IMW 2013 Kazuyuki Shimizu President, International Myeloma Workshop 2013 Kyoto
Clinical Lymphoma, Myeloma & Leukemia Vol. 14, No. 1, 2-4
Overview of the International Myeloma Workshop 2013 Kyoto Introduction “Workshop” has been defined as a style of reciprocal learning and creation in which participants proactively learn about a problem and create a solution for it through experience and interaction. The history of the International Myeloma Workshop (IMW) dates back to 1985, when Professor Timothy McElwain from the Institute of Cancer Research and Royal Marsden Hospital (London, UK), suggested establishment of an IMW to Professor Robert Kyle from Mayo Clinic (Rochester, MN). Table 1 lists the time, location, and organizers of previous IMWs. From April 3 to 7, 2013, IMW 2013 Kyoto was held at the Kyoto International Conference Center (Kyoto, Japan), with the cherry blossoms in full bloom everywhere around the venue. The IMW 2013 Kyoto was the 14th of the biennial meetings and was held in Asia for the first time. More than 1700 participants attended from 64 countries, with 528 participants from 11 Asian countries, including 315 Japanese participants. About 100 interesting talks were given under 18 different themes, including 5 company-sponsored satellites. The presenters at different scientific positions debated on 5 currently unsolved important clinical questions, including the response assessment, treatment strategy in induction therapy, timing of autologous stem cell transplantation (ASCT), and timing for the initiation of treatment of smoldering multiple myeloma and relapsed disease. In addition, 488 poster presentations were given from 30 countries. Among them, 4 young investigators, who gave excellent presentations and fulfilled the selection criteria, received a travel award. The participants shared the latest results of molecular biology and clinical studies during the 5-day period. IMW 2013 Kyoto provided opportunities to re-evaluate response criteria and propose new methods for the response assessment, discuss treatment strategies, debate on important clinical questions, learn the latest findings of genomics and biomarkers relevant to disease relapse and progression, learn the various disease- and patient-related risk factors of myeloma, and know the situation of myeloma treatment in Asia. Accordingly, IMW 2013 Kyoto was a very productive conference and also an excellent scientific meeting specializing in myeloma and thus going beyond the mere framework of a “workshop.”
Submitted: Dec 4, 2013; Accepted: Dec 12, 2013; Epub: Dec 21, 2013 Address for correspondence: Kazuyuki Shimizu, President of the Japanese Society of Myeloma, Head of Hematology Unit, Tokai Central Hospital, 504-8601 Kakamigahara, Japan E-mail contact: [email protected]
2
-
Clinical Lymphoma, Myeloma & Leukemia February 2014
Highlights and Key Messages From the IMW 2013 Kyoto Assessment of Minimal Residual Disease Studies of the molecular biologic mechanism of myeloma have clarified the role of the bone marrow microenvironment to support the proliferation and survival of myeloma cells and eventually resulted in the development of novel agents that exert significant activities on both myeloma cells and the microenvironment. By incorporating such novel agents into treatment armamentarium, we are now able to obtain complete responses (CRs) in greater proportions of patients with newly diagnosed myeloma. In addition, many clinical trials have demonstrated that achievement of a CR is associated with extended survival. However, studies have been published that have denied such a positive correlation between CR achievement and extended survival. One of the reasons for this inconsistency is a difference in the detection sensitivity of a method to assess the response. Currently, the response has been assessed using serum and/or urine M-protein. However, we know the emergence of a clone that does not produce M-protein but has a sustained ability to cause end-organ damage after treatment. Accordingly, as long as we use M-protein as the surrogate of response, such a discrepancy in outcomes among patients who have obtained a CR seems inevitable. One of the highlights was a symposium on the methods to assess minimal residual disease (MRD). The methods use bone marrow samples but not serum. One of the methods involves analysis based on immunophenotypes of tumor cells and another evaluates MRD using real-time quantitative polymerase chain reaction with tumor cloneespecific primers derived from immunoglobulin heavy-chain rearrangement of tumor cells contained in the collected bone marrow samples.1 Both methods are considered to be able to assess a deeper response than stringent CR determined by the normal k/l ratio of serum free light chains. As a result, new criteria for the CR, assessed by immunophenotyping termed “immunophenotypic CR,” and another, assessed using real-time quantitative polymerase chain reaction termed “molecular CR,” were defined at the IMW 2011 Paris. However, we should realize that the MRD status assessed using these 2 new methods is confined to the bone marrow from which the sample was obtained and cannot provide any information regarding distant sites, including extramedullary disease. To overcome such limitations of these 2 methods, MRD assessment using imaging techniques such as magnetic resonance imaging and positron emission tomography-computed tomography was introduced.1,2 When these new methods to assess MRD have been validated, the risk of overtreatment in patients without MRD and of
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.007
Number
Year
1
1987
Blenheim Palace, Woodstock, UK
R. Kyle, B. Barlogie, B. Durie, G. Gahrton, D. Joshua
appropriate but the “response-adapted” or “risk- adapted” strategy would be most appropriate. In addition to these debates, an interesting treatment algorithm that included the patient’s age, comorbidities, activities of daily living, and instrumental activities of daily living was proposed to guide the dose adjustment for fit, unfit, and frail patients.6
2 3
1989 1991
Houston, TX Torino, Italy
B. Barlogie, R. Alexanian A. Pileri, M. Boccadoro
Early vs. Delayed ASCT
4 5
1993 1995
Rochester, MN Labaule, France
R. Kyle J.-L. Harousseau
6 7
1997 1999
Boston, MA Stockholm, Sweden
K. Anderson G. Gahrton, H. Mellstedt
8 9
2001 2003
Banff, Canada Salamanca, Spain
L. Pilarski J. San Miguel, J. Bladé
10 11
2005 2007
Sydney, Australia Kos, Greece
D. Joshua M. Dimopoulos
12
2009
Washington DC
13
2011
Paris, France
N. Munshi, V. Rajkumar, S. Jagannath J.-P. Fermand, T. Facon, P. Moreau
14
2013
Kyoto, Japan
Table 1 Previous International Myeloma Workshops Venue
Organizers
K. Shimizu
early treatment discontinuation in patients with MRD could be avoided.
“One-size-fits-all” vs. “Risk-adapted” Strategy We know that patients with myeloma have disease-related risk factors such as abnormal cytogenetics,3 including t(4;14), t(14;16), and del17p determined by fluorescence in situ hybridization, and noncytogenetic risk factors such as tumor burden, extramedullary disease, high lactate dehydrogenase, IgA myeloma, and plasma cell leukemia. In addition, patients with myeloma have patient-related risk factors such as age, performance status, and the presence of complications and/or comorbidities. Currently, risk assessment has been mostly based on the presence of cytogenetic abnormalities, which forms the backbone of the Mayo Stratification of Myeloma and Risk-Adapted Therapy. In the symposium of treatment strategy, the presenters actively debated the mode of strategy: “riskadapted” versus “one-size-fits-all.” The rationale for supporting the “risk-adapted” strategy was that myeloma is a heterogeneous disease and, accordingly, treatment should be adjusted according to the risk. The rationale for supporting the “one-size-fits-all” strategy was that patients who benefit most from intensive treatment will be those with standard risk and, accordingly, the patients should receive the most effective intensive combination therapy, irrespective of the risk. No conclusion resulted from the debate of which of the 2 strategies should be adopted in the treatment of transplant-eligible patients.4,5 However, a key message was that administration of the most effective TRIPLET, regardless of the risk (ie, “one-size-fits-all”) would be the most appropriate in the setting of induction therapy because an initial significant reduction in the tumor burden could be likely to result in high CR rates, which have been associated with extended survival. The key message also indicated that the decision of whether to give consolidation therapy, including ASCT and/or maintenance therapy, should be determined from the response to induction therapy and the patient’s risks. Therefore, the “one-size-fits-all” strategy would not be
A recent greater frequency of a deep response after induction therapy incorporating novel agents has resulted in questioning the role and position of ASCT. In the symposium of the role of ASCT in the era of novel agents, the presenters debated the timing of ASCT (early vs. delayed).7 The presenter who supported early ASCT showed evidence that the complementary effect of high-dose melphalan further enhanced the CR rates obtained after induction therapy, with costeffectiveness, a low mortality rate, and a longer period without symptoms, treatment, and treatment toxicity, and emphasized the risk of resistant relapse and the development of renal impairment if consolidation with ASCT has been delayed. The problem is that, at present, we are not able to define the group of patients at diagnosis who will benefit most from ASCT and when to use it. Currently, the initial treatment is composed of induction therapy followed by consolidation with ASCT, because a consensus has been reached that the initial treatment should be the most effective treatment for all patients, regardless of their risk status (the “one-size-fits-all” strategy). To determine the role and timing of ASCT, we must wait for the results of a phase III trial comparing early and delayed ASCT, which is currently being conducted by a US and French group.
Role of Consolidation and Maintenance Therapy Although consolidation is a type of treatment that is administered at a higher dose or more intense fashion within a few days or weeks to achieve an additional reduction in the myeloma tumor burden, maintenance treatment is administered for a long period, typically years, in an effort to sustain or enhance the response that has already been achieved with previous therapy. In the IMW 2013 Kyoto, we witnessed that novel agentebased consolidation therapy after ASCT has consistently shown the ability to increase the CR rate, even to the molecular level.8 Regarding maintenance, a meta-analysis of the 6 randomized trials of thalidomide maintenance after ASCT revealed a beneficial effect for overall survival.9 In addition, 1 of the 2 trials of lenalidomide maintenance after ASCT showed a sustained overall survival benefit.10 However, as a caveat, an increased incidence of a second primary malignancy (SPM) in patients given lenalidomide maintenance has been reported in the 3 studies of lenalidomide maintenance. At present, we are not sure whether lenalidomide itself is a risk of SPM or whether an additive risk exists with melphalan or doxorubicin. However, the follow-up studies disclosed that the frequency of SPM had reached a plateau, with no tendency found for a cumulative increase over time.10 Thus, it was concluded that the risk of SPM should be evaluated within the context of the risk of disease progression and death from myeloma.
Timing of Treatment of Relapsed Myeloma The initiation of treatment of relapsed disease has been recommended at the development of CRAB (calcium [elevated], renal failure, anemia, and bone lesions), which has been termed “clinical
Clinical Lymphoma, Myeloma & Leukemia February 2014
-3
Overview of International Myeloma Workshop relapse,” and/or when the M-protein has doubled within 2 months, which has been termed “biochemical relapse.” However, we are not sure whether we should start treatment if a patient develops an insignificant increase in M-protein without a clinical relapse. In the IMW 2013 Kyoto, an interesting debate occurred on this clinical question. The message delivered from the debater who supported treatment was that such a change during the follow-up period should not be equated to the change occurring in patients with asymptomatic or smoldering myeloma, because these patients had already had symptomatic disease requiring therapy. However, the opponent expressed a concern of inducing an expansion of an aggressive clone by the eradication of the dominant suppressive clone within the intraclonal heterogeneity11 by the early treatment.
Should Smoldering Multiple Myeloma Be Treated? The important key message from the IMW 2013 was that high-risk smoldering multiple myeloma, defined by the presence of > 60% of bone marrow plasma cells, an increase in plasma cells with abnormal immunophenotypes (aberrant plasma cells) with a decrease in the uninvolved immunoglobulin levels in serum (immunoparesis), abnormal magnetic resonance imaging findings indicating 2 focal lesions and a diffuse pattern, an evolving pattern manifested by a doubling of M-protein within 3 months, high-risk cytogenetics, an abnormal serum free light chain ratio, and/or increased clonal immunoglobulin-secreting cells in the peripheral blood, should be considered early myeloma and should be treated.12 The debater who opposed early treatment raised a concern of inducing expansion of an aggressive clone that could have been suppressed by an indolent clone, similar to the concern expressed for the possible treatment outcome in the context of asymptomatic insignificant M-protein relapse.13 The opponent expressed, in turn, a concern of insidious progression of renal impairment, so-called monoclonal gammopathy of renal significance, and bone disease, if left untreated.14
New Novel Agents The participants were impressed with the outstanding efficacy of the second-generation proteasome inhibitor and the thirdgeneration immunomodulatory drug in the treatment of relapsed and/or refractory disease. Also in the workshop, a possible promising combination of a proteasome inhibitor and other inhibitors such as the histone deacetylase inhibitor or heat shock protein inhibitor, with synergistic effects expected in the protein handling pathway, was introduced.15 As a next step, progress in the studies of genomics and exonomics could result in the identification of the genetic lesions to which the development of targeted therapy will hopefully ensue. In the future, personalized targeted therapy will become a principal treatment.
Myeloma in Asia
4
-
We are interested to know whether ethnic differences in myeloma exist. As the first IMW held in Asia, myeloma experts from China, Hong Kong, Korea, Japan, Singapore, and Taiwan gathered and introduced each situation in the diagnosis and treatment of myeloma. We found no significant differences in the clinical symptoms and presentations at diagnosis, although it was noted that in some parts of Asia, because of economic reasons, the
Clinical Lymphoma, Myeloma & Leukemia February 2014
patients tended to present with advanced disease.16 Also, as the only country that experienced the atomic bomb, the incidence of monoclonal gammopathy of undetermined significance and the evolution rate to symptomatic myeloma among the survivors in the Nagasaki area in 1945 were presented by a Japanese investigator.17 An introductory talk was given about the Asian Myeloma Network, founded under the auspices of the International Myeloma Foundation (IMF). The Asian Myeloma Network has already initiated several retrospective and prospective clinical studies. As a privilege of the host country, the history of the Japanese Society of Myeloma was introduced under the title of “showcase Japan,” according to the suggestion of Dr Brian Durie, president of the IMF.18 The career of the Japanese Society of Myeloma is unprecedented and unique in the world, because the activity of the society has focused not only on scientific activities, but also on a close cooperation with the patient association, IMF Japan.
Conclusion After the IMW 2013 Kyoto, we will be arriving at the idea that myeloma treatment will become tailored and determined by the disease-related risks, patient-related risks, and, perhaps, in the future, individual gene lesion. However, as a practical view of the current daily practice, we should perform in-depth MRD monitoring to avoid under- and overtreatment.
References 1. Orfao A, Paiva B, Vidriales MB, et al. What is the best surrogate marker for longterm survival in multiple myeloma, sCR, iCR, mCR or PET/CT? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S7-11. 2. Zamagni E. Usefulness of newer imaging techniques as predictor of outcomes in MM e Comparisonbetween PET/CT and MRI in different settings. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S6-11. 3. Avet-Liseau H. Risk assessment. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1): S9-11. 4. Rajkumar SV. Debate: Induction therapy: risk-adapted, response-adapted, or one size fits all strategy. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S9-12. 5. Sonneveld P. Debate: Induction therapy: risk-adapted, response-adapted, or one size fits all. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S9-13. 6. Palumbo A. Tailoring multiple myeloma therapy for special populations. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S1-4. 7. Moreau P, Richardson PG. Debate: Early or delayed transplantation for multiple myeloma in the era of novel therapies: does one size fit all? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S9-14. 8. Cavo M. What is the role of post-transplant consolidation therapy? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S15-21. 9. Spencer A. What is the optimal duration of maintenance therapy? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S15-24. 10. MaCarthy P, Owzar K, Hofmeister C, et al. Analysis of overall survival (OS) in the context of cross-over from placebo to lenalidomide and the incidence of second primary malignancies (SPM) in the phase III study of lenalidomide versus placebo maintenance therapy following autologous stem cell transplant (ASCT) for multiple myeloma (MM) CALGB (alliance) ECOG BMT-CTN 100104. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S15-25. 11. Pilarski LM. Clonal dynamics in multiple myeloma. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S3-4. 12. Mateos MV, San Miguel J. Should we treat smoldering multiple myeloma? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S11-3. 13. Landgren O. The molecular pathway to myeloma. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S11-21. 14. Munshi N, Fermand JP. Smoldering MM in 2013: “To treat or not to treat”?]. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S11-4. 15. Richardson PG, Laubach J, Chauhan D, et al. Extending treatment options for patients with advanced MM and optimizing the management of relapsed and refractory disease. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1): S14-24. 16. Lee JH. Report from Asian Myeloma Network (AMN). Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S16-21. 17. Iwanaga M, Tomonaga M. MGUS prevalence among Nagasaki Atomic Bomb survivors. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S16-23. 18. Suzuki K. Showcase Japan e Histories and trials. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S16-24.
Clinical Lymphoma, Myeloma & Leukemia Vol. 14, No. 1, 2-4
Overview of the International Myeloma Workshop 2013 Kyoto Introduction “Workshop” has been defined as a style of reciprocal learning and creation in which participants proactively learn about a problem and create a solution for it through experience and interaction. The history of the International Myeloma Workshop (IMW) dates back to 1985, when Professor Timothy McElwain from the Institute of Cancer Research and Royal Marsden Hospital (London, UK), suggested establishment of an IMW to Professor Robert Kyle from Mayo Clinic (Rochester, MN). Table 1 lists the time, location, and organizers of previous IMWs. From April 3 to 7, 2013, IMW 2013 Kyoto was held at the Kyoto International Conference Center (Kyoto, Japan), with the cherry blossoms in full bloom everywhere around the venue. The IMW 2013 Kyoto was the 14th of the biennial meetings and was held in Asia for the first time. More than 1700 participants attended from 64 countries, with 528 participants from 11 Asian countries, including 315 Japanese participants. About 100 interesting talks were given under 18 different themes, including 5 company-sponsored satellites. The presenters at different scientific positions debated on 5 currently unsolved important clinical questions, including the response assessment, treatment strategy in induction therapy, timing of autologous stem cell transplantation (ASCT), and timing for the initiation of treatment of smoldering multiple myeloma and relapsed disease. In addition, 488 poster presentations were given from 30 countries. Among them, 4 young investigators, who gave excellent presentations and fulfilled the selection criteria, received a travel award. The participants shared the latest results of molecular biology and clinical studies during the 5-day period. IMW 2013 Kyoto provided opportunities to re-evaluate response criteria and propose new methods for the response assessment, discuss treatment strategies, debate on important clinical questions, learn the latest findings of genomics and biomarkers relevant to disease relapse and progression, learn the various disease- and patient-related risk factors of myeloma, and know the situation of myeloma treatment in Asia. Accordingly, IMW 2013 Kyoto was a very productive conference and also an excellent scientific meeting specializing in myeloma and thus going beyond the mere framework of a “workshop.”
Submitted: Dec 4, 2013; Accepted: Dec 12, 2013; Epub: Dec 21, 2013 Address for correspondence: Kazuyuki Shimizu, President of the Japanese Society of Myeloma, Head of Hematology Unit, Tokai Central Hospital, 504-8601 Kakamigahara, Japan E-mail contact: [email protected]
2
-
Clinical Lymphoma, Myeloma & Leukemia February 2014
Highlights and Key Messages From the IMW 2013 Kyoto Assessment of Minimal Residual Disease Studies of the molecular biologic mechanism of myeloma have clarified the role of the bone marrow microenvironment to support the proliferation and survival of myeloma cells and eventually resulted in the development of novel agents that exert significant activities on both myeloma cells and the microenvironment. By incorporating such novel agents into treatment armamentarium, we are now able to obtain complete responses (CRs) in greater proportions of patients with newly diagnosed myeloma. In addition, many clinical trials have demonstrated that achievement of a CR is associated with extended survival. However, studies have been published that have denied such a positive correlation between CR achievement and extended survival. One of the reasons for this inconsistency is a difference in the detection sensitivity of a method to assess the response. Currently, the response has been assessed using serum and/or urine M-protein. However, we know the emergence of a clone that does not produce M-protein but has a sustained ability to cause end-organ damage after treatment. Accordingly, as long as we use M-protein as the surrogate of response, such a discrepancy in outcomes among patients who have obtained a CR seems inevitable. One of the highlights was a symposium on the methods to assess minimal residual disease (MRD). The methods use bone marrow samples but not serum. One of the methods involves analysis based on immunophenotypes of tumor cells and another evaluates MRD using real-time quantitative polymerase chain reaction with tumor cloneespecific primers derived from immunoglobulin heavy-chain rearrangement of tumor cells contained in the collected bone marrow samples.1 Both methods are considered to be able to assess a deeper response than stringent CR determined by the normal k/l ratio of serum free light chains. As a result, new criteria for the CR, assessed by immunophenotyping termed “immunophenotypic CR,” and another, assessed using real-time quantitative polymerase chain reaction termed “molecular CR,” were defined at the IMW 2011 Paris. However, we should realize that the MRD status assessed using these 2 new methods is confined to the bone marrow from which the sample was obtained and cannot provide any information regarding distant sites, including extramedullary disease. To overcome such limitations of these 2 methods, MRD assessment using imaging techniques such as magnetic resonance imaging and positron emission tomography-computed tomography was introduced.1,2 When these new methods to assess MRD have been validated, the risk of overtreatment in patients without MRD and of
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.007
Number
Year
1
1987
Blenheim Palace, Woodstock, UK
R. Kyle, B. Barlogie, B. Durie, G. Gahrton, D. Joshua
appropriate but the “response-adapted” or “risk- adapted” strategy would be most appropriate. In addition to these debates, an interesting treatment algorithm that included the patient’s age, comorbidities, activities of daily living, and instrumental activities of daily living was proposed to guide the dose adjustment for fit, unfit, and frail patients.6
2 3
1989 1991
Houston, TX Torino, Italy
B. Barlogie, R. Alexanian A. Pileri, M. Boccadoro
Early vs. Delayed ASCT
4 5
1993 1995
Rochester, MN Labaule, France
R. Kyle J.-L. Harousseau
6 7
1997 1999
Boston, MA Stockholm, Sweden
K. Anderson G. Gahrton, H. Mellstedt
8 9
2001 2003
Banff, Canada Salamanca, Spain
L. Pilarski J. San Miguel, J. Bladé
10 11
2005 2007
Sydney, Australia Kos, Greece
D. Joshua M. Dimopoulos
12
2009
Washington DC
13
2011
Paris, France
N. Munshi, V. Rajkumar, S. Jagannath J.-P. Fermand, T. Facon, P. Moreau
14
2013
Kyoto, Japan
Table 1 Previous International Myeloma Workshops Venue
Organizers
K. Shimizu
early treatment discontinuation in patients with MRD could be avoided.
“One-size-fits-all” vs. “Risk-adapted” Strategy We know that patients with myeloma have disease-related risk factors such as abnormal cytogenetics,3 including t(4;14), t(14;16), and del17p determined by fluorescence in situ hybridization, and noncytogenetic risk factors such as tumor burden, extramedullary disease, high lactate dehydrogenase, IgA myeloma, and plasma cell leukemia. In addition, patients with myeloma have patient-related risk factors such as age, performance status, and the presence of complications and/or comorbidities. Currently, risk assessment has been mostly based on the presence of cytogenetic abnormalities, which forms the backbone of the Mayo Stratification of Myeloma and Risk-Adapted Therapy. In the symposium of treatment strategy, the presenters actively debated the mode of strategy: “riskadapted” versus “one-size-fits-all.” The rationale for supporting the “risk-adapted” strategy was that myeloma is a heterogeneous disease and, accordingly, treatment should be adjusted according to the risk. The rationale for supporting the “one-size-fits-all” strategy was that patients who benefit most from intensive treatment will be those with standard risk and, accordingly, the patients should receive the most effective intensive combination therapy, irrespective of the risk. No conclusion resulted from the debate of which of the 2 strategies should be adopted in the treatment of transplant-eligible patients.4,5 However, a key message was that administration of the most effective TRIPLET, regardless of the risk (ie, “one-size-fits-all”) would be the most appropriate in the setting of induction therapy because an initial significant reduction in the tumor burden could be likely to result in high CR rates, which have been associated with extended survival. The key message also indicated that the decision of whether to give consolidation therapy, including ASCT and/or maintenance therapy, should be determined from the response to induction therapy and the patient’s risks. Therefore, the “one-size-fits-all” strategy would not be
A recent greater frequency of a deep response after induction therapy incorporating novel agents has resulted in questioning the role and position of ASCT. In the symposium of the role of ASCT in the era of novel agents, the presenters debated the timing of ASCT (early vs. delayed).7 The presenter who supported early ASCT showed evidence that the complementary effect of high-dose melphalan further enhanced the CR rates obtained after induction therapy, with costeffectiveness, a low mortality rate, and a longer period without symptoms, treatment, and treatment toxicity, and emphasized the risk of resistant relapse and the development of renal impairment if consolidation with ASCT has been delayed. The problem is that, at present, we are not able to define the group of patients at diagnosis who will benefit most from ASCT and when to use it. Currently, the initial treatment is composed of induction therapy followed by consolidation with ASCT, because a consensus has been reached that the initial treatment should be the most effective treatment for all patients, regardless of their risk status (the “one-size-fits-all” strategy). To determine the role and timing of ASCT, we must wait for the results of a phase III trial comparing early and delayed ASCT, which is currently being conducted by a US and French group.
Role of Consolidation and Maintenance Therapy Although consolidation is a type of treatment that is administered at a higher dose or more intense fashion within a few days or weeks to achieve an additional reduction in the myeloma tumor burden, maintenance treatment is administered for a long period, typically years, in an effort to sustain or enhance the response that has already been achieved with previous therapy. In the IMW 2013 Kyoto, we witnessed that novel agentebased consolidation therapy after ASCT has consistently shown the ability to increase the CR rate, even to the molecular level.8 Regarding maintenance, a meta-analysis of the 6 randomized trials of thalidomide maintenance after ASCT revealed a beneficial effect for overall survival.9 In addition, 1 of the 2 trials of lenalidomide maintenance after ASCT showed a sustained overall survival benefit.10 However, as a caveat, an increased incidence of a second primary malignancy (SPM) in patients given lenalidomide maintenance has been reported in the 3 studies of lenalidomide maintenance. At present, we are not sure whether lenalidomide itself is a risk of SPM or whether an additive risk exists with melphalan or doxorubicin. However, the follow-up studies disclosed that the frequency of SPM had reached a plateau, with no tendency found for a cumulative increase over time.10 Thus, it was concluded that the risk of SPM should be evaluated within the context of the risk of disease progression and death from myeloma.
Timing of Treatment of Relapsed Myeloma The initiation of treatment of relapsed disease has been recommended at the development of CRAB (calcium [elevated], renal failure, anemia, and bone lesions), which has been termed “clinical
Clinical Lymphoma, Myeloma & Leukemia February 2014
-3
Overview of International Myeloma Workshop relapse,” and/or when the M-protein has doubled within 2 months, which has been termed “biochemical relapse.” However, we are not sure whether we should start treatment if a patient develops an insignificant increase in M-protein without a clinical relapse. In the IMW 2013 Kyoto, an interesting debate occurred on this clinical question. The message delivered from the debater who supported treatment was that such a change during the follow-up period should not be equated to the change occurring in patients with asymptomatic or smoldering myeloma, because these patients had already had symptomatic disease requiring therapy. However, the opponent expressed a concern of inducing an expansion of an aggressive clone by the eradication of the dominant suppressive clone within the intraclonal heterogeneity11 by the early treatment.
Should Smoldering Multiple Myeloma Be Treated? The important key message from the IMW 2013 was that high-risk smoldering multiple myeloma, defined by the presence of > 60% of bone marrow plasma cells, an increase in plasma cells with abnormal immunophenotypes (aberrant plasma cells) with a decrease in the uninvolved immunoglobulin levels in serum (immunoparesis), abnormal magnetic resonance imaging findings indicating 2 focal lesions and a diffuse pattern, an evolving pattern manifested by a doubling of M-protein within 3 months, high-risk cytogenetics, an abnormal serum free light chain ratio, and/or increased clonal immunoglobulin-secreting cells in the peripheral blood, should be considered early myeloma and should be treated.12 The debater who opposed early treatment raised a concern of inducing expansion of an aggressive clone that could have been suppressed by an indolent clone, similar to the concern expressed for the possible treatment outcome in the context of asymptomatic insignificant M-protein relapse.13 The opponent expressed, in turn, a concern of insidious progression of renal impairment, so-called monoclonal gammopathy of renal significance, and bone disease, if left untreated.14
New Novel Agents The participants were impressed with the outstanding efficacy of the second-generation proteasome inhibitor and the thirdgeneration immunomodulatory drug in the treatment of relapsed and/or refractory disease. Also in the workshop, a possible promising combination of a proteasome inhibitor and other inhibitors such as the histone deacetylase inhibitor or heat shock protein inhibitor, with synergistic effects expected in the protein handling pathway, was introduced.15 As a next step, progress in the studies of genomics and exonomics could result in the identification of the genetic lesions to which the development of targeted therapy will hopefully ensue. In the future, personalized targeted therapy will become a principal treatment.
Myeloma in Asia
4
-
We are interested to know whether ethnic differences in myeloma exist. As the first IMW held in Asia, myeloma experts from China, Hong Kong, Korea, Japan, Singapore, and Taiwan gathered and introduced each situation in the diagnosis and treatment of myeloma. We found no significant differences in the clinical symptoms and presentations at diagnosis, although it was noted that in some parts of Asia, because of economic reasons, the
Clinical Lymphoma, Myeloma & Leukemia February 2014
patients tended to present with advanced disease.16 Also, as the only country that experienced the atomic bomb, the incidence of monoclonal gammopathy of undetermined significance and the evolution rate to symptomatic myeloma among the survivors in the Nagasaki area in 1945 were presented by a Japanese investigator.17 An introductory talk was given about the Asian Myeloma Network, founded under the auspices of the International Myeloma Foundation (IMF). The Asian Myeloma Network has already initiated several retrospective and prospective clinical studies. As a privilege of the host country, the history of the Japanese Society of Myeloma was introduced under the title of “showcase Japan,” according to the suggestion of Dr Brian Durie, president of the IMF.18 The career of the Japanese Society of Myeloma is unprecedented and unique in the world, because the activity of the society has focused not only on scientific activities, but also on a close cooperation with the patient association, IMF Japan.
Conclusion After the IMW 2013 Kyoto, we will be arriving at the idea that myeloma treatment will become tailored and determined by the disease-related risks, patient-related risks, and, perhaps, in the future, individual gene lesion. However, as a practical view of the current daily practice, we should perform in-depth MRD monitoring to avoid under- and overtreatment.
References 1. Orfao A, Paiva B, Vidriales MB, et al. What is the best surrogate marker for longterm survival in multiple myeloma, sCR, iCR, mCR or PET/CT? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S7-11. 2. Zamagni E. Usefulness of newer imaging techniques as predictor of outcomes in MM e Comparisonbetween PET/CT and MRI in different settings. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S6-11. 3. Avet-Liseau H. Risk assessment. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1): S9-11. 4. Rajkumar SV. Debate: Induction therapy: risk-adapted, response-adapted, or one size fits all strategy. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S9-12. 5. Sonneveld P. Debate: Induction therapy: risk-adapted, response-adapted, or one size fits all. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S9-13. 6. Palumbo A. Tailoring multiple myeloma therapy for special populations. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S1-4. 7. Moreau P, Richardson PG. Debate: Early or delayed transplantation for multiple myeloma in the era of novel therapies: does one size fit all? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S9-14. 8. Cavo M. What is the role of post-transplant consolidation therapy? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S15-21. 9. Spencer A. What is the optimal duration of maintenance therapy? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S15-24. 10. MaCarthy P, Owzar K, Hofmeister C, et al. Analysis of overall survival (OS) in the context of cross-over from placebo to lenalidomide and the incidence of second primary malignancies (SPM) in the phase III study of lenalidomide versus placebo maintenance therapy following autologous stem cell transplant (ASCT) for multiple myeloma (MM) CALGB (alliance) ECOG BMT-CTN 100104. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S15-25. 11. Pilarski LM. Clonal dynamics in multiple myeloma. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S3-4. 12. Mateos MV, San Miguel J. Should we treat smoldering multiple myeloma? Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S11-3. 13. Landgren O. The molecular pathway to myeloma. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S11-21. 14. Munshi N, Fermand JP. Smoldering MM in 2013: “To treat or not to treat”?]. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S11-4. 15. Richardson PG, Laubach J, Chauhan D, et al. Extending treatment options for patients with advanced MM and optimizing the management of relapsed and refractory disease. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1): S14-24. 16. Lee JH. Report from Asian Myeloma Network (AMN). Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S16-21. 17. Iwanaga M, Tomonaga M. MGUS prevalence among Nagasaki Atomic Bomb survivors. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S16-23. 18. Suzuki K. Showcase Japan e Histories and trials. Clin Lymphoma Myeloma Leuk 2013; 13(suppl 1):S16-24.
