
Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease.
Zhou Xiang,Flüchter Patricia,Nickel Katharina,Meckel Katharina,Messerschmidt Janin,Böckle David,Knorz Sebastian,Steinhardt Maximilian Johannes,Krummenast Franziska,Danhof Sophia,Einsele Hermann,Kortüm K Martin,Rasche Leo
Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40-80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5-6.5) and ten (95% CI, 7.5-12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS ( = 0.004) and OS ( = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.