Leukemia & Lymphoma
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China Jin Lu, Jian Hou, Kai-Yan Liu, Simrit Parmar, Adolfo De La Fuente, Börje Andersson, ChenHua Yan, Daobin Zhou, Daryl Tan, David Ritchie, Deipei Wu, Elizabeth Shpall, Ginna G. Laport, JianYong Li, Jiong Hu, Lian Sheng Zhang, Michael Wang, Pankaj Malhotra, Qian Jiang, Yazhen Qin, Raymond Wong, Richard Champlin, Surapol Issaragrisil, Swaminathan Iyer, Vikram Mathews, Yu Wang, Yu Hu, Zhijian Xiao, Zonghong Shao, Rafael Rosengarten, Jon Steuernagle Iv, Jun Huang Xiao, Robert Orlowski & James Chor Sang Chim To cite this article: Jin Lu, Jian Hou, Kai-Yan Liu, Simrit Parmar, Adolfo De La Fuente, Börje Andersson, ChenHua Yan, Daobin Zhou, Daryl Tan, David Ritchie, Deipei Wu, Elizabeth Shpall, Ginna G. Laport, JianYong Li, Jiong Hu, Lian Sheng Zhang, Michael Wang, Pankaj Malhotra, Qian Jiang, Yazhen Qin, Raymond Wong, Richard Champlin, Surapol Issaragrisil, Swaminathan Iyer, Vikram Mathews, Yu Wang, Yu Hu, Zhijian Xiao, Zonghong Shao, Rafael Rosengarten, Jon Steuernagle Iv, Jun Huang Xiao, Robert Orlowski & James Chor Sang Chim (2016): Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China, Leukemia & Lymphoma, DOI: 10.3109/10428194.2015.1135434 To link to this article: http://dx.doi.org/10.3109/10428194.2015.1135434
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LEUKEMIA & LYMPHOMA, 2016 http://dx.doi.org/10.3109/10428194.2015.1135434
REPORT
Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China
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€rje Anderssonc, ChenHua Yana, Jin Lua, Jian Houb, Kai-Yan Liua, Simrit Parmarc, Adolfo De La Fuented, Bo e f g h c Daobin Zhou , Daryl Tan , David Ritchie , Deipei Wu , Elizabeth Shpall , Ginna G. Laporti, JianYong Lij, Jiong Huk, Lian Sheng Zhangl, Michael Wangc, Pankaj Malhotram, Qian Jianga, Yazhen Qina, Raymond Wongn, Richard Champlinc, Surapol Issaragrisilo, Swaminathan Iyerp, Vikram Mathewsq, Yu Wanga, Yu Hur, Zhijian Xiaos, Zonghong Shaot, Rafael Rosengartenu,v, Jon Steuernagle Ivv,w, Jun Huang Xiaoa, Robert Orlowskic and James Chor Sang Chimx a Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China; bShanghai Changzheng Hospital, Shanghai, China; cDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; dMD Anderson Cancer Center, Madrid, Spain; ePeking Union Medical College Hospital, Beijing, China; fSingapore General Hospital, Singapore, Singapore; gRoyal Melbourne Hospital, Melbourne, Australia; hFirst Affiliated Hospital of Soochow University, Jiangsu, China, Jiangsu Institute of Hematology; iStanford University, Palo Alto, CA, USA; jFirst Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China; kRuijin Hospital, Shanghai, China; lGansu Provincial Key Laboratory of Hematology, Lanzhou, China; mPost Graduate Institute of Medical Education and Research, Chandigarh, India; nPrince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong, China; oFaculty of Medicine Siriraj Hospital, Bangkok, Thailand; pMethodist Hospital, Houston, TX, USA; qChristian Medical College and Hospital, Vellore, India; rWuhan Union Hospital, Wuhan, China; sInstitute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China; tGeneral Hospital of Tianjin Medical University, Tianjin, China; uBaylor College of Medicine, Houston, TX, USA; vMDRing, Houston, TX, USA; wJohns Hopkins Medical Institute, Baltimore, MD, USA; xQueen Mary Hospital, Hong Kong
ABSTRACT
ARTICLE HISTORY
The Asia-Pacific Hematology Consortium (APHCON), in partnership with MDRingTM, a mobile global physician education network, has initiated a detailed longitudinal study of physician knowledge and practice preferences in the Asia-Pacific sphere. The first dataset comes from a series of surveys answered by delegates at the APHCON Bridging The Gap (BTG) conference in Beijing in January, 2015. In this report we present our findings regarding diagnosis and treatment of multiple myeloma (MM). We aim to create a conduit for physicians in this region to share their experiences with the rest of the world, to identify areas of consensus and best practices, and to highlight opportunities for improvement in communication, education and patient care.
Received 2 October 2015 Revised 10 December 2015 Accepted 16 December 2015
The Asia-Pacific Hematology Consortium (APHCON), in partnership with MDRingTM, a mobile global physician education network, has initiated a detailed longitudinal study of physician knowledge and practice preferences in the Asia-Pacific sphere. The first dataset comes from a series of surveys answered by delegates at the APHCON Bridging The Gap (BTG) conference held in Beijing in January, 2015. A previous publication describes the results from the acute myeloid leukemia module.[1] In this letter, we present our findings regarding diagnosis and treatment of multiple myeloma (MM). We aim to create a conduit for physicians in this region to share their experiences with the rest of the world, to identify areas of consensus and best
KEYWORDS
Myeloma; China; MDRing; APHCON; survey
practices, and to highlight opportunities for improvement in communication, education, and patient care. Multiple myeloma is a still largely incurable malignancy of plasma cells that adversely affects bone integrity and marrow function.[2] Our MM survey module asked 25 questions about patient profiles, diagnostic approaches, and treatment preferences among 62 physicians from China and 17 physicians from other countries including Australia, India, Japan, Nepal, Thailand, and the United States of America. The complete survey results are provided in Supplemental Table 1. The average per-question response rate was 85% for Chinese physicians and 86% for the others. Throughout, we report survey results as the percentage
CONTACT Simrit Parmar [email protected] Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA Supplemental data for this article can be accessed at http://dx.doi.org/10.3109/10428194.2015.1135434. ß 2016 Taylor & Francis
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of respondents, excluding those who did not provide an answer to a particular question. Over half of all respondents reported seeing over 15 new MM patients each year. A majority of these patients were less than 60 years old, in contrast to the western countries, where the median age at diagnosis is 70 years.[3] A recent publication from the Asian Myeloma Network reported that almost 60% of myeloma patients in China are younger than 65 years.[4] The observed mean age for myeloma patients might reflect a cultural bias in which the elderly are less likely to actively seek treatment, or there may be less inclination to perform aggressive diagnostic evaluation in the elderly population. On the other hand, the disease demographics may be different in the Asian sector. A larger study will be required to systematically answer this question. Physicians of all represented nationalities rely on multiple tests to diagnose MM. Nearly all (96%) perform bone marrow biopsy as a primary diagnostic tool. Additional widely cited diagnostics include serum protein electrophoresis (SPEP) and serum free light chain ratio (FLC). Twenty-four hour urine protein electrophoresis (UPEP) and bone surveys are also used, although tending to be favored among Chinese doctors more than their international colleagues. A large majority (81%) of Chinese respondents employ both the International Staging System (ISS) and Durie-Salmon criteria, while 67% of international colleagues rely solely on the ISS, with the remainder using both systems. Recent guidelines suggest 80% of multiple myeloma originates from non-IgM immunoglobulin monoclonal gammopathy of undetermined significance (non-IgM MGUS), and 20% from light-chain immunoglobulin MGUS (LC-MGUS).[5] Most survey respondents reported observing either less than 10%, or 10–30%, light chain disease, consistent with global estimates. Nearly two-thirds of the physicians approach MGUS with observation only, with few proactive options to prevent disease progression. The other one-third of physicians opt for initiating treatment in only high-risk patients. Meanwhile, a majority considers various symptoms, including anemia, bone lesions, renal insufficiency, and unexplained paraprotein as general criteria for referral to a specialist. Over half of the Chinese respondents make their diagnosis within 2 weeks of the appearance of symptoms, and a large majority (82%) of respondents report that patients begin some therapy within 2 weeks of diagnosis. In contrast, over half of the international representatives define the time from symptoms to diagnosis as 2–6 weeks, and the time from diagnosis to therapy varies. Physicians of all nationalities largely agree on the criteria for transplant eligibility, ranking
patient age and performance status most highly, followed by the level of disease risk and affordability. Unfortunately, among the practices of two thirds of Chinese respondents, fewer than 20% of eligible Chinese patients receive transplants (see also reference [4]). International respondents were evenly split between the three transplantation rate categories in describing their patients’ treatment. We do not have enough resolution in the survey to ascertain whether there are nation-specific trends among these physicians, but the actualization of transplantation does not seem as poor as that described by their Chinese colleagues. Not everyone in the survey focuses on the same treatment guidelines – the National Comprehensive Cancer Network (NCCN) is most widely referenced among the Chinese respondents, with the international contingent split between the NCCN and International Myeloma Working Group (IMWG) guidelines.[5] Nevertheless, the surveyed doctors share common goals for treating newly diagnosed MM, with 76% of all respondents reporting a curative approach, and the rest aiming for disease control. When weighing outcomes to make treatment decisions, overall survival (OS) is most widely considered, followed by progression-free survival (PFS), complete remission (CR), and then very good partial remission (VGPR). This ranking seems to reflect a balance of realism and optimism based on today’s best treatment options. A plurality of survey respondents (42% overall) preferred the induction regimen of bortezomib, thalidomide, and dexamethasone (VTD) for newly diagnosed transplant eligible MM patients [Figure 1a]. Another third reported the use of bortezomib and dexamethasone. Both options are recommended as category 1 protocols by NCCN, and the inclusion of all three agents was recently established in the literature as a potent treatment option.[6] Other drug combinations using the bortezomib þ dexamethasone backbone have been subject to intensive clinical study as well. A European consortium recently showed that an induction regimen including cyclophosphamide (VCD) was not inferior to the addition of doxorubicin (PAd).[7] For transplant ineligible patients, a similar plurality of Chinese physicians proceeds with the same VTD induction regimen [Figure 1b]. Physicians from the other countries were more likely to suggest a melphalan-based approach, which has proven effective as a primary treatment but may compromise the stem-cell reserve and thus is restricted to transplant ineligible patients.[8–10] The difference in melphalan preference likely reflects the lack of availability of this drug in China. When asked to rank the key drivers for their treatment decisions, the most common response
APPROACH TO MULTIPLE MYELOMA IN CHINA
(a)
Preferred induction for newly diagnosed transplant eligible MM?
Bortezomib + Dex
3
China Other Overall
Lenalidomide + Dex Bortezomib + Thal + Dex Bortezomib + Len + Dex Other
(b)
First line treatment for transplant ineligible MM?
Bortezomib + Dex Lenalidomide + Dex Bortezomib + Thal + Dex Melphalan-based Other 0%
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(c)
Treatment of choice for first relapse?
25%
50%
75%
100%
25%
50%
75%
100%
25%
50%
75%
100%
Lenalidomide based therapy Bortezomib based therapy Bortezomib + lenalidomide Other
(d) Choice for relapsed refractory with prior regimens including bortezomib, lenalidomide & thalidomide?
CyBORD VRD VTD Pomalidomide-based Carfilzomib-based 0%
(e) Based on ASPIRE data, which line of therapy do you expect to prescribe carfilzomib-based regimen upon regulatory approval? (Select all that apply)
2nd line 3rd line 4th line or later Never
(f) Have you ever treated any MM patient with the following agents? (Select all that apply)
Carfilzomib Pomalidomide Lenalidomide Bortezomib 0%
Figure 1. Drug availability is reflected in physician preferences for multiple myeloma treatment. The responses to multiple-choice questions pertaining to first-line treatment (a and b), relapse treatment (c and d), and general therapeutic usage (e and f) are shown. The percent of respondents (x-axis) is stratified by nationality: physicians from China represented by red markers, other nationalities by blue markers, and the overall average by black bars. Light red or blue shading indicates a particular answer choice with a statistical overrepresentation of one geographic group or the other. Statistical significance was determined by v-squared analysis, p value < 0.05. Gray shading (f) calls attention to a significantly large number of physicians of both nationalities holding a similar outlook on the drug carfilzomib.
among Chinese physicians was published guidelines, while their international colleagues reported relying most heavily on newly available data. This difference highlights to us the inherent value of meetings like BTG where physicians from many different backgrounds have a free exchange of ideas and practice preferences.
Greater accord was seen in regard to treating first relapse, with a statistically even split among physicians recommending either lenalidomide, bortezomib, or a combination of bortezomib and lenalidomide [Figure 1c]. Physicians also similarly reported offering maintenance therapy to all patients, or at least to those post-transplant. In cases of relapsed refractory MM with
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prior treatment including bortezomib, lenalidomide, and/or thalidomide, international respondents overwhelmingly favor carfilzomib (78%), while Chinese physicians were nearly evenly split among the other options including CyBorD (27%), VRD (17%), VTD (19%), Pomalidomide based (13%), and Carfilzomib based (25%) [Figure 1d]. The difference in reliance on carfilzomib between nationality groups reflects the relative availability of the drug, which is currently only in clinical trials in China. Another factor contributing to the choice of one drug over another may be the decision drivers of recent data versus established guidelines. While carfilzomib, a proteasome inhibitor, combined with len-dex is a category 1 recommendation in the relapsed setting, its promise is only now being realized.[11,12] Since the undertaking of this survey, updated results from the ASPIRE and ENDEAVOR demonstrating the efficacy of carfilzomib in the relapsed setting have been presented at ASCO 2015 and other conferences. Although our responses were collected prior to the full appreciation of these clinical data, 84% of Chinese respondents (and 80% overall) were aware of carfilzomib, and nearly 70% expected to prescribe carfilzomib as a second-line therapy upon regulatory approval [Figure 1e]. This number will likely be even higher in follow-up surveys, and we expect carfilzomib to join lenalidomide and bortezomib, both first-line drugs, among the most commonly employed therapeutic agents [Figure 1f]. Carfilzomib was adopted more for robustness with response in relapsed setting rather than lack of neuropathy. Many experts are cautiously optimistic that we are at an inflection point in the treatment of MM. The addition of carfilzomib to a lenalidomide–dexamethasone backbone in the relapsed setting has moved the goal posts for the depth and duration of response to treatment. Another promising new drug is elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7).[13] The phase 3 trial ELOQUENT-2 examined elotuzumab in combination with len-dex in the relapsed setting, and found significantly improved PFS compared with len-dex alone.[13] Daratumumab, a CD38-targeting, human IgG1j monoclonal antibody, also showed a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma.[14]. Thus, next-generation therapies, with more specific and efficacious modes of action, are expanding and improving upon MM treatment options. The survey results presented herein highlight the importance of communication and ongoing education to ensure more uniform global best practices. By sharing their experiences, physicians reveal their knowledge
and their needs, including gaps in access or training. Access to therapeutics will come as regulatory processes allow, and will be driven by demand that is dependent on information. Although limited in its sample size and inherent with bias driven due to English as the primary language of the conference, this survey report adds to the ‘‘lay of the land’’ and will allow for future expansion and build up on to the database. Continuous engagement, via platforms such as MDRingTM and participation in groups such as APHCON, will allow for collaboration and cooperation in better understanding of the available resources and future endeavors.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2015. 1135434.
References [1]
[2] [3] [4]
[5]
[6]
[7]
[8]
[9]
[10]
Liu K, Malhotra P, Parmar S, et al. Approach to AML Treatment. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China. J Leuk. 2015;3:186. . DOI: 10.4172/2329-6917.1000186. Moreau P, Attal M, Facon T. Frontline therapy of multiple myeloma. Blood. 2015;125:3076–3084. Palumbo A, Anderson K. Multiple myeloma. N Eng J Med. 2011;364:1046–1060. 2011/03/18 Kim K, Lee JH, Kim JS, et al. Clinical profiles of multiple myeloma in Asia – an Asian Myeloma Network study. Am J Hematol. 2014;89:751–756. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–e548. ~ol L, Oriol A, Teruel Al, et al. Superiority of borteRosin zomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 2012;120:1589–1596. Mai EK, Bertsch U, Durig J, et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015;29:1721–1729. ~ol L, Kumar S, Moreau P, et al. Initial treatment of Rosin transplant-eligible patients in multiple myeloma. Expert Rev Hematol. 2014;7:43–53. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib–melphalan–prednisone versus melphalan–prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:448–455. Palumbo A, Bringhen S, Larocca A, et al. Bortezomib–melphalan–prednisone–thalidomide
APPROACH TO MULTIPLE MYELOMA IN CHINA
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[11]
followed by maintenance with bortezomib-thalidomide compared with bortezomib–melphalan–prednisone for initial treatment of multiple myeloma: updated followup and improved survival. J Clin Oncol. 2014;32:634–640. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–152.
[12]
[13]
[14]
5
Killock D. Haematological cancer: ASPIRE for unprecedented benefit with carfilzomib in MM. Nat Rev Clin Oncol. 2015;12:65. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621–631. Lokhorst HM, Pleasner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–1219.
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China Jin Lu, Jian Hou, Kai-Yan Liu, Simrit Parmar, Adolfo De La Fuente, Börje Andersson, ChenHua Yan, Daobin Zhou, Daryl Tan, David Ritchie, Deipei Wu, Elizabeth Shpall, Ginna G. Laport, JianYong Li, Jiong Hu, Lian Sheng Zhang, Michael Wang, Pankaj Malhotra, Qian Jiang, Yazhen Qin, Raymond Wong, Richard Champlin, Surapol Issaragrisil, Swaminathan Iyer, Vikram Mathews, Yu Wang, Yu Hu, Zhijian Xiao, Zonghong Shao, Rafael Rosengarten, Jon Steuernagle Iv, Jun Huang Xiao, Robert Orlowski & James Chor Sang Chim To cite this article: Jin Lu, Jian Hou, Kai-Yan Liu, Simrit Parmar, Adolfo De La Fuente, Börje Andersson, ChenHua Yan, Daobin Zhou, Daryl Tan, David Ritchie, Deipei Wu, Elizabeth Shpall, Ginna G. Laport, JianYong Li, Jiong Hu, Lian Sheng Zhang, Michael Wang, Pankaj Malhotra, Qian Jiang, Yazhen Qin, Raymond Wong, Richard Champlin, Surapol Issaragrisil, Swaminathan Iyer, Vikram Mathews, Yu Wang, Yu Hu, Zhijian Xiao, Zonghong Shao, Rafael Rosengarten, Jon Steuernagle Iv, Jun Huang Xiao, Robert Orlowski & James Chor Sang Chim (2016): Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China, Leukemia & Lymphoma, DOI: 10.3109/10428194.2015.1135434 To link to this article: http://dx.doi.org/10.3109/10428194.2015.1135434
View supplementary material
Published online: 17 Feb 2016.
Submit your article to this journal
Article views: 66
View related articles
Downloaded by [University of California Santa Barbara] at 00:56 07 March 2016
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [University of California Santa Barbara]
Date: 07 March 2016, At: 00:56
LEUKEMIA & LYMPHOMA, 2016 http://dx.doi.org/10.3109/10428194.2015.1135434
REPORT
Asia-Pacific Hematology Consortium Report on approach to multiple myeloma. Survey results from the 6th International Hematologic Malignancies Conference: Bridging the Gap 2015, Beijing, China
Downloaded by [University of California Santa Barbara] at 00:56 07 March 2016
€rje Anderssonc, ChenHua Yana, Jin Lua, Jian Houb, Kai-Yan Liua, Simrit Parmarc, Adolfo De La Fuented, Bo e f g h c Daobin Zhou , Daryl Tan , David Ritchie , Deipei Wu , Elizabeth Shpall , Ginna G. Laporti, JianYong Lij, Jiong Huk, Lian Sheng Zhangl, Michael Wangc, Pankaj Malhotram, Qian Jianga, Yazhen Qina, Raymond Wongn, Richard Champlinc, Surapol Issaragrisilo, Swaminathan Iyerp, Vikram Mathewsq, Yu Wanga, Yu Hur, Zhijian Xiaos, Zonghong Shaot, Rafael Rosengartenu,v, Jon Steuernagle Ivv,w, Jun Huang Xiaoa, Robert Orlowskic and James Chor Sang Chimx a Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China; bShanghai Changzheng Hospital, Shanghai, China; cDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; dMD Anderson Cancer Center, Madrid, Spain; ePeking Union Medical College Hospital, Beijing, China; fSingapore General Hospital, Singapore, Singapore; gRoyal Melbourne Hospital, Melbourne, Australia; hFirst Affiliated Hospital of Soochow University, Jiangsu, China, Jiangsu Institute of Hematology; iStanford University, Palo Alto, CA, USA; jFirst Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China; kRuijin Hospital, Shanghai, China; lGansu Provincial Key Laboratory of Hematology, Lanzhou, China; mPost Graduate Institute of Medical Education and Research, Chandigarh, India; nPrince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong, China; oFaculty of Medicine Siriraj Hospital, Bangkok, Thailand; pMethodist Hospital, Houston, TX, USA; qChristian Medical College and Hospital, Vellore, India; rWuhan Union Hospital, Wuhan, China; sInstitute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin, China; tGeneral Hospital of Tianjin Medical University, Tianjin, China; uBaylor College of Medicine, Houston, TX, USA; vMDRing, Houston, TX, USA; wJohns Hopkins Medical Institute, Baltimore, MD, USA; xQueen Mary Hospital, Hong Kong
ABSTRACT
ARTICLE HISTORY
The Asia-Pacific Hematology Consortium (APHCON), in partnership with MDRingTM, a mobile global physician education network, has initiated a detailed longitudinal study of physician knowledge and practice preferences in the Asia-Pacific sphere. The first dataset comes from a series of surveys answered by delegates at the APHCON Bridging The Gap (BTG) conference in Beijing in January, 2015. In this report we present our findings regarding diagnosis and treatment of multiple myeloma (MM). We aim to create a conduit for physicians in this region to share their experiences with the rest of the world, to identify areas of consensus and best practices, and to highlight opportunities for improvement in communication, education and patient care.
Received 2 October 2015 Revised 10 December 2015 Accepted 16 December 2015
The Asia-Pacific Hematology Consortium (APHCON), in partnership with MDRingTM, a mobile global physician education network, has initiated a detailed longitudinal study of physician knowledge and practice preferences in the Asia-Pacific sphere. The first dataset comes from a series of surveys answered by delegates at the APHCON Bridging The Gap (BTG) conference held in Beijing in January, 2015. A previous publication describes the results from the acute myeloid leukemia module.[1] In this letter, we present our findings regarding diagnosis and treatment of multiple myeloma (MM). We aim to create a conduit for physicians in this region to share their experiences with the rest of the world, to identify areas of consensus and best
KEYWORDS
Myeloma; China; MDRing; APHCON; survey
practices, and to highlight opportunities for improvement in communication, education, and patient care. Multiple myeloma is a still largely incurable malignancy of plasma cells that adversely affects bone integrity and marrow function.[2] Our MM survey module asked 25 questions about patient profiles, diagnostic approaches, and treatment preferences among 62 physicians from China and 17 physicians from other countries including Australia, India, Japan, Nepal, Thailand, and the United States of America. The complete survey results are provided in Supplemental Table 1. The average per-question response rate was 85% for Chinese physicians and 86% for the others. Throughout, we report survey results as the percentage
CONTACT Simrit Parmar [email protected] Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA Supplemental data for this article can be accessed at http://dx.doi.org/10.3109/10428194.2015.1135434. ß 2016 Taylor & Francis
Downloaded by [University of California Santa Barbara] at 00:56 07 March 2016
2
J. LU ET AL.
of respondents, excluding those who did not provide an answer to a particular question. Over half of all respondents reported seeing over 15 new MM patients each year. A majority of these patients were less than 60 years old, in contrast to the western countries, where the median age at diagnosis is 70 years.[3] A recent publication from the Asian Myeloma Network reported that almost 60% of myeloma patients in China are younger than 65 years.[4] The observed mean age for myeloma patients might reflect a cultural bias in which the elderly are less likely to actively seek treatment, or there may be less inclination to perform aggressive diagnostic evaluation in the elderly population. On the other hand, the disease demographics may be different in the Asian sector. A larger study will be required to systematically answer this question. Physicians of all represented nationalities rely on multiple tests to diagnose MM. Nearly all (96%) perform bone marrow biopsy as a primary diagnostic tool. Additional widely cited diagnostics include serum protein electrophoresis (SPEP) and serum free light chain ratio (FLC). Twenty-four hour urine protein electrophoresis (UPEP) and bone surveys are also used, although tending to be favored among Chinese doctors more than their international colleagues. A large majority (81%) of Chinese respondents employ both the International Staging System (ISS) and Durie-Salmon criteria, while 67% of international colleagues rely solely on the ISS, with the remainder using both systems. Recent guidelines suggest 80% of multiple myeloma originates from non-IgM immunoglobulin monoclonal gammopathy of undetermined significance (non-IgM MGUS), and 20% from light-chain immunoglobulin MGUS (LC-MGUS).[5] Most survey respondents reported observing either less than 10%, or 10–30%, light chain disease, consistent with global estimates. Nearly two-thirds of the physicians approach MGUS with observation only, with few proactive options to prevent disease progression. The other one-third of physicians opt for initiating treatment in only high-risk patients. Meanwhile, a majority considers various symptoms, including anemia, bone lesions, renal insufficiency, and unexplained paraprotein as general criteria for referral to a specialist. Over half of the Chinese respondents make their diagnosis within 2 weeks of the appearance of symptoms, and a large majority (82%) of respondents report that patients begin some therapy within 2 weeks of diagnosis. In contrast, over half of the international representatives define the time from symptoms to diagnosis as 2–6 weeks, and the time from diagnosis to therapy varies. Physicians of all nationalities largely agree on the criteria for transplant eligibility, ranking
patient age and performance status most highly, followed by the level of disease risk and affordability. Unfortunately, among the practices of two thirds of Chinese respondents, fewer than 20% of eligible Chinese patients receive transplants (see also reference [4]). International respondents were evenly split between the three transplantation rate categories in describing their patients’ treatment. We do not have enough resolution in the survey to ascertain whether there are nation-specific trends among these physicians, but the actualization of transplantation does not seem as poor as that described by their Chinese colleagues. Not everyone in the survey focuses on the same treatment guidelines – the National Comprehensive Cancer Network (NCCN) is most widely referenced among the Chinese respondents, with the international contingent split between the NCCN and International Myeloma Working Group (IMWG) guidelines.[5] Nevertheless, the surveyed doctors share common goals for treating newly diagnosed MM, with 76% of all respondents reporting a curative approach, and the rest aiming for disease control. When weighing outcomes to make treatment decisions, overall survival (OS) is most widely considered, followed by progression-free survival (PFS), complete remission (CR), and then very good partial remission (VGPR). This ranking seems to reflect a balance of realism and optimism based on today’s best treatment options. A plurality of survey respondents (42% overall) preferred the induction regimen of bortezomib, thalidomide, and dexamethasone (VTD) for newly diagnosed transplant eligible MM patients [Figure 1a]. Another third reported the use of bortezomib and dexamethasone. Both options are recommended as category 1 protocols by NCCN, and the inclusion of all three agents was recently established in the literature as a potent treatment option.[6] Other drug combinations using the bortezomib þ dexamethasone backbone have been subject to intensive clinical study as well. A European consortium recently showed that an induction regimen including cyclophosphamide (VCD) was not inferior to the addition of doxorubicin (PAd).[7] For transplant ineligible patients, a similar plurality of Chinese physicians proceeds with the same VTD induction regimen [Figure 1b]. Physicians from the other countries were more likely to suggest a melphalan-based approach, which has proven effective as a primary treatment but may compromise the stem-cell reserve and thus is restricted to transplant ineligible patients.[8–10] The difference in melphalan preference likely reflects the lack of availability of this drug in China. When asked to rank the key drivers for their treatment decisions, the most common response
APPROACH TO MULTIPLE MYELOMA IN CHINA
(a)
Preferred induction for newly diagnosed transplant eligible MM?
Bortezomib + Dex
3
China Other Overall
Lenalidomide + Dex Bortezomib + Thal + Dex Bortezomib + Len + Dex Other
(b)
First line treatment for transplant ineligible MM?
Bortezomib + Dex Lenalidomide + Dex Bortezomib + Thal + Dex Melphalan-based Other 0%
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(c)
Treatment of choice for first relapse?
25%
50%
75%
100%
25%
50%
75%
100%
25%
50%
75%
100%
Lenalidomide based therapy Bortezomib based therapy Bortezomib + lenalidomide Other
(d) Choice for relapsed refractory with prior regimens including bortezomib, lenalidomide & thalidomide?
CyBORD VRD VTD Pomalidomide-based Carfilzomib-based 0%
(e) Based on ASPIRE data, which line of therapy do you expect to prescribe carfilzomib-based regimen upon regulatory approval? (Select all that apply)
2nd line 3rd line 4th line or later Never
(f) Have you ever treated any MM patient with the following agents? (Select all that apply)
Carfilzomib Pomalidomide Lenalidomide Bortezomib 0%
Figure 1. Drug availability is reflected in physician preferences for multiple myeloma treatment. The responses to multiple-choice questions pertaining to first-line treatment (a and b), relapse treatment (c and d), and general therapeutic usage (e and f) are shown. The percent of respondents (x-axis) is stratified by nationality: physicians from China represented by red markers, other nationalities by blue markers, and the overall average by black bars. Light red or blue shading indicates a particular answer choice with a statistical overrepresentation of one geographic group or the other. Statistical significance was determined by v-squared analysis, p value < 0.05. Gray shading (f) calls attention to a significantly large number of physicians of both nationalities holding a similar outlook on the drug carfilzomib.
among Chinese physicians was published guidelines, while their international colleagues reported relying most heavily on newly available data. This difference highlights to us the inherent value of meetings like BTG where physicians from many different backgrounds have a free exchange of ideas and practice preferences.
Greater accord was seen in regard to treating first relapse, with a statistically even split among physicians recommending either lenalidomide, bortezomib, or a combination of bortezomib and lenalidomide [Figure 1c]. Physicians also similarly reported offering maintenance therapy to all patients, or at least to those post-transplant. In cases of relapsed refractory MM with
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prior treatment including bortezomib, lenalidomide, and/or thalidomide, international respondents overwhelmingly favor carfilzomib (78%), while Chinese physicians were nearly evenly split among the other options including CyBorD (27%), VRD (17%), VTD (19%), Pomalidomide based (13%), and Carfilzomib based (25%) [Figure 1d]. The difference in reliance on carfilzomib between nationality groups reflects the relative availability of the drug, which is currently only in clinical trials in China. Another factor contributing to the choice of one drug over another may be the decision drivers of recent data versus established guidelines. While carfilzomib, a proteasome inhibitor, combined with len-dex is a category 1 recommendation in the relapsed setting, its promise is only now being realized.[11,12] Since the undertaking of this survey, updated results from the ASPIRE and ENDEAVOR demonstrating the efficacy of carfilzomib in the relapsed setting have been presented at ASCO 2015 and other conferences. Although our responses were collected prior to the full appreciation of these clinical data, 84% of Chinese respondents (and 80% overall) were aware of carfilzomib, and nearly 70% expected to prescribe carfilzomib as a second-line therapy upon regulatory approval [Figure 1e]. This number will likely be even higher in follow-up surveys, and we expect carfilzomib to join lenalidomide and bortezomib, both first-line drugs, among the most commonly employed therapeutic agents [Figure 1f]. Carfilzomib was adopted more for robustness with response in relapsed setting rather than lack of neuropathy. Many experts are cautiously optimistic that we are at an inflection point in the treatment of MM. The addition of carfilzomib to a lenalidomide–dexamethasone backbone in the relapsed setting has moved the goal posts for the depth and duration of response to treatment. Another promising new drug is elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7).[13] The phase 3 trial ELOQUENT-2 examined elotuzumab in combination with len-dex in the relapsed setting, and found significantly improved PFS compared with len-dex alone.[13] Daratumumab, a CD38-targeting, human IgG1j monoclonal antibody, also showed a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma.[14]. Thus, next-generation therapies, with more specific and efficacious modes of action, are expanding and improving upon MM treatment options. The survey results presented herein highlight the importance of communication and ongoing education to ensure more uniform global best practices. By sharing their experiences, physicians reveal their knowledge
and their needs, including gaps in access or training. Access to therapeutics will come as regulatory processes allow, and will be driven by demand that is dependent on information. Although limited in its sample size and inherent with bias driven due to English as the primary language of the conference, this survey report adds to the ‘‘lay of the land’’ and will allow for future expansion and build up on to the database. Continuous engagement, via platforms such as MDRingTM and participation in groups such as APHCON, will allow for collaboration and cooperation in better understanding of the available resources and future endeavors.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2015. 1135434.
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