SPECIAL FOCUS y The comprehensive clinical management of MM
Review
Response evaluation and monitoring of multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by Michigan University on 10/10/14 For personal use only.
Expert Rev. Hematol. 7(1), 33–42 (2014)
Carlos Ferna´ndez de Larrea1, Michel Delforge2, Faith Davies3 and Joan Blade´*1 1 Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clı´nic de Barcelona, Institut d’Investigacions Biome`diques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain 2 Department of Hematology, University Hospital Leuven, Leuven, Belgium 3 Department of Haemato-oncology, Royal Marsden Hospital, London, UK *Author for correspondence: Tel.: +34 932 275 428 Fax: +34 932 275 484 [email protected]
informahealthcare.com
Monitoring multiple myeloma (MM) is essential during the evaluation of response to each therapy line, after transplantation and at the time of relapse or progression in all patients. An initial complete workup, including appropriate protein studies in serum and urine is mandatory. The use of uniform criteria is particularly important in the context of clinical trials. Complete remission (CR) definition, the goal for the majority of patients, is now in constant evolution, with immunophenotypic and molecular minimal residual disease measurement in bone marrow as well as imaging techniques. Identification of relapse/progression with traditional and novel techniques for eventual prompt intervention with rescue treatment is a current issue of debate. KEYWORDS: complete remission . criteria . evaluation . myeloma . progression . relapse . response
Multiple myeloma (MM) is the prototype of malignant plasma cell dyscrasias [1,2], where plasma cell tumor proliferation, the amount of paraprotein and the associated immunodeficiency result in the characteristic clinicalbiological picture. As in other hematological malignancies, such as acute leukemia or lymphoproliferative disorders [3,4], MM requires the identification of criteria for monitoring the response to treatment and to identify potential disease-related complications. This issue is crucial when reporting the results of clinical trials, in an attempt to properly compare the results across studies [5]. The measurableness of the disease is a critical point, impacting the potential inclusion in clinical trials and the routine follow-up of patients in daily clinical practice. Historically, response criteria [6–11] to be discussed in this review had been mainly based on the relative and absolute changes of M-spike and plasmacytoma size. Most of the patients, particularly at diagnosis, will have measurable disease in serum and/or urine, defined by at least 10 g/l and/or light chain urine protein excretion higher than 200 mg/24 h. Therefore, monitoring of the paraprotein is mandatory in patients with a secretory monoclonal gammopathy. Others will have oligosecretory disease, under these thresholds but with positive immunofixation
10.1586/17474086.2014.876899
electrophoresis (IFE), as the usual serum and urine electrophoresis assays can be inadequate. Truly non-secretory myelomas are characterized by the absence of any detectable monoclonal proteins in serum and urine, but they are rare [12,13]. Nowadays, symptomatic MM is still diagnosed on the basis of symptoms and signs derived from organ or tissue impairment due to M-protein or plasma cell proliferation. This end-organ damage includes hypercalcemia, renal failure, anemia and bone (CRAB) manifestations that are felt related to a plasma cell proliferative disorder and not explained by another unrelated disease [14]. These characteristics are summarized in BOX 1. These clinical elements will be also fundamental in the diagnosis of symptomatic progression or relapse. A new proposal with an evidence-based approach using more sensitive and highly specific biomarkers to update the definition of MM are under development [15]. Diagnosis, response criteria and follow-up standards on primary AL amyloidosis, associated or not with MM, are described elsewhere in this monograph, so it is not discussed in this article. In the present review, we will focus on the disease monitoring in MM in four sections: initial diagnostic/staging work-up; response
2014 Informa UK Ltd
ISSN 1747-4086
33
Review
´ ndez de Larrea, Delforge, Davies & Blade ´ Ferna
Box 1. Myeloma-related organ or tissue impairment (end-organ damage) due to the plasma cell proliferative process. . . . .
Expert Review of Hematology Downloaded from informahealthcare.com by Michigan University on 10/10/14 For personal use only.
.
Increased serum calcium (>11.5 mg/dl) Renal insufficiency (creatinine >2 mg/dl) Anemia: hemoglobin 2 g/dl below the lower normal limit Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Other: symptomatic hyperviscosity (rare), amyloidosis, recurrent bacterial infections (‡episodes in 12 months), extramedullary plasmacytomas.
CRAB: Calcium, renal insufficiency, anemia or bone lesions.
evaluation, including the evolving concept of complete remission (CR); follow-up during treatment and treatment-free intervals and, finally, monitoring at progression or relapse. Initial diagnostic work-up
The initial diagnostic work-up in patients with MM is summarized in BOX 2. Particular attention should be focused on: establishing the baseline values (serum and/or urine M-protein, plasma cell infiltration, serum free light chain [FLC], extramedullary plasmacytomas) of the indicator(s) for follow-up during treatment; presence and degree of end-organ damage, mainly summarized under the acronym CRAB and other clinical myeloma-related manifestations; risk-stratification of the disease (useful for further decisions) and identification of potential limitations for certain drug regimens. Serum and urine total protein and both electrophoresis are crucial in order to establish in a quantitative manner the M-spike, as well as IFE for determining the specific light and heavy chain constituting the Box 2. Initial studies for patients with multiple myeloma. .
.
. . . . . .
.
.
. .
Complete blood count and differential; peripheral blood smear Biochemistry, including calcium, creatinine, b2-microglobulin and lactate dehydrogenase Serum protein electrophoresis 24 h urine collection for protein electrophoresis Total immunoglobulin quantification (nephelometry) Serum and urine IFE Measurement of serum free light chains Radiological skeletal bone survey including spine, pelvis and skull Bone marrow aspirate and/or biopsy; morphology and immunophenotype Bone marrow plasma cells cytogenetics (metaphase karyotype and FISH) CT scan and/or MRI if clinically indicated PET/CT investigational; useful if extramedullay plasmacytomas
IFE: Immunofixation electrophoresis.
34
monoclonal component. Careful examination of peripheral blood by conventional microscopy should be done in all patients with MM to rule out primary plasma cell leukemia (PCL). Present criteria include more than 20% and/or an absolute count greater than 2 109/l circulating plasma cells [16]. However, lower peripheral blood plasma cell counts should be recorded to revisit the diagnostic criteria of PCL nowadays [17]. Several imaging techniques can be used for the assessment of bone and soft-tissue disease in MM, and a consensus statement of guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of MM by the International Myeloma Working Group (IMWG) has been published [18]. Some recommendations have been summarized and updated in even more recent criteria [19]. The skeletal survey remains the standard method for imaging screening at diagnosis, is readily available and with modest cost, although its limitations in sensitivity must be noted. MRI or computed tomography (CT) should be performed when extramedullary involvement is suspected (i.e., non-skeletal severe localized pain, palpable masses or suspected nervous system involvement [spinal cord compression or cranial nerve palsies]). An MRI of the spine and pelvis is mandatory in all patients with a presumed diagnosis of solitary plasmacytoma of bone, spinal cord compression as well as pre-kypho or vertebroplasty. It may also be of value in cases of non-secretory myeloma. Low-dose CT is a promising tool to detect bone lesions at diagnosis of monoclonal gammopathy, but to date has not been used for response evaluation yet [20]. [18F]Fuorodeoxyglucose PET/CT may be particularly useful in extramedullary disease evaluation [21], allowing the measurement in size and metabolic activity of soft-tissue masses, similarly to the lymphoma experience. Its use in patients with solitary plasmacytoma of bone and in those with at least one extramedullary location is still investigational [22]. Evaluating response in multiple myeloma Response criteria
The evolution of the response monitoring in MM began in the 60s, when there was an attempt to measure response, based on the reduction of more than 15 g/l in the serum M-protein or an increase in more than 2 g/dl of hemoglobin [6]. Subsequently, few years later it was proposed to define response in this disease as at least 50% decrease in the monoclonal component and also a decrease in plasmacytomas size, considering extramedullary disease as an essential part of any evaluation of the response for the first time [7]. The Southwest Cancer Chemotherapy Study Group (SWOG) also established criteria, taking into account the decrease in the synthetic index of serum M-protein and light-chain urine protein excretion, as well as hypoalbuminemia and anemia correction [8]. Based on mathematical models, according to the equation of Smith and Salmon, it was also estimated that the response should be established when a 75% decrease in the synthesis of M-protein was reached [9]. However, this approach was only applicable for patients with involvement of the heavy chain isotype IgG. At that time, CRs were rare and the prognosis of patients with Expert Rev. Hematol. 7(1), (2014)
Response evaluation & monitoring of MM
Review
Expert Review of Hematology Downloaded from informahealthcare.com by Michigan University on 10/10/14 For personal use only.
Table 1. Historical evolution of main diagnostic criteria (1962–1998). Response criteria
Criteria
Mass (1962)
Reduction of more than 15 g/l in the serum M-protein or increased in more than 20 g/l of hemoglobin
[6]
Chronic Leukemia – Myeloma Task Force (1968 and 1973)
One or more of the following: Serum M-protein: reduction to 50% or less of the pre-treatment value Urinary M-protein: decrease to 50% or less of the pre-treatment value if the amount was greater than 1 g/24 h Reduction of 50% or more in the product of the two largest diameters of palpable or X-ray visualized plasmacytomas Radiographic evidence of skeletal healing
[7]
Southwest Cancer Chemotherapy Study Group (1972)
All of the following criteria sustained for at least 2 months: Decrease in the synthetic index of serum M-protein to 25% or less of the pre-treatment value and to less than 25 g/l Decrease in light-chain urine protein excretion to less than 10% of the pre-treatment value and to less than 0.2 g/24 h Improvement in bone pain and performance status In all responsive patients the size and number of lytic skull lesions must not increase and serum calcium remain within normal limits Correction of anemia (Hb >9 g/dl, and hypoalbuminemia (>30 g/l) if they are considered to be secondary to myeloma
[8]
MM was usually very poor. It was not until the end of the 90s when a new and almost universal system was adopted. TABLE 1 describes the historical evolution of these response criteria. The main key milestone in the history of the assessment of response to treatment is the publication of the European Group for Blood and Marrow Transplantation (EBMT) group criteria [10], as shown in TABLE 2. For the first time, CR in the MM was defined as the disappearance of the M-protein by serum and urine IFE, along with the disappearance of plasmacytomas and normal numbers of bone marrow plasma cells (BMPCs). These three elements (serum and urine component, medullary disease and extramedullary involvement) constitute the basis of MM response evaluation in this review, and have also been used in most MM clinical trials during the last 15 years. Briefly, CR requires the disappearance of the original myeloma protein in serum and urine IFE, confirmed by less than 5% BMPCs. Partial response (PR) requires a serum M-protein decrease of 50% or more and a urine M-protein decrease ‡90% or more, and/or to
Review
Response evaluation and monitoring of multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by Michigan University on 10/10/14 For personal use only.
Expert Rev. Hematol. 7(1), 33–42 (2014)
Carlos Ferna´ndez de Larrea1, Michel Delforge2, Faith Davies3 and Joan Blade´*1 1 Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clı´nic de Barcelona, Institut d’Investigacions Biome`diques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain 2 Department of Hematology, University Hospital Leuven, Leuven, Belgium 3 Department of Haemato-oncology, Royal Marsden Hospital, London, UK *Author for correspondence: Tel.: +34 932 275 428 Fax: +34 932 275 484 [email protected]
informahealthcare.com
Monitoring multiple myeloma (MM) is essential during the evaluation of response to each therapy line, after transplantation and at the time of relapse or progression in all patients. An initial complete workup, including appropriate protein studies in serum and urine is mandatory. The use of uniform criteria is particularly important in the context of clinical trials. Complete remission (CR) definition, the goal for the majority of patients, is now in constant evolution, with immunophenotypic and molecular minimal residual disease measurement in bone marrow as well as imaging techniques. Identification of relapse/progression with traditional and novel techniques for eventual prompt intervention with rescue treatment is a current issue of debate. KEYWORDS: complete remission . criteria . evaluation . myeloma . progression . relapse . response
Multiple myeloma (MM) is the prototype of malignant plasma cell dyscrasias [1,2], where plasma cell tumor proliferation, the amount of paraprotein and the associated immunodeficiency result in the characteristic clinicalbiological picture. As in other hematological malignancies, such as acute leukemia or lymphoproliferative disorders [3,4], MM requires the identification of criteria for monitoring the response to treatment and to identify potential disease-related complications. This issue is crucial when reporting the results of clinical trials, in an attempt to properly compare the results across studies [5]. The measurableness of the disease is a critical point, impacting the potential inclusion in clinical trials and the routine follow-up of patients in daily clinical practice. Historically, response criteria [6–11] to be discussed in this review had been mainly based on the relative and absolute changes of M-spike and plasmacytoma size. Most of the patients, particularly at diagnosis, will have measurable disease in serum and/or urine, defined by at least 10 g/l and/or light chain urine protein excretion higher than 200 mg/24 h. Therefore, monitoring of the paraprotein is mandatory in patients with a secretory monoclonal gammopathy. Others will have oligosecretory disease, under these thresholds but with positive immunofixation
10.1586/17474086.2014.876899
electrophoresis (IFE), as the usual serum and urine electrophoresis assays can be inadequate. Truly non-secretory myelomas are characterized by the absence of any detectable monoclonal proteins in serum and urine, but they are rare [12,13]. Nowadays, symptomatic MM is still diagnosed on the basis of symptoms and signs derived from organ or tissue impairment due to M-protein or plasma cell proliferation. This end-organ damage includes hypercalcemia, renal failure, anemia and bone (CRAB) manifestations that are felt related to a plasma cell proliferative disorder and not explained by another unrelated disease [14]. These characteristics are summarized in BOX 1. These clinical elements will be also fundamental in the diagnosis of symptomatic progression or relapse. A new proposal with an evidence-based approach using more sensitive and highly specific biomarkers to update the definition of MM are under development [15]. Diagnosis, response criteria and follow-up standards on primary AL amyloidosis, associated or not with MM, are described elsewhere in this monograph, so it is not discussed in this article. In the present review, we will focus on the disease monitoring in MM in four sections: initial diagnostic/staging work-up; response
2014 Informa UK Ltd
ISSN 1747-4086
33
Review
´ ndez de Larrea, Delforge, Davies & Blade ´ Ferna
Box 1. Myeloma-related organ or tissue impairment (end-organ damage) due to the plasma cell proliferative process. . . . .
Expert Review of Hematology Downloaded from informahealthcare.com by Michigan University on 10/10/14 For personal use only.
.
Increased serum calcium (>11.5 mg/dl) Renal insufficiency (creatinine >2 mg/dl) Anemia: hemoglobin 2 g/dl below the lower normal limit Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Other: symptomatic hyperviscosity (rare), amyloidosis, recurrent bacterial infections (‡episodes in 12 months), extramedullary plasmacytomas.
CRAB: Calcium, renal insufficiency, anemia or bone lesions.
evaluation, including the evolving concept of complete remission (CR); follow-up during treatment and treatment-free intervals and, finally, monitoring at progression or relapse. Initial diagnostic work-up
The initial diagnostic work-up in patients with MM is summarized in BOX 2. Particular attention should be focused on: establishing the baseline values (serum and/or urine M-protein, plasma cell infiltration, serum free light chain [FLC], extramedullary plasmacytomas) of the indicator(s) for follow-up during treatment; presence and degree of end-organ damage, mainly summarized under the acronym CRAB and other clinical myeloma-related manifestations; risk-stratification of the disease (useful for further decisions) and identification of potential limitations for certain drug regimens. Serum and urine total protein and both electrophoresis are crucial in order to establish in a quantitative manner the M-spike, as well as IFE for determining the specific light and heavy chain constituting the Box 2. Initial studies for patients with multiple myeloma. .
.
. . . . . .
.
.
. .
Complete blood count and differential; peripheral blood smear Biochemistry, including calcium, creatinine, b2-microglobulin and lactate dehydrogenase Serum protein electrophoresis 24 h urine collection for protein electrophoresis Total immunoglobulin quantification (nephelometry) Serum and urine IFE Measurement of serum free light chains Radiological skeletal bone survey including spine, pelvis and skull Bone marrow aspirate and/or biopsy; morphology and immunophenotype Bone marrow plasma cells cytogenetics (metaphase karyotype and FISH) CT scan and/or MRI if clinically indicated PET/CT investigational; useful if extramedullay plasmacytomas
IFE: Immunofixation electrophoresis.
34
monoclonal component. Careful examination of peripheral blood by conventional microscopy should be done in all patients with MM to rule out primary plasma cell leukemia (PCL). Present criteria include more than 20% and/or an absolute count greater than 2 109/l circulating plasma cells [16]. However, lower peripheral blood plasma cell counts should be recorded to revisit the diagnostic criteria of PCL nowadays [17]. Several imaging techniques can be used for the assessment of bone and soft-tissue disease in MM, and a consensus statement of guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of MM by the International Myeloma Working Group (IMWG) has been published [18]. Some recommendations have been summarized and updated in even more recent criteria [19]. The skeletal survey remains the standard method for imaging screening at diagnosis, is readily available and with modest cost, although its limitations in sensitivity must be noted. MRI or computed tomography (CT) should be performed when extramedullary involvement is suspected (i.e., non-skeletal severe localized pain, palpable masses or suspected nervous system involvement [spinal cord compression or cranial nerve palsies]). An MRI of the spine and pelvis is mandatory in all patients with a presumed diagnosis of solitary plasmacytoma of bone, spinal cord compression as well as pre-kypho or vertebroplasty. It may also be of value in cases of non-secretory myeloma. Low-dose CT is a promising tool to detect bone lesions at diagnosis of monoclonal gammopathy, but to date has not been used for response evaluation yet [20]. [18F]Fuorodeoxyglucose PET/CT may be particularly useful in extramedullary disease evaluation [21], allowing the measurement in size and metabolic activity of soft-tissue masses, similarly to the lymphoma experience. Its use in patients with solitary plasmacytoma of bone and in those with at least one extramedullary location is still investigational [22]. Evaluating response in multiple myeloma Response criteria
The evolution of the response monitoring in MM began in the 60s, when there was an attempt to measure response, based on the reduction of more than 15 g/l in the serum M-protein or an increase in more than 2 g/dl of hemoglobin [6]. Subsequently, few years later it was proposed to define response in this disease as at least 50% decrease in the monoclonal component and also a decrease in plasmacytomas size, considering extramedullary disease as an essential part of any evaluation of the response for the first time [7]. The Southwest Cancer Chemotherapy Study Group (SWOG) also established criteria, taking into account the decrease in the synthetic index of serum M-protein and light-chain urine protein excretion, as well as hypoalbuminemia and anemia correction [8]. Based on mathematical models, according to the equation of Smith and Salmon, it was also estimated that the response should be established when a 75% decrease in the synthesis of M-protein was reached [9]. However, this approach was only applicable for patients with involvement of the heavy chain isotype IgG. At that time, CRs were rare and the prognosis of patients with Expert Rev. Hematol. 7(1), (2014)
Response evaluation & monitoring of MM
Review
Expert Review of Hematology Downloaded from informahealthcare.com by Michigan University on 10/10/14 For personal use only.
Table 1. Historical evolution of main diagnostic criteria (1962–1998). Response criteria
Criteria
Mass (1962)
Reduction of more than 15 g/l in the serum M-protein or increased in more than 20 g/l of hemoglobin
[6]
Chronic Leukemia – Myeloma Task Force (1968 and 1973)
One or more of the following: Serum M-protein: reduction to 50% or less of the pre-treatment value Urinary M-protein: decrease to 50% or less of the pre-treatment value if the amount was greater than 1 g/24 h Reduction of 50% or more in the product of the two largest diameters of palpable or X-ray visualized plasmacytomas Radiographic evidence of skeletal healing
[7]
Southwest Cancer Chemotherapy Study Group (1972)
All of the following criteria sustained for at least 2 months: Decrease in the synthetic index of serum M-protein to 25% or less of the pre-treatment value and to less than 25 g/l Decrease in light-chain urine protein excretion to less than 10% of the pre-treatment value and to less than 0.2 g/24 h Improvement in bone pain and performance status In all responsive patients the size and number of lytic skull lesions must not increase and serum calcium remain within normal limits Correction of anemia (Hb >9 g/dl, and hypoalbuminemia (>30 g/l) if they are considered to be secondary to myeloma
[8]
MM was usually very poor. It was not until the end of the 90s when a new and almost universal system was adopted. TABLE 1 describes the historical evolution of these response criteria. The main key milestone in the history of the assessment of response to treatment is the publication of the European Group for Blood and Marrow Transplantation (EBMT) group criteria [10], as shown in TABLE 2. For the first time, CR in the MM was defined as the disappearance of the M-protein by serum and urine IFE, along with the disappearance of plasmacytomas and normal numbers of bone marrow plasma cells (BMPCs). These three elements (serum and urine component, medullary disease and extramedullary involvement) constitute the basis of MM response evaluation in this review, and have also been used in most MM clinical trials during the last 15 years. Briefly, CR requires the disappearance of the original myeloma protein in serum and urine IFE, confirmed by less than 5% BMPCs. Partial response (PR) requires a serum M-protein decrease of 50% or more and a urine M-protein decrease ‡90% or more, and/or to
