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A626 Multiple Myeloma in Black Africans: Does It Behave Differently?
XII International Myeloma Workshop 1
Dana-Farber Cancer Institute, Boston, MA; 2Hopital de Nantes,
A626
France
Multiple Myeloma in Black Africans: Does It Behave Differently? N Cécile,1 L Michaux,1 A Robert,2 A Ferrant,1 MC Vekemans3 1
UCL Saint-Luc; 2ESP, Unité d’Epidéliologie, Biostatistiques et Méthodes opérationnelles en Santé Publique; 3UCL Louvain
Introduction: Multiple myeloma (MM) is the most common hematologic malignancy in African-Americans, with an approximately 2-fold higher incidence compared to Caucasians. However, little is known about the characteristics of the disease in black Africans. Aim: To determine differences in clinical features and outcome between black African and Caucasian MM patients referred to our hospital. Material and Methods: From December 1987 to October 2008, 705 consecutive cases of MM were diagnosed in our institution. Among them, 18 black Africans were identified and compared to a control cohort of Caucasian MM patients (ratio 1:4) matched for age, sex, stage, and ISS at diagnosis, medical history (ie, infections, HIV status, antecedent of MGUS). Results: Black African MM patients resided in Belgium for professional, political or medical reasons. They were characterized by a peculiar medical history of HIV (n = 1), MGUS (n = 5), infections (n = 9), hypertension (n = 9), and by a median age of 44 years (range, 34-65 years), no gender predominance, Durie-Salmon stage I (n = 8)/III (n = 10), ISS I (n = 4)/II-III (n = 10), IgG/A/light chain isotypes (n = 10/4/4), kappa/ lambda/both (n = 12/5/1). Treatment was required in 12 patients (DS I (n = 1)/III (n = 11)). Front-line therapy consisted of VAD (n = 7), VACD (n = 1), TD (n = 2) or melphalan/prednisone (MP; n = 1), followed by either single/double/tandem ASCT-RIC/alloSCT; n = 6/1/1/1), or MP/bortezomid (n = 1). Patients treated by single/ double/tandem ASCT-RIC achieved at least PR (n = 5); one treated by alloSCT developed PD at 49 m, was subsequently diagnosed with AML, is in CR for both diseases after conventional chemotherapy at 102 m; 2 patients did not respond to ASCT but were rescued by a MP combination! All except one patient treated upfront without ASCT (n = 4) developed rapid PD. After a median follow-up of 33.5 m, 13 patients (SD I (n = 5)/III (n = 8)) are alive (1 CR, 5 PR, 5 SD, 2 PD; median 57 m, range 11-117 m), and 5 (SD I (n = 2)/III (n = 3)) died of PD (n = 2; 1 and 2 m after diagnosis) or unrelated causes (n = 3; 8, 21, 22 m after diagnosis). Comparison with the Caucasian cohort and epidemiological data from the Belgian Registry for Cancer and the International Agency Research and Treatment of Cancers will be provided. Conclusion: We had the unique opportunity to study a group of black African MM patients and compare them to a matched Caucasian cohort, regarding national and international epidemiological data.
A627
A628 MicroRNA Profile Identifies Distinct Clinically Relevant Subgroups in Multiple Myeloma A Sophia,1 H AvetLoiseau,2 SB Amin,1 YT Tai,1 SP Treon,1 P Moreau,2 S Minvielle,2 C Li,1 KC Anderson,1 NC Munshi1 1
Dana-Farber Cancer Institute, Boston, MA; 2Hopital de Nantes,
Alternate Splicing Is Frequently Observed in Myeloma and Has Impact on Clinical Outcome SB Amin,1 C Li,1 S Minvielle,2 P Moreau,2 F Magrangeas,2 KC Anderson,1 H Avetloiseau,2 NC Munshi1
Gene function is modulated at multiple levels. Besides the change in level of expression, post-transcriptional changes such as alternate splicing alter specificity of gene function. Although various genes have normal alternate spliced form, misregulation of alternate splicing is associated with various disease processes including cancer. We have analyzed alternate splicing in myeloma (MM) using high-throughput exon array analysis. GeneChip Human Exon 1.0 ST Arrays used in this investigation, besides expression levels, also provides information on presence of each exon and identifies recurrent alternately spliced genes. We evaluated 170 newly-diagnosed patients with MM treated homogeneously in tandem transplantation IFM trials using CD138 purified MM cells and the GeneChip Human Exon 1.0 ST Arrays. The dChip software was modified to analyze exon array data. We first normalized gene-level expression values across samples, and then identified differentially expressed exons to identify alternate splicing events. We observed over 100 genes with alternate splicing in myeloma with frequency in more than 20% patients. Dividing the group based on response, 52 alternately spliced exons were identified as influencing response to therapy including CD79A exon 5 and 6, EDNRB exon 2, RASSF1 exon 8, CD1d exon 9, TGFBetaRII exon 1, Calmin exon 2, MADH1 exon 7, TBX5 exon 2, Amyloid beta exon 14, and Thymidylate synthetase exon 7 with the highest frequency of alternate splicing. Among these genes, 32 genes had the most influence on response with over 50% differential frequency in patients achieving CR. Similarly we have identified 85 alternately spliced genes as influencing overall survival between groups divided by less than or more than 48 months’ survival. Forty-nine genes within this group had the most influence on overall survival. Number of spliced variants were shared between both response and survival groups suggesting their biologic and functional significance. Further validation of these alternate splicing is under investigations. This study highlights that alternate splicing is observed with significant frequency and points to the need for evaluation of not only the expression level of genes but also post translational modifications. The spliced genes identified here are important target for therapy as well as possible immune modulation.
France
MicroRNA, a small endogenous RNA regulating specific expressed gene function has been implicated in normal biologic processes as well as in malignant transformation. Here we have investigated the role of microRNAs in multiple myeloma (MM)
Clinical Lymphoma & Myeloma Supplement February 2009
•
S93
Dana-Farber Cancer Institute, Boston, MA; 2Hopital de Nantes,
A626
France
Multiple Myeloma in Black Africans: Does It Behave Differently? N Cécile,1 L Michaux,1 A Robert,2 A Ferrant,1 MC Vekemans3 1
UCL Saint-Luc; 2ESP, Unité d’Epidéliologie, Biostatistiques et Méthodes opérationnelles en Santé Publique; 3UCL Louvain
Introduction: Multiple myeloma (MM) is the most common hematologic malignancy in African-Americans, with an approximately 2-fold higher incidence compared to Caucasians. However, little is known about the characteristics of the disease in black Africans. Aim: To determine differences in clinical features and outcome between black African and Caucasian MM patients referred to our hospital. Material and Methods: From December 1987 to October 2008, 705 consecutive cases of MM were diagnosed in our institution. Among them, 18 black Africans were identified and compared to a control cohort of Caucasian MM patients (ratio 1:4) matched for age, sex, stage, and ISS at diagnosis, medical history (ie, infections, HIV status, antecedent of MGUS). Results: Black African MM patients resided in Belgium for professional, political or medical reasons. They were characterized by a peculiar medical history of HIV (n = 1), MGUS (n = 5), infections (n = 9), hypertension (n = 9), and by a median age of 44 years (range, 34-65 years), no gender predominance, Durie-Salmon stage I (n = 8)/III (n = 10), ISS I (n = 4)/II-III (n = 10), IgG/A/light chain isotypes (n = 10/4/4), kappa/ lambda/both (n = 12/5/1). Treatment was required in 12 patients (DS I (n = 1)/III (n = 11)). Front-line therapy consisted of VAD (n = 7), VACD (n = 1), TD (n = 2) or melphalan/prednisone (MP; n = 1), followed by either single/double/tandem ASCT-RIC/alloSCT; n = 6/1/1/1), or MP/bortezomid (n = 1). Patients treated by single/ double/tandem ASCT-RIC achieved at least PR (n = 5); one treated by alloSCT developed PD at 49 m, was subsequently diagnosed with AML, is in CR for both diseases after conventional chemotherapy at 102 m; 2 patients did not respond to ASCT but were rescued by a MP combination! All except one patient treated upfront without ASCT (n = 4) developed rapid PD. After a median follow-up of 33.5 m, 13 patients (SD I (n = 5)/III (n = 8)) are alive (1 CR, 5 PR, 5 SD, 2 PD; median 57 m, range 11-117 m), and 5 (SD I (n = 2)/III (n = 3)) died of PD (n = 2; 1 and 2 m after diagnosis) or unrelated causes (n = 3; 8, 21, 22 m after diagnosis). Comparison with the Caucasian cohort and epidemiological data from the Belgian Registry for Cancer and the International Agency Research and Treatment of Cancers will be provided. Conclusion: We had the unique opportunity to study a group of black African MM patients and compare them to a matched Caucasian cohort, regarding national and international epidemiological data.
A627
A628 MicroRNA Profile Identifies Distinct Clinically Relevant Subgroups in Multiple Myeloma A Sophia,1 H AvetLoiseau,2 SB Amin,1 YT Tai,1 SP Treon,1 P Moreau,2 S Minvielle,2 C Li,1 KC Anderson,1 NC Munshi1 1
Dana-Farber Cancer Institute, Boston, MA; 2Hopital de Nantes,
Alternate Splicing Is Frequently Observed in Myeloma and Has Impact on Clinical Outcome SB Amin,1 C Li,1 S Minvielle,2 P Moreau,2 F Magrangeas,2 KC Anderson,1 H Avetloiseau,2 NC Munshi1
Gene function is modulated at multiple levels. Besides the change in level of expression, post-transcriptional changes such as alternate splicing alter specificity of gene function. Although various genes have normal alternate spliced form, misregulation of alternate splicing is associated with various disease processes including cancer. We have analyzed alternate splicing in myeloma (MM) using high-throughput exon array analysis. GeneChip Human Exon 1.0 ST Arrays used in this investigation, besides expression levels, also provides information on presence of each exon and identifies recurrent alternately spliced genes. We evaluated 170 newly-diagnosed patients with MM treated homogeneously in tandem transplantation IFM trials using CD138 purified MM cells and the GeneChip Human Exon 1.0 ST Arrays. The dChip software was modified to analyze exon array data. We first normalized gene-level expression values across samples, and then identified differentially expressed exons to identify alternate splicing events. We observed over 100 genes with alternate splicing in myeloma with frequency in more than 20% patients. Dividing the group based on response, 52 alternately spliced exons were identified as influencing response to therapy including CD79A exon 5 and 6, EDNRB exon 2, RASSF1 exon 8, CD1d exon 9, TGFBetaRII exon 1, Calmin exon 2, MADH1 exon 7, TBX5 exon 2, Amyloid beta exon 14, and Thymidylate synthetase exon 7 with the highest frequency of alternate splicing. Among these genes, 32 genes had the most influence on response with over 50% differential frequency in patients achieving CR. Similarly we have identified 85 alternately spliced genes as influencing overall survival between groups divided by less than or more than 48 months’ survival. Forty-nine genes within this group had the most influence on overall survival. Number of spliced variants were shared between both response and survival groups suggesting their biologic and functional significance. Further validation of these alternate splicing is under investigations. This study highlights that alternate splicing is observed with significant frequency and points to the need for evaluation of not only the expression level of genes but also post translational modifications. The spliced genes identified here are important target for therapy as well as possible immune modulation.
France
MicroRNA, a small endogenous RNA regulating specific expressed gene function has been implicated in normal biologic processes as well as in malignant transformation. Here we have investigated the role of microRNAs in multiple myeloma (MM)
Clinical Lymphoma & Myeloma Supplement February 2009
•
S93