IMW 2013 Jean-Paul Fermand Professor of Clinical Immunology, Head of ImmunoHematology Unit, Hôpital Saint Louis, Paris, France
Clinical Lymphoma, Myeloma & Leukemia Vol. 14, No. 1, 5-7
Treatment of Smoldering Myeloma: Early or Delayed? Introduction
Prevention of Bone and Neurologic Complications
Approximately 15% of patients with myeloma (MM) have an asymptomatic “smoldering” MM (SMM) and are recognized incidentally.1 Until recently, it was recommended that these patients should not be treated until unequivocal signs of progression appear. Regular monitoring including serum protein electrophoresis to measure the level of the tumor marker, the monoclonal immunoglobulin (MIg) characteristic of the disease, was sufficient. Because the introduction of the so-called novel antimyeloma agents has dramatically improved our capabilities for reducing myeloma tumor mass, new issues recently emerged: is it time to treat some patients with SMM on diagnosis? If yes, which ones? If no, when should treatment be initiated?
In SMM, x-ray skeletal survey is, by definition, negative. Magnetic resonance imaging (MRI) can detect infraradiological abnormalities which have a strong prognostic value, as demonstrated nearly 15 years ago.4 If MRI detects multiple clear-cut signal abnormalities, many investigators now consider that it is an indication to treat. In the same way, if MRI detects isolated lesions that could be threatening, at least local radiotherapy is indicated to prevent vertebral collapse, or worse, spinal cord compression. This outlines the importance of MRI and at least a spine examination should imperatively be part of the initial staging of all patients with SMM. The interest of whole body MRI has been outlined and positron emission tomography scanning appears to be less sensitive than MRI for detection of infraradiological myeloma lesions.5 The therapeutic strategy to propose to patients with MRI-detected bone lesions remains poorly defined. Some investigators would recommend an aggressive approach such as high-dose therapy and autotransplant as first-line treatment in an eligible patient, whereas others would propose a “soft” approach, such as a few months of an Imid-based regimen, keeping the high-dose therapy as a rescue treatment, when the disease will progress. Of course, the second option implies performing blood stem cell collection early to avoid the stem cell damaging potential of drugs such as lenalidomide. To prevent progression of bone disease, bisphopshonates are effective drugs with low toxicity. As suggested by results of 2 Italian studies, when given to patients with SMM, pamidronate and zoledronate do not delay and do not reduce the rate of progression to overt myeloma as compared with observation alone. However, both drugs reduced very significantly the incidence of skeletal-related events at progression.6,7 Accordingly, using this treatment in an attempt to protect patients from vertebral collapse, pain, and discomfort deserves consideration, at least for patients most at risk, as indicated by bone densitometry data. Although this has not been formally assessed, spacing the infusions, for instance, every 3 months, is likely to be a good option because of the prolonged persistence of the drug in bone.
Situations at Particular Risk of Complications “Monoclonal Gammopathy of Renal Significance” Initiating early therapy might be indicated to prevent complications due to the monoclonal immunoglobulin. Indeed, in some patients, the MIg is toxic by itself even though it belongs to a small B-cell clone featuring an SMM or even a monoclonal gammopathy of undetermined significance. The main target organ is the kidney and the expression “monoclonal gammopathy of renal significance” (or MGRS) was recently coined out to outline the specificity of this setting.2 Most MGRS are due to deposition of a MIg fragment resulting in glomerulopathies with organized deposits, such as AL amyloidosis, cryoglobulinemias, and immunotactoid glomerulopathy or nonorganized deposits such as Randall type MIg deposition disease. MGRS also includes tubular disorders. In contrast, myeloma cast nephropathy, which almost invariably occurs during the course of high tumor mass myeloma, is not part of MGRS. Recognizing MGRS relies on careful analysis of urine proteins which usually contain a significant amount of albumin. Targeting the underlying B-cell clone, although it is not toxic per se, is the only available therapeutic option and, in the absence of any way to specifically reduce the MIg production, requires chemotherapy. The therapeutic choice depends on the type of renal disorder, the nature of the B-cell clone, possible extrarenal lesions, and renal function.3
To Delay Progression and Improve Survival Redefining High-Risk SMM
Submitted: Dec 12, 2013; Accepted: Dec 12, 2013; Epub: Dec 19, 2013 Address for correspondence: Jean-Paul Fermand, Professor of Clinical Immunology, Head of Immuno-Hematology Unit, Hôpital Saint Louis, 75010 Paris, France E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.008
To delay and reduce the rate of progression is, of course, a major issue. To improve overall survival and cure at least some patients represents, of course, the ultimate goal. These objectives imply clearly identifying patients most at risk. The 2 main current risk
Clinical Lymphoma, Myeloma & Leukemia February 2014
-5
Treatment of Smoldering Myeloma: Early or Delayed? stratification schemes obviously need to be improved because even in high-risk groups, approximately 1 in 4 patients with SMM remains nonprogressive at 5 years.8 Introducing the molecular markers that were identified as poor prognosis indicators in symptomatic MM, such as the t (4, 14) translocation is a potential option. However, although the outcome of t (4, 14) gammopathies is globally poor, this subgroup is heterogeneous, including more than 20% of patients with asymptomatic disease, some of whom enjoy a very long progression-free period without any therapy. Among the 3 main breakpoint regions that the translocation involves on chromosome 4, the MB4-2 pattern appears to be rare among the asymptomatic t (4, 14) diseases whereas it characterizes those who have a particularly poor outcome among all t (4, 14) proliferations (B. Arnulf, unpublished results). This illustrates new approaches for improving the identification of high-risk SMM, which remains a crucial issue.
Risks and Uncertainties of Premature Treatment Initiation Risks of premature treatment initiation combine toxicity and resistance issues. Regarding toxicity, an early therapeutic intervention might negatively affect patients’ quality of life whereas they have no myeloma symptoms. It can also complicate further therapy at the time of progression because of, for instance, impairment in hematopoietic reserve or harmful neurological effects. Finally, it can favor the emergence of secondary hematological malignancy and solid tumor. In addition, and maybe more importantly, early therapy can produce differential responses within the myeloma clone that can lead to the selection and expansion of resistant subclones. This risk is likely to be particularly high in the multiclonal, unstable, and prone to clonal divergence forms of the disease but might also be of concern in genetically stable and linearly evolving diseases, at least with use of some of the agents.9 Obviously, improving our understanding of mechanisms that maintain clonal stability in SMM and of their risk of destabilization caused by one or the other drug is a critical issue. Because of our current lack of knowledge of the biology of the different forms of SMM and of mechanisms of drug resistance, conducting well designed clinical trials to assess any early intervention is particularly mandatory.
Randomized Clinical Trials
6
-
Very few randomized trials have been performed to evaluate a chemotherapeutic treatment to prevent progression of SMM and a pioneering study was reported only very recently.10 In this study, patients with high-risk SMM were randomly assigned to early treatment or observation alone. In the treatment arm, patients received 9 cycles of a classical lenalidomide plus dexamethasone induction regimen followed by a maintenance regimen using lenalidomide alone for 2 years. One hundred and nine patients were enrolled and, after a median follow-up of 40 months, the early treatment appeared not only to delay progression to symptomatic myeloma (median not reached vs. 21 months; P < .001) but also to increase overall survival (3-year survival rate 94% vs. 80%; P ¼ .03). These results are impressive but the study has weaknesses. First, the authors assumed that disease characteristics were well balanced between the 2 groups but they did not report data on comparison of
Clinical Lymphoma, Myeloma & Leukemia February 2014
patients’ bone status. In particular, no MRI was performed at baseline and a higher incidence of MRI signal abnormalities in the observation group could not be excluded. Second, the addition of dexamethasone was allowed at the time of asymptomatic biologic progression in the treatment group whereas it was not in the observation group. This resulted in a so-called “time-varying confounding,” producing biased estimates of treatment effect.11 Accordingly, assessment of time to progression to symptomatic disease (the primary end point) might have been biased. Even more importantly, the observed difference in overall survival might not have been due to the early lenalidomide treatment but to a more delayed initiation of symptomatic myeloma therapy, at a time when patients presented with more advanced manifestations of the disease. This would explain the very unusual rate of mortality at progression that was observed in the observation group (13 deaths in 44 patients; ie, nearly a third of progressing patients). Finally, patients in the observation arm were not only differently managed compared with patients in the treatment arm, but were also not managed according to current “good” clinical practices, checking the monoclonal immunoglobulin and other disease markers including MRI for initiating treatment before the occurrence of symptomatic disease (see next section).12 The rate of adverse events, particularly infection, was much higher in the treatment group than in the observation group (all grade infection: 47% [including a fatal respiratory infection] vs. 22%). Moreover, follow-up was not sufficient to allow assessment of different consequences of the treatment such as secondary malignancies and negative effect on further therapy. For all these reasons, this study cannot be considered as convincing for recommendation of lenalidomide and dexamethasone as standard treatment for high-risk SMM. It points the way for the evaluation of new approaches—including, for instance, monoclonal antiplasma cell antibodies and, might be, with the objective of cure, an intensive rather than soft strategy—to be proposed to appropriately selected patients with SMM.
Facing a Patient With SMM: What Should We Do Now? Except for patients with particular risks of complications, there is no current indication for chemotherapy in patients with SMM outside of clinical trials. Risks and uncertainties of premature treatment initiation do not incite to treat too early. Thus, in most patients, only regular monitoring is indicated. For these, waiting for the onset of clinical symptoms, namely for the occurrence of the socalled CRAB features, exposes the patient to renal, bone, and neurological complications with the associated risk of definitive lesions. Trying to detect “a preclinical window” to initiate therapy appears to be much more logical. For this purpose, regular monitoring of the MIg is of major value. Indeed, an increase in tumor mass is usually reflected by a parallel increase in the MIg, which represents a real tumor marker. However, time to increase in tumor mass differs from one patient to another and a same proportional increase in MIg, for instance a doubling, does not mean the same things at all in terms of tumor mass progression when occurring in a few weeks compared with a few months. In other words, time to doubling is much more important than doubling by itself.
Jean-Paul Fermand Moreover, the tumor marker, although it is a good one, has limitations. In most cases, changes in MIg are easy to assess by comparing consecutive serum electrophoresis results. However, this test can be less sensitive, particularly when the peak is small and/or when it migrates in beta. In addition, follow-up of SMM secreting light chain only is still difficult, despite the contribution of the free light chain assay. In any case, a clear and significant increase in the MIg level justifies reinforcement of the monitoring, by repeating clinical, biological, and radiological (including MRI) examinations. A rapid increase in the MIg, with an estimated doubling time of less than 3 months, and/or the worsening of other characteristics of the disease are indications to treat. Conversely, when the MIg increase is slow and the others parameters are stable, monitoring only can be continued. Whenever there is doubt, bisphosphonate introduction might be considered while continuing to take into account the progression. Bisphosphonates can also be proposed for patients with a stable disease, according to bone densitometry data.
Conclusion Early treatment of SMM should be proposed only in patients with MGRS and in those who have clear cut MRI-detected bone lesions. In addition, bisphopshonates (preferentially intravenous) should be discussed whenever there is evidence of a significant loss in bone mass. Otherwise, no treatment is indicated because currently we cannot clearly identify high-risk patients and demonstrate a favorable benefit to risk ratio of any therapy in terms of overall survival. During follow-up, we must not treat too early but rather try to target the preclinical window. For this purpose, the tumor marker, MIg, is pivotal, considering time to doubling and not absolute increase, and taking into account changes in other disease features,
including bone involvement, assessed using MRI. For the future, the development of new markers of genetic instability and disease progression is mandatory to move from this pragmatic approach to a more rational one.
Disclosure The author has stated that he has no conflicts of interest.
References 1. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356:2582-90. 2. Leung N, Bridoux F, Hutchison CA, et al. International Kidney and Monoclonal Gammopathy Research Group. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood 2012; 120:4292-5. 3. Fermand JP, Bridoux F, Kyle RA, et al. How I treat monoclonal gammopathy of renal significance (MGRS)? Blood 2013; 122:3583-90. 4. Mariette X, Zagdanski AM, Guermazi A, et al. Prognostic value of vertebral lesions detected by magnetic resonance imaging in patients with stage I multiple myeloma. Br J Haematol 1999; 104:723-9. 5. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010; 28:1606-10. 6. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008; 113:1588-95. 7. D’Arena G, Gobbi PG, Broglia C, et al. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma 2011; 52:771-5. 8. Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117:5573-81. 9. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12:335-48. 10. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013; 369:438-47. 11. Hernán MA, Hernández-Díaz S. Beyond the intention-to-treat in comparative effectiveness research. Clin Trials 2012; 9:48-55. 12. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010; 24:1121-7.
Clinical Lymphoma, Myeloma & Leukemia February 2014
-7
Clinical Lymphoma, Myeloma & Leukemia Vol. 14, No. 1, 5-7
Treatment of Smoldering Myeloma: Early or Delayed? Introduction
Prevention of Bone and Neurologic Complications
Approximately 15% of patients with myeloma (MM) have an asymptomatic “smoldering” MM (SMM) and are recognized incidentally.1 Until recently, it was recommended that these patients should not be treated until unequivocal signs of progression appear. Regular monitoring including serum protein electrophoresis to measure the level of the tumor marker, the monoclonal immunoglobulin (MIg) characteristic of the disease, was sufficient. Because the introduction of the so-called novel antimyeloma agents has dramatically improved our capabilities for reducing myeloma tumor mass, new issues recently emerged: is it time to treat some patients with SMM on diagnosis? If yes, which ones? If no, when should treatment be initiated?
In SMM, x-ray skeletal survey is, by definition, negative. Magnetic resonance imaging (MRI) can detect infraradiological abnormalities which have a strong prognostic value, as demonstrated nearly 15 years ago.4 If MRI detects multiple clear-cut signal abnormalities, many investigators now consider that it is an indication to treat. In the same way, if MRI detects isolated lesions that could be threatening, at least local radiotherapy is indicated to prevent vertebral collapse, or worse, spinal cord compression. This outlines the importance of MRI and at least a spine examination should imperatively be part of the initial staging of all patients with SMM. The interest of whole body MRI has been outlined and positron emission tomography scanning appears to be less sensitive than MRI for detection of infraradiological myeloma lesions.5 The therapeutic strategy to propose to patients with MRI-detected bone lesions remains poorly defined. Some investigators would recommend an aggressive approach such as high-dose therapy and autotransplant as first-line treatment in an eligible patient, whereas others would propose a “soft” approach, such as a few months of an Imid-based regimen, keeping the high-dose therapy as a rescue treatment, when the disease will progress. Of course, the second option implies performing blood stem cell collection early to avoid the stem cell damaging potential of drugs such as lenalidomide. To prevent progression of bone disease, bisphopshonates are effective drugs with low toxicity. As suggested by results of 2 Italian studies, when given to patients with SMM, pamidronate and zoledronate do not delay and do not reduce the rate of progression to overt myeloma as compared with observation alone. However, both drugs reduced very significantly the incidence of skeletal-related events at progression.6,7 Accordingly, using this treatment in an attempt to protect patients from vertebral collapse, pain, and discomfort deserves consideration, at least for patients most at risk, as indicated by bone densitometry data. Although this has not been formally assessed, spacing the infusions, for instance, every 3 months, is likely to be a good option because of the prolonged persistence of the drug in bone.
Situations at Particular Risk of Complications “Monoclonal Gammopathy of Renal Significance” Initiating early therapy might be indicated to prevent complications due to the monoclonal immunoglobulin. Indeed, in some patients, the MIg is toxic by itself even though it belongs to a small B-cell clone featuring an SMM or even a monoclonal gammopathy of undetermined significance. The main target organ is the kidney and the expression “monoclonal gammopathy of renal significance” (or MGRS) was recently coined out to outline the specificity of this setting.2 Most MGRS are due to deposition of a MIg fragment resulting in glomerulopathies with organized deposits, such as AL amyloidosis, cryoglobulinemias, and immunotactoid glomerulopathy or nonorganized deposits such as Randall type MIg deposition disease. MGRS also includes tubular disorders. In contrast, myeloma cast nephropathy, which almost invariably occurs during the course of high tumor mass myeloma, is not part of MGRS. Recognizing MGRS relies on careful analysis of urine proteins which usually contain a significant amount of albumin. Targeting the underlying B-cell clone, although it is not toxic per se, is the only available therapeutic option and, in the absence of any way to specifically reduce the MIg production, requires chemotherapy. The therapeutic choice depends on the type of renal disorder, the nature of the B-cell clone, possible extrarenal lesions, and renal function.3
To Delay Progression and Improve Survival Redefining High-Risk SMM
Submitted: Dec 12, 2013; Accepted: Dec 12, 2013; Epub: Dec 19, 2013 Address for correspondence: Jean-Paul Fermand, Professor of Clinical Immunology, Head of Immuno-Hematology Unit, Hôpital Saint Louis, 75010 Paris, France E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.008
To delay and reduce the rate of progression is, of course, a major issue. To improve overall survival and cure at least some patients represents, of course, the ultimate goal. These objectives imply clearly identifying patients most at risk. The 2 main current risk
Clinical Lymphoma, Myeloma & Leukemia February 2014
-5
Treatment of Smoldering Myeloma: Early or Delayed? stratification schemes obviously need to be improved because even in high-risk groups, approximately 1 in 4 patients with SMM remains nonprogressive at 5 years.8 Introducing the molecular markers that were identified as poor prognosis indicators in symptomatic MM, such as the t (4, 14) translocation is a potential option. However, although the outcome of t (4, 14) gammopathies is globally poor, this subgroup is heterogeneous, including more than 20% of patients with asymptomatic disease, some of whom enjoy a very long progression-free period without any therapy. Among the 3 main breakpoint regions that the translocation involves on chromosome 4, the MB4-2 pattern appears to be rare among the asymptomatic t (4, 14) diseases whereas it characterizes those who have a particularly poor outcome among all t (4, 14) proliferations (B. Arnulf, unpublished results). This illustrates new approaches for improving the identification of high-risk SMM, which remains a crucial issue.
Risks and Uncertainties of Premature Treatment Initiation Risks of premature treatment initiation combine toxicity and resistance issues. Regarding toxicity, an early therapeutic intervention might negatively affect patients’ quality of life whereas they have no myeloma symptoms. It can also complicate further therapy at the time of progression because of, for instance, impairment in hematopoietic reserve or harmful neurological effects. Finally, it can favor the emergence of secondary hematological malignancy and solid tumor. In addition, and maybe more importantly, early therapy can produce differential responses within the myeloma clone that can lead to the selection and expansion of resistant subclones. This risk is likely to be particularly high in the multiclonal, unstable, and prone to clonal divergence forms of the disease but might also be of concern in genetically stable and linearly evolving diseases, at least with use of some of the agents.9 Obviously, improving our understanding of mechanisms that maintain clonal stability in SMM and of their risk of destabilization caused by one or the other drug is a critical issue. Because of our current lack of knowledge of the biology of the different forms of SMM and of mechanisms of drug resistance, conducting well designed clinical trials to assess any early intervention is particularly mandatory.
Randomized Clinical Trials
6
-
Very few randomized trials have been performed to evaluate a chemotherapeutic treatment to prevent progression of SMM and a pioneering study was reported only very recently.10 In this study, patients with high-risk SMM were randomly assigned to early treatment or observation alone. In the treatment arm, patients received 9 cycles of a classical lenalidomide plus dexamethasone induction regimen followed by a maintenance regimen using lenalidomide alone for 2 years. One hundred and nine patients were enrolled and, after a median follow-up of 40 months, the early treatment appeared not only to delay progression to symptomatic myeloma (median not reached vs. 21 months; P < .001) but also to increase overall survival (3-year survival rate 94% vs. 80%; P ¼ .03). These results are impressive but the study has weaknesses. First, the authors assumed that disease characteristics were well balanced between the 2 groups but they did not report data on comparison of
Clinical Lymphoma, Myeloma & Leukemia February 2014
patients’ bone status. In particular, no MRI was performed at baseline and a higher incidence of MRI signal abnormalities in the observation group could not be excluded. Second, the addition of dexamethasone was allowed at the time of asymptomatic biologic progression in the treatment group whereas it was not in the observation group. This resulted in a so-called “time-varying confounding,” producing biased estimates of treatment effect.11 Accordingly, assessment of time to progression to symptomatic disease (the primary end point) might have been biased. Even more importantly, the observed difference in overall survival might not have been due to the early lenalidomide treatment but to a more delayed initiation of symptomatic myeloma therapy, at a time when patients presented with more advanced manifestations of the disease. This would explain the very unusual rate of mortality at progression that was observed in the observation group (13 deaths in 44 patients; ie, nearly a third of progressing patients). Finally, patients in the observation arm were not only differently managed compared with patients in the treatment arm, but were also not managed according to current “good” clinical practices, checking the monoclonal immunoglobulin and other disease markers including MRI for initiating treatment before the occurrence of symptomatic disease (see next section).12 The rate of adverse events, particularly infection, was much higher in the treatment group than in the observation group (all grade infection: 47% [including a fatal respiratory infection] vs. 22%). Moreover, follow-up was not sufficient to allow assessment of different consequences of the treatment such as secondary malignancies and negative effect on further therapy. For all these reasons, this study cannot be considered as convincing for recommendation of lenalidomide and dexamethasone as standard treatment for high-risk SMM. It points the way for the evaluation of new approaches—including, for instance, monoclonal antiplasma cell antibodies and, might be, with the objective of cure, an intensive rather than soft strategy—to be proposed to appropriately selected patients with SMM.
Facing a Patient With SMM: What Should We Do Now? Except for patients with particular risks of complications, there is no current indication for chemotherapy in patients with SMM outside of clinical trials. Risks and uncertainties of premature treatment initiation do not incite to treat too early. Thus, in most patients, only regular monitoring is indicated. For these, waiting for the onset of clinical symptoms, namely for the occurrence of the socalled CRAB features, exposes the patient to renal, bone, and neurological complications with the associated risk of definitive lesions. Trying to detect “a preclinical window” to initiate therapy appears to be much more logical. For this purpose, regular monitoring of the MIg is of major value. Indeed, an increase in tumor mass is usually reflected by a parallel increase in the MIg, which represents a real tumor marker. However, time to increase in tumor mass differs from one patient to another and a same proportional increase in MIg, for instance a doubling, does not mean the same things at all in terms of tumor mass progression when occurring in a few weeks compared with a few months. In other words, time to doubling is much more important than doubling by itself.
Jean-Paul Fermand Moreover, the tumor marker, although it is a good one, has limitations. In most cases, changes in MIg are easy to assess by comparing consecutive serum electrophoresis results. However, this test can be less sensitive, particularly when the peak is small and/or when it migrates in beta. In addition, follow-up of SMM secreting light chain only is still difficult, despite the contribution of the free light chain assay. In any case, a clear and significant increase in the MIg level justifies reinforcement of the monitoring, by repeating clinical, biological, and radiological (including MRI) examinations. A rapid increase in the MIg, with an estimated doubling time of less than 3 months, and/or the worsening of other characteristics of the disease are indications to treat. Conversely, when the MIg increase is slow and the others parameters are stable, monitoring only can be continued. Whenever there is doubt, bisphosphonate introduction might be considered while continuing to take into account the progression. Bisphosphonates can also be proposed for patients with a stable disease, according to bone densitometry data.
Conclusion Early treatment of SMM should be proposed only in patients with MGRS and in those who have clear cut MRI-detected bone lesions. In addition, bisphopshonates (preferentially intravenous) should be discussed whenever there is evidence of a significant loss in bone mass. Otherwise, no treatment is indicated because currently we cannot clearly identify high-risk patients and demonstrate a favorable benefit to risk ratio of any therapy in terms of overall survival. During follow-up, we must not treat too early but rather try to target the preclinical window. For this purpose, the tumor marker, MIg, is pivotal, considering time to doubling and not absolute increase, and taking into account changes in other disease features,
including bone involvement, assessed using MRI. For the future, the development of new markers of genetic instability and disease progression is mandatory to move from this pragmatic approach to a more rational one.
Disclosure The author has stated that he has no conflicts of interest.
References 1. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356:2582-90. 2. Leung N, Bridoux F, Hutchison CA, et al. International Kidney and Monoclonal Gammopathy Research Group. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood 2012; 120:4292-5. 3. Fermand JP, Bridoux F, Kyle RA, et al. How I treat monoclonal gammopathy of renal significance (MGRS)? Blood 2013; 122:3583-90. 4. Mariette X, Zagdanski AM, Guermazi A, et al. Prognostic value of vertebral lesions detected by magnetic resonance imaging in patients with stage I multiple myeloma. Br J Haematol 1999; 104:723-9. 5. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010; 28:1606-10. 6. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008; 113:1588-95. 7. D’Arena G, Gobbi PG, Broglia C, et al. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma 2011; 52:771-5. 8. Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117:5573-81. 9. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12:335-48. 10. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013; 369:438-47. 11. Hernán MA, Hernández-Díaz S. Beyond the intention-to-treat in comparative effectiveness research. Clin Trials 2012; 9:48-55. 12. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010; 24:1121-7.
Clinical Lymphoma, Myeloma & Leukemia February 2014
-7
