Clinical Outcomes in t(4;14) Multiple Myeloma: A Chemotherapy-Sensitive Disease Characterized by Rapid Relapse and Alkylating Agent Resistan
http://www.100md.com
《临床肿瘤学》
the Department of Medical Oncology and Hematology
Department of Laboratory Medicine and Pathobiology, Princess Margaret Hospital/University Health Network
McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Canada
ABSTRACT
PURPOSE: To determine whether primary drug resistance or rapid relapse explains the poor prognosis seen in t(4;14)-positive multiple myeloma (MM).
PATIENTS AND METHODS: A total of 131 patients treated with high-dose therapy (HDT) were assessed, of whom 19 were t(4;14) positive. We examined the presentation features, chemotherapy responsiveness at presentation and to salvage therapies at relapse, and overall survival outcomes.
RESULTS: t(4;14)-positive patients had a predominance of the immunoglobulin A isotype (52.6%) but otherwise baseline characteristics were indistinguishable. After treatment with vincristine, doxorubicin, and dexamethasone or dexamethasone alone, 17 (89.7%) of the 19 patients achieved a partial response and 11 patients (57.9%) demonstrated an additional 50% reduction in paraprotein after HDT. Thus, t(4;14)-positive patients are chemotherapy sensitive; however, early progression was common, with 26% of patients progressing before HDT and a median progression-free survival after HDT of only 14.1 months. At relapse, a resistance to alkylating agents was evident, with no responses (zero of 11 patients) seen with conventional-dose alkylating agents. Salvage regimens using thalidomide and/or dexamethasone achieved at least minimal response in 59% of patients. The duration of response was short, however, with a median of only 4.7 months. The median overall survival after HDT was 24.2 months.
CONCLUSION: We conclude that t(4;14)-positive MM is chemotherapy sensitive but rapid relapse occurs. Resistance to alkylating agents is evident at relapse. The development of novel therapeutic agents is required, including the early clinical study of targeted fibroblast growth factor receptor 3 tyrosine kinase inhibitors, which have shown promise in preclinical studies.
INTRODUCTION
Multiple myeloma (MM) is an incurable plasma cell dyscrasia characterized by recurrent chromosomal translocations involving the immunoglobulin heavy-chain (IgH) locus, believed to arise during isotype-class switching.1 Identified translocations involve several partner genes including cyclin D1,2 cyclin D3,3 fgfr3-mmset,4 c-maf, 5 and mafB.6 The t(4;14)(p16.3;q32.3) translocation simultaneously dysregulates expression of fibroblast growth factor receptor 3 (FGFR3) on the der(14) and MMSET on the der(4).7 The t(4;14) translocation is found in 15% of patients with MM and has been documented in patients with monoclonal gammopathy of undetermined significance, thus likely representing an early event in MM pathogenesis.8
IgH translocations appear to confer a unique clinical outcome.9 The t(4;14) translocation, in particular, is reported as a poor prognostic factor for event-free and overall survival in MM patients treated with either conventional or intensive chemotherapy.9–12 The reasons underpinning this poor clinical outcome have not yet been defined. Presumably, either primary drug resistance or, alternatively, rapid relapse after treatment must explain this outcome. To address this clinical issue, we analyzed the presentation features, chemotherapy responsiveness, and survival outcomes of 19 patients with t(4;14)-positive MM treated at our center.
PATIENTS AND METHODS
Patient Identification and Characterization
Using cytoplasmic immunoglobulin-enhanced interphase fluorescent in situ hybridization (i-FISH), we identified 19 patients with t(4;14)-positive MM from a homogeneous test population of 131 patients diagnosed and treated with high-dose chemotherapy followed by autologous stem-cell transplantation at the Princess Margaret Hospital/University Health Network (Toronto, Canada) between January 1998 and December 2002. Pretreatment evaluation included complete blood counts, biochemical tests for renal and liver function tests, electrophoresis of serum and urine, and analysis of beta2-microglobulin and C-reactive protein. Bone marrow aspirates were assessed to determine the percentage of bone marrow plasma cells by morphology. A radiologic skeletal survey was performed to assess the presence of bone disease, with a computed tomography or magnetic resonance imaging (MRI) scan performed if clinically indicated.
Patient Treatment
Sixteen t(4;14)-positive patients presented with newly diagnosed disease, of whom 14 patients received induction with four to five cycles of vincristine, doxorubicin, and dexamethasone (VAD), and two patients received pulsed dexamethasone alone. Three patients presented with relapsed disease, with one patient receiving reinduction with VAD and two patients receiving thalidomide alone. Subsequently, all patients had stem cells mobilized with cyclophosphamide 2.5 g/m2 and granulocyte colony-stimulating factor 10 μg/kg followed by one course of melphalan 200 mg/m2 as intensive chemotherapy before autologous stem-cell transplantation (ASCT). The median duration from diagnosis to transplantation was 9.8 months. The three patients presenting at the time of relapse underwent transplantation 35, 44, and 132 months after initial diagnosis, respectively. At relapse after ASCT, patients were treated with a number of salvage regimens and the response to these therapies was analyzed.
Cytoplasmic Ig i-FISH
After Institutional Research Review Board (University Health Network, Toronto, Canada) approval, i-FISH was performed on bone marrow samples obtained at the time of active disease. The probes used were IgH (14q32.3), a Bac probe (158A2) covering the IgH joint and constant regions (provided by H. Avet-Loiseau, MD),13 and a 22-kb FGFR3 segment in a cosmid vector obtained from P.L. Bergsagel, MD.7 The methodology has been described previously.10 The i-FISH probes were validated on MM cell line NCI-H929. A fusion signal with colocalization of two different colored signals was expected if a cell carried a translocation. Patients were considered assessable if at least 100 clonal plasma cells from each slide could be scored. Two independent scorers evaluated a total of 200 cells per sample. The background cutoff level was set at 10% for all of the probe sets.
Outcome Analysis
The response to induction chemotherapy, high-dose melphalan therapy with ASCT, and salvage treatments at relapse were assessed using modified Blade criteria.14 A minimal response (MR) required a 25% to 49% reduction, a partial response (PR) required a 50% to 90% reduction, and a very good partial response (VGPR) required a greater than 90% reduction in monoclonal protein. Immunofixation was not done on all relevant samples; therefore, complete response (CR) with negative immunofixation could not be determined. Progressive disease was defined as a greater than 25% increase in the level of serum monoclonal protein, with an absolute increase of at least 5 g/L. Progression-free survival and overall survival were calculated from the time of ASCT by the Kaplan-Meier method. Duration of response to salvage therapy was calculated from the commencement of treatment to the time of evidence of progression.
RESULTS
The main clinical and biologic features of t(4;14) patients are listed in Table 1. t(4;14)-positive patients had a predominance of the IgA isotype (52.6%) compared with t(4;14)-negative patients (17.7%). Of the 28 patients with the IgA isotype, 10 patients (35.7%) were t(4;14) positive. Otherwise baseline characteristics including sex, age, beta2-microglobulin, C-reactive protein, calcium, creatinine, hemoglobin, albumin, or percentage of bone marrow cells were indistinguishable from those of t(4;14)-negative patients. This comparison of baseline characteristics has been published previously.10 Sixteen patients (84.2%) had bone lytic lesions or fractures on radiologic skeletal survey at presentation, confirmed with computed tomography or MRI scan in eight patients. One patient presented with renal failure and required dialysis therapy.
Induction Therapy and ASCT Responses
Seventeen of the nineteen (89.7%) t(4;14)-positive patients responded to induction chemotherapy and experienced a greater than 50% reduction in the paraprotein. Four patients (21%) achieved a VGPR (> 90% reduction), 13 patients (68%) achieved a PR (50% to 90% reduction), one patient achieved an MR (25% to 49% reduction), and one patient did not experience significantly reduced paraprotein. The mean reduction in paraprotein from baseline was 70.8% (range, 11% to 99%). Thus, this is a highly chemotherapy-sensitive population. However, five (26.3%) of these 19 patients demonstrated early progression of disease (greater than 25% increase in monoclonal paraprotein, with an absolute increase of at least 5 g/L) during later cycles of VAD or during stem-cell collection and required additional salvage therapy before ASCT.
Use of high-dose melphalan and ASCT resulted in an additional 57.9% of patients achieving a greater than 50% paraprotein decrease, with a mean paraprotein reduction from presentation of 81.2% (range, 39% to 99%). From presentation, nine patients (47.4%) achieved a VGPR, eight patients (42.1%) achieved a PR, and two patients achieved an MR. Despite this impressive initial response to induction therapy and ASCT, there was early progression of disease, with a median progression-free survival from the time of ASCT of only 14.1 months (Fig 1). This was significantly shorter than for t(4;14)-negative patients, who had a median progression-free survival of 25.8 months (P = .0003).
Response to Salvage Therapy
Given the surprisingly short progression-free survival after chemotherapy with a high-dose alkylating agent, we next examined all salvage regimens used. A number of patients received more than one salvage regimen (Table 2). Eleven patients received a regimen based on a conventional-dose alkylating agent as salvage (cyclophosphamide or melphalan). The response was poor, with stable disease in seven patients and progressive disease in four patients. In contrast, 17 patients at some point received salvage thalidomide or high-dose dexamethasone, either as a single agent or in combination. Seven patients demonstrated a partial response (> 50% to 90% paraprotein reduction), three patients demonstrated a minor response (25% to 49% reduction), and seven patients had stable disease, for an overall response rate of 59% (partial response plus minor response). Nevertheless, of the 10 patients who responded to thalidomide, dexamethasone, or a combination of both drugs, the median duration of response was only 4.7 months (range, 1.3 to 23.5 months; Fig 2). One patient achieved a partial response to bortezomib, with a duration of response of 11.5 months. The median overall survival for t(4;14)-positive patients from the time of ASCT was only 24.2 months (Fig 3).
DISCUSSION
More than 60% of MM patients are characterized by chromosomal translocations involving the IgH locus at 14q32.9,15 The t(4;14) translocation is unusual because it dysregulates two potential oncogenes, fgfr3 and mmset. The exact role of each of these genes in the pathogenesis and adverse prognosis of MM is yet to be fully elucidated; however, there are several lines of evidence that MMSET may be required absolutely for myeloma initiation, and that the overexpression of FGFR3 associated with t(4;14) is involved in subsequent tumor progression.11,16 For example, acquisition of activating mutations of FGFR3 in some MM patients is associated with progression and is strongly transforming in experimental models.17–19 Additional genetic evidence suggests that FGFR3 may be dispensable11,16; however, the der(4)-containing MMSET is never lost, suggesting that it is biologically and clinically relevant. The possible contributory role of MMSET dysregulation in the adverse prognosis of t(4;14)-positive MM is supported by the persistent adverse prognosis seen in t(4;14) MM patients who lacked FGFR3 expression.11
In this study, we evaluated the outcome of 19 t(4;14)-positive MM patients identified by i-FISH, treated with high-dose chemotherapy followed by ASCT. The baseline characteristics of these patients were similar to those of t(4;14)-negative patients except for an increase in the IgA isotype. The presence of bone lytic lesions or crush fractures in 16 patients (84.2%) is in keeping with the finding by Nakazawa20 of an association between lytic bone lesions and an overexpression of FGFR3; however, others did not find such a high incidence of bone lesions.9,21 In fact, Robbiani22 reported the presence of at least one lesion on MRI scan in 57% of 28 t(4;14)-positive patients, which is substantially lower than the findings in this study. The reasons for these differences are unclear but suggest that additional study is required to define the characteristics of MM molecular subtypes clearly.
Although frequent (89.7%) responses to induction therapy and high-dose melphalan were the norm, the aggressive nature of t(4;14)-positive myeloma is evident with early progression of disease in five patients before ASCT, and a short median progression-free survival after high-dose melphalan of only 14.1 months.
The outcome of salvage therapy at relapse suggests an inherent resistance to alkylating agents (zero of 11 patients responding). The higher responses seen with thalidomide and/or dexamethasone are encouraging, but the duration of response was short, with a median progression-free survival of only 4.7 months. However, notably, some patients demonstrated durable responses to thalidomide-based therapy, with responses lasting 21 and 23.8 months in two patients, respectively, both receiving thalidomide and prednisone in combination. The clinical response to dexamethasone is in contrast to our in vitro data reporting murine B-cell lines that overexpress FGFR3 demonstrate resistance to dexamethasone.23
this preliminary analysis we conclude that t(4;14)-positive MM is poorly responsive to alkylating agents, including high-dose melphalan, and thus the use of these agents, including ASCT, is possibly of no long-term value in this patient population. Given the high response rates of 78% at induction and 73% at salvage, the use of salvage regimens containing high-dose dexamethasone and/or thalidomide are favored at the time of relapse. Nevertheless, because response to these agents is short-lived, novel therapeutic regimens are required. Anecdotal evidence suggests that response to Bortezomib is high (P.L. Bergsagel, personal communication, May 2005); however, long-term remission rates are not known. Preclinical studies have validated FGFR3 as a therapeutic target in t(4;14) positive MM24–26 and a candidate small-molecule inhibitor has been identified for future clinical evaluation.27 Whether MMSET, which has homology to histone methyl transferases, also represents a novel therapeutic target in t(4;14) positive MM remains to be determined. The classification of molecular subtypes is needed in MM studies to determine the optimal therapeutic approach in this poor-risk MM subtype.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grants from the Multiple Myeloma Research Foundation, the National Cancer Institute of Canada, and the Canadian Institutes for Health Research.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Bergsagel PL, Kuehl WM: Chromosome translocations in multiple myeloma. Oncogene 20:5611-5622, 2001
Chesi M, Bergsagel PL, Brents LA, et al: Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88:674-681, 1996
Shaughnessy J Jr, Gabrea A, Qi Y, et al: Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 98:217-223, 2001
Chesi M, Nardini E, Lim RS, et al: The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92:3025-3034, 1998
Chesi M, Bergsagel PL, Shonukan OO, et al: Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457-4463, 1998
Hanamura I, Iida S, Akano Y, et al: Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations. Jpn J Cancer Res 92:638-644, 2001
Chesi M, Nardini E, Brents LA, et al: Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16:260-264, 1997
Avet-Loiseau H, Facon T, Grosbois B, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99:2185-2191, 2002
Fonseca R, Blood E, Rue M, et al: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101:4569-4575, 2003
Chang H, Sloan S, Li D, et al: The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 125:64-68, 2004
Keats JJ, Reiman T, Maxwell CA, et al: In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101:1520-1529, 2003
Moreau P, Facon T, Leleu X, et al: Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100:1579-1583, 2002
Avet-Loiseau H, Brigaudeau C, Morineau N, et al: High incidence of cryptic translocations involving the Ig heavy chain gene in multiple myeloma, as shown by fluorescence in situ hybridization. Genes Chromosomes Cancer 24:9-15, 1999
Blade J, Samson D, Reece D, et al: Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT—European Group for Blood and Marrow Transplant. Br J Haematol 102:1115-1123, 1998
Nishida K, Tamura A, Nakazawa N, et al: The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood 90:526-534, 1997
Santra M, Zhan F, Tian E, et al: A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101:2374-2376, 2003
Chesi M, Brents LA, Ely SA, et al: Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97:729-736, 2001
Plowright EE, Li Z, Bergsagel PL, et al: Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 95:992-998, 2000
Li Z, Zhu YX, Plowright EE, et al: The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 97:2413-2419, 2001
Nakazawa N, Nishida K, Tamura A, et al: Interphase detection of t(4;14)(p16.3;q32.3) by in situ hybridization and FGFR3 overexpression in plasma cell malignancies. Cancer Genet Cytogenet 117:89-96, 2000
Sibley K, Fenton JA, Dring AM, et al: A molecular study of the t(4;14) in multiple myeloma. Br J Haematol 118:514-520, 2002
Robbiani DF, Chesi M, Bergsagel PL: Bone lesions in molecular subtypes of multiple myeloma. N Engl J Med 351:197-198, 2004
Pollett JB, Trudel S, Stern D, et al: Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance. Blood 100:3819-3821, 2002
Trudel S, Ely S, Farooqi Y, et al: Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 103:3521-3528, 2004
Paterson JL, Li Z, Wen XY, et al: Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol 124:595-603, 2004
Kuehl WM, Bergsagel PL: Multiple myeloma: Evolving genetic events and host interactions. Nat Rev Cancer 2:175-187, 2002
Trudel S, Li ZH, Wei E, et al: CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105:2941-2948, 2005(Wilfrid Jaksic, Suzanne T)
Department of Laboratory Medicine and Pathobiology, Princess Margaret Hospital/University Health Network
McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Canada
ABSTRACT
PURPOSE: To determine whether primary drug resistance or rapid relapse explains the poor prognosis seen in t(4;14)-positive multiple myeloma (MM).
PATIENTS AND METHODS: A total of 131 patients treated with high-dose therapy (HDT) were assessed, of whom 19 were t(4;14) positive. We examined the presentation features, chemotherapy responsiveness at presentation and to salvage therapies at relapse, and overall survival outcomes.
RESULTS: t(4;14)-positive patients had a predominance of the immunoglobulin A isotype (52.6%) but otherwise baseline characteristics were indistinguishable. After treatment with vincristine, doxorubicin, and dexamethasone or dexamethasone alone, 17 (89.7%) of the 19 patients achieved a partial response and 11 patients (57.9%) demonstrated an additional 50% reduction in paraprotein after HDT. Thus, t(4;14)-positive patients are chemotherapy sensitive; however, early progression was common, with 26% of patients progressing before HDT and a median progression-free survival after HDT of only 14.1 months. At relapse, a resistance to alkylating agents was evident, with no responses (zero of 11 patients) seen with conventional-dose alkylating agents. Salvage regimens using thalidomide and/or dexamethasone achieved at least minimal response in 59% of patients. The duration of response was short, however, with a median of only 4.7 months. The median overall survival after HDT was 24.2 months.
CONCLUSION: We conclude that t(4;14)-positive MM is chemotherapy sensitive but rapid relapse occurs. Resistance to alkylating agents is evident at relapse. The development of novel therapeutic agents is required, including the early clinical study of targeted fibroblast growth factor receptor 3 tyrosine kinase inhibitors, which have shown promise in preclinical studies.
INTRODUCTION
Multiple myeloma (MM) is an incurable plasma cell dyscrasia characterized by recurrent chromosomal translocations involving the immunoglobulin heavy-chain (IgH) locus, believed to arise during isotype-class switching.1 Identified translocations involve several partner genes including cyclin D1,2 cyclin D3,3 fgfr3-mmset,4 c-maf, 5 and mafB.6 The t(4;14)(p16.3;q32.3) translocation simultaneously dysregulates expression of fibroblast growth factor receptor 3 (FGFR3) on the der(14) and MMSET on the der(4).7 The t(4;14) translocation is found in 15% of patients with MM and has been documented in patients with monoclonal gammopathy of undetermined significance, thus likely representing an early event in MM pathogenesis.8
IgH translocations appear to confer a unique clinical outcome.9 The t(4;14) translocation, in particular, is reported as a poor prognostic factor for event-free and overall survival in MM patients treated with either conventional or intensive chemotherapy.9–12 The reasons underpinning this poor clinical outcome have not yet been defined. Presumably, either primary drug resistance or, alternatively, rapid relapse after treatment must explain this outcome. To address this clinical issue, we analyzed the presentation features, chemotherapy responsiveness, and survival outcomes of 19 patients with t(4;14)-positive MM treated at our center.
PATIENTS AND METHODS
Patient Identification and Characterization
Using cytoplasmic immunoglobulin-enhanced interphase fluorescent in situ hybridization (i-FISH), we identified 19 patients with t(4;14)-positive MM from a homogeneous test population of 131 patients diagnosed and treated with high-dose chemotherapy followed by autologous stem-cell transplantation at the Princess Margaret Hospital/University Health Network (Toronto, Canada) between January 1998 and December 2002. Pretreatment evaluation included complete blood counts, biochemical tests for renal and liver function tests, electrophoresis of serum and urine, and analysis of beta2-microglobulin and C-reactive protein. Bone marrow aspirates were assessed to determine the percentage of bone marrow plasma cells by morphology. A radiologic skeletal survey was performed to assess the presence of bone disease, with a computed tomography or magnetic resonance imaging (MRI) scan performed if clinically indicated.
Patient Treatment
Sixteen t(4;14)-positive patients presented with newly diagnosed disease, of whom 14 patients received induction with four to five cycles of vincristine, doxorubicin, and dexamethasone (VAD), and two patients received pulsed dexamethasone alone. Three patients presented with relapsed disease, with one patient receiving reinduction with VAD and two patients receiving thalidomide alone. Subsequently, all patients had stem cells mobilized with cyclophosphamide 2.5 g/m2 and granulocyte colony-stimulating factor 10 μg/kg followed by one course of melphalan 200 mg/m2 as intensive chemotherapy before autologous stem-cell transplantation (ASCT). The median duration from diagnosis to transplantation was 9.8 months. The three patients presenting at the time of relapse underwent transplantation 35, 44, and 132 months after initial diagnosis, respectively. At relapse after ASCT, patients were treated with a number of salvage regimens and the response to these therapies was analyzed.
Cytoplasmic Ig i-FISH
After Institutional Research Review Board (University Health Network, Toronto, Canada) approval, i-FISH was performed on bone marrow samples obtained at the time of active disease. The probes used were IgH (14q32.3), a Bac probe (158A2) covering the IgH joint and constant regions (provided by H. Avet-Loiseau, MD),13 and a 22-kb FGFR3 segment in a cosmid vector obtained from P.L. Bergsagel, MD.7 The methodology has been described previously.10 The i-FISH probes were validated on MM cell line NCI-H929. A fusion signal with colocalization of two different colored signals was expected if a cell carried a translocation. Patients were considered assessable if at least 100 clonal plasma cells from each slide could be scored. Two independent scorers evaluated a total of 200 cells per sample. The background cutoff level was set at 10% for all of the probe sets.
Outcome Analysis
The response to induction chemotherapy, high-dose melphalan therapy with ASCT, and salvage treatments at relapse were assessed using modified Blade criteria.14 A minimal response (MR) required a 25% to 49% reduction, a partial response (PR) required a 50% to 90% reduction, and a very good partial response (VGPR) required a greater than 90% reduction in monoclonal protein. Immunofixation was not done on all relevant samples; therefore, complete response (CR) with negative immunofixation could not be determined. Progressive disease was defined as a greater than 25% increase in the level of serum monoclonal protein, with an absolute increase of at least 5 g/L. Progression-free survival and overall survival were calculated from the time of ASCT by the Kaplan-Meier method. Duration of response to salvage therapy was calculated from the commencement of treatment to the time of evidence of progression.
RESULTS
The main clinical and biologic features of t(4;14) patients are listed in Table 1. t(4;14)-positive patients had a predominance of the IgA isotype (52.6%) compared with t(4;14)-negative patients (17.7%). Of the 28 patients with the IgA isotype, 10 patients (35.7%) were t(4;14) positive. Otherwise baseline characteristics including sex, age, beta2-microglobulin, C-reactive protein, calcium, creatinine, hemoglobin, albumin, or percentage of bone marrow cells were indistinguishable from those of t(4;14)-negative patients. This comparison of baseline characteristics has been published previously.10 Sixteen patients (84.2%) had bone lytic lesions or fractures on radiologic skeletal survey at presentation, confirmed with computed tomography or MRI scan in eight patients. One patient presented with renal failure and required dialysis therapy.
Induction Therapy and ASCT Responses
Seventeen of the nineteen (89.7%) t(4;14)-positive patients responded to induction chemotherapy and experienced a greater than 50% reduction in the paraprotein. Four patients (21%) achieved a VGPR (> 90% reduction), 13 patients (68%) achieved a PR (50% to 90% reduction), one patient achieved an MR (25% to 49% reduction), and one patient did not experience significantly reduced paraprotein. The mean reduction in paraprotein from baseline was 70.8% (range, 11% to 99%). Thus, this is a highly chemotherapy-sensitive population. However, five (26.3%) of these 19 patients demonstrated early progression of disease (greater than 25% increase in monoclonal paraprotein, with an absolute increase of at least 5 g/L) during later cycles of VAD or during stem-cell collection and required additional salvage therapy before ASCT.
Use of high-dose melphalan and ASCT resulted in an additional 57.9% of patients achieving a greater than 50% paraprotein decrease, with a mean paraprotein reduction from presentation of 81.2% (range, 39% to 99%). From presentation, nine patients (47.4%) achieved a VGPR, eight patients (42.1%) achieved a PR, and two patients achieved an MR. Despite this impressive initial response to induction therapy and ASCT, there was early progression of disease, with a median progression-free survival from the time of ASCT of only 14.1 months (Fig 1). This was significantly shorter than for t(4;14)-negative patients, who had a median progression-free survival of 25.8 months (P = .0003).
Response to Salvage Therapy
Given the surprisingly short progression-free survival after chemotherapy with a high-dose alkylating agent, we next examined all salvage regimens used. A number of patients received more than one salvage regimen (Table 2). Eleven patients received a regimen based on a conventional-dose alkylating agent as salvage (cyclophosphamide or melphalan). The response was poor, with stable disease in seven patients and progressive disease in four patients. In contrast, 17 patients at some point received salvage thalidomide or high-dose dexamethasone, either as a single agent or in combination. Seven patients demonstrated a partial response (> 50% to 90% paraprotein reduction), three patients demonstrated a minor response (25% to 49% reduction), and seven patients had stable disease, for an overall response rate of 59% (partial response plus minor response). Nevertheless, of the 10 patients who responded to thalidomide, dexamethasone, or a combination of both drugs, the median duration of response was only 4.7 months (range, 1.3 to 23.5 months; Fig 2). One patient achieved a partial response to bortezomib, with a duration of response of 11.5 months. The median overall survival for t(4;14)-positive patients from the time of ASCT was only 24.2 months (Fig 3).
DISCUSSION
More than 60% of MM patients are characterized by chromosomal translocations involving the IgH locus at 14q32.9,15 The t(4;14) translocation is unusual because it dysregulates two potential oncogenes, fgfr3 and mmset. The exact role of each of these genes in the pathogenesis and adverse prognosis of MM is yet to be fully elucidated; however, there are several lines of evidence that MMSET may be required absolutely for myeloma initiation, and that the overexpression of FGFR3 associated with t(4;14) is involved in subsequent tumor progression.11,16 For example, acquisition of activating mutations of FGFR3 in some MM patients is associated with progression and is strongly transforming in experimental models.17–19 Additional genetic evidence suggests that FGFR3 may be dispensable11,16; however, the der(4)-containing MMSET is never lost, suggesting that it is biologically and clinically relevant. The possible contributory role of MMSET dysregulation in the adverse prognosis of t(4;14)-positive MM is supported by the persistent adverse prognosis seen in t(4;14) MM patients who lacked FGFR3 expression.11
In this study, we evaluated the outcome of 19 t(4;14)-positive MM patients identified by i-FISH, treated with high-dose chemotherapy followed by ASCT. The baseline characteristics of these patients were similar to those of t(4;14)-negative patients except for an increase in the IgA isotype. The presence of bone lytic lesions or crush fractures in 16 patients (84.2%) is in keeping with the finding by Nakazawa20 of an association between lytic bone lesions and an overexpression of FGFR3; however, others did not find such a high incidence of bone lesions.9,21 In fact, Robbiani22 reported the presence of at least one lesion on MRI scan in 57% of 28 t(4;14)-positive patients, which is substantially lower than the findings in this study. The reasons for these differences are unclear but suggest that additional study is required to define the characteristics of MM molecular subtypes clearly.
Although frequent (89.7%) responses to induction therapy and high-dose melphalan were the norm, the aggressive nature of t(4;14)-positive myeloma is evident with early progression of disease in five patients before ASCT, and a short median progression-free survival after high-dose melphalan of only 14.1 months.
The outcome of salvage therapy at relapse suggests an inherent resistance to alkylating agents (zero of 11 patients responding). The higher responses seen with thalidomide and/or dexamethasone are encouraging, but the duration of response was short, with a median progression-free survival of only 4.7 months. However, notably, some patients demonstrated durable responses to thalidomide-based therapy, with responses lasting 21 and 23.8 months in two patients, respectively, both receiving thalidomide and prednisone in combination. The clinical response to dexamethasone is in contrast to our in vitro data reporting murine B-cell lines that overexpress FGFR3 demonstrate resistance to dexamethasone.23
this preliminary analysis we conclude that t(4;14)-positive MM is poorly responsive to alkylating agents, including high-dose melphalan, and thus the use of these agents, including ASCT, is possibly of no long-term value in this patient population. Given the high response rates of 78% at induction and 73% at salvage, the use of salvage regimens containing high-dose dexamethasone and/or thalidomide are favored at the time of relapse. Nevertheless, because response to these agents is short-lived, novel therapeutic regimens are required. Anecdotal evidence suggests that response to Bortezomib is high (P.L. Bergsagel, personal communication, May 2005); however, long-term remission rates are not known. Preclinical studies have validated FGFR3 as a therapeutic target in t(4;14) positive MM24–26 and a candidate small-molecule inhibitor has been identified for future clinical evaluation.27 Whether MMSET, which has homology to histone methyl transferases, also represents a novel therapeutic target in t(4;14) positive MM remains to be determined. The classification of molecular subtypes is needed in MM studies to determine the optimal therapeutic approach in this poor-risk MM subtype.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grants from the Multiple Myeloma Research Foundation, the National Cancer Institute of Canada, and the Canadian Institutes for Health Research.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Bergsagel PL, Kuehl WM: Chromosome translocations in multiple myeloma. Oncogene 20:5611-5622, 2001
Chesi M, Bergsagel PL, Brents LA, et al: Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88:674-681, 1996
Shaughnessy J Jr, Gabrea A, Qi Y, et al: Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 98:217-223, 2001
Chesi M, Nardini E, Lim RS, et al: The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92:3025-3034, 1998
Chesi M, Bergsagel PL, Shonukan OO, et al: Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457-4463, 1998
Hanamura I, Iida S, Akano Y, et al: Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations. Jpn J Cancer Res 92:638-644, 2001
Chesi M, Nardini E, Brents LA, et al: Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16:260-264, 1997
Avet-Loiseau H, Facon T, Grosbois B, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99:2185-2191, 2002
Fonseca R, Blood E, Rue M, et al: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101:4569-4575, 2003
Chang H, Sloan S, Li D, et al: The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 125:64-68, 2004
Keats JJ, Reiman T, Maxwell CA, et al: In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101:1520-1529, 2003
Moreau P, Facon T, Leleu X, et al: Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100:1579-1583, 2002
Avet-Loiseau H, Brigaudeau C, Morineau N, et al: High incidence of cryptic translocations involving the Ig heavy chain gene in multiple myeloma, as shown by fluorescence in situ hybridization. Genes Chromosomes Cancer 24:9-15, 1999
Blade J, Samson D, Reece D, et al: Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT—European Group for Blood and Marrow Transplant. Br J Haematol 102:1115-1123, 1998
Nishida K, Tamura A, Nakazawa N, et al: The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood 90:526-534, 1997
Santra M, Zhan F, Tian E, et al: A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 101:2374-2376, 2003
Chesi M, Brents LA, Ely SA, et al: Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97:729-736, 2001
Plowright EE, Li Z, Bergsagel PL, et al: Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 95:992-998, 2000
Li Z, Zhu YX, Plowright EE, et al: The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. Blood 97:2413-2419, 2001
Nakazawa N, Nishida K, Tamura A, et al: Interphase detection of t(4;14)(p16.3;q32.3) by in situ hybridization and FGFR3 overexpression in plasma cell malignancies. Cancer Genet Cytogenet 117:89-96, 2000
Sibley K, Fenton JA, Dring AM, et al: A molecular study of the t(4;14) in multiple myeloma. Br J Haematol 118:514-520, 2002
Robbiani DF, Chesi M, Bergsagel PL: Bone lesions in molecular subtypes of multiple myeloma. N Engl J Med 351:197-198, 2004
Pollett JB, Trudel S, Stern D, et al: Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance. Blood 100:3819-3821, 2002
Trudel S, Ely S, Farooqi Y, et al: Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 103:3521-3528, 2004
Paterson JL, Li Z, Wen XY, et al: Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol 124:595-603, 2004
Kuehl WM, Bergsagel PL: Multiple myeloma: Evolving genetic events and host interactions. Nat Rev Cancer 2:175-187, 2002
Trudel S, Li ZH, Wei E, et al: CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105:2941-2948, 2005(Wilfrid Jaksic, Suzanne T)