SIMPOSIUM EDUCACIONAL 1: Linfoma / Mieloma Jueves 4 Octubre 2007 INTEGRACIÓN DE LOS NUEVOS FÁRMACOS EN EL TRATAMIENTO DEL MIELOMA MÚLTIPLE José Gómez Codina Oncología Médica Hospital Universitari La Fe Valencia

Mieloma múltiple. Introducción Segunda neoplasia hematológica más frecuente. Incidencia: 4 casos/100.000/año. Prevalencia: 60.000 casos (Europa). Aumento de incidencia con edad: 80% de pacientes > 60 años. Curso clínico: Enfermedad “crónica” con múltiples recaídas y respuestas. Eventualmente situación de enfermedad refractaria. Con tratamiento actual: Mortalidad a 5 año 75%. Mortalidad a 10 años 95-98% Enfermedad refractaria: mediana de supervivencia de 6-8 meses

Primer caso conocido: Sarah Newberry, 1844.

MIELOMA MÚLTIPLE CRITERIOS DIAGNÓSTICOS mayores: I- plasmocitoma en biopsia tisular II- plasmocitosis medular >30% III- paraproteína en EFP suero IgG >3.5g/dl IgA >2.0g/dl IV-cadena liviana >1.0g/dl en EFP orina menores a-plasmocitosis medular 10 a 30% b-paraproteína de valores inferiores a III c-lesiones osteolíticas d-disminución de inmunoglobulinas normales IgM<50; IgG<600; IgA<100

M.M.: FACTORES PRONÓSTICO HUESPED Edad Estado General (PS) TUMOR Labelling index / S-phase Alt.Citogenéticas CARGA TUMORAL/LESIONES DE ÓRGANOS 2-microglobulina Función Renal Hemoglobina

Factores Pronóstico Edad ECOG RB ISS Fase de síntesis B2micro+albúmina 1.0 Dos copias del cromosoma 13 (Rb) Monosomía 13 (-Rb) p=0’0025 RB IGH Translocation 50 40 30 20 10 .8 .6 .4 .2 0.0 P=0.006

FACTORES DE RIESGO MOLECULARES-GENÉTICOS Mayo Stratified Myeloma and Risk-Adapted Therapy (mSMART) classification of multiple myeloma. *Low risk with beta- 2-microglobulin > 5.5 (in absence of renal failure) or lactate dehydrogenase >upper limit of normal may be at higher risk.

Mieloma Múltiple: ¿Tratamiento? Smoldering Multiple Myeloma (Asymptomatic Myeloma) Diagnostic Criteria* Monoclonal Gammopathy of Undetermined Significance (MGUS) Diagnostic Criteria* Serum M protein size ≥3g/dL and / or Bone marrow plasma cells ≥10% No clinical manifestations or other laboratory abnormalities due to the monoclonal gammopathy Serum M protein size <3g/dL Bone marrow plasma cells <10% No clinical manifestations or other laboratory abnormalities attributable to the monoclonal gammopathy The International Myeloma Working Group. Br J Haematol 2003; 121: 749-757.

MM. Medidas de soporte y Tratamiento de soporte Medidas generales: hidratación, antibióticos Vacunación neumocócica Radioterapia - dolor local persistente - plasmocitomas Insuficiencia renal: diálisis, plasmaféresis Anemia: eritropoyetina Afectación ósea: pamidronato, zoledronato

Mieloma múltiple. Evolución del tratamiento Myeloma Trialists Collaborative Group, J Clin Oncol 1998. Equivalencia entre melfalan-prednisona y poliQT Attal et al, N Engl J Med 1996. Superioridad de la QAD y del ATSP como tratamiento de 1ª línea Berenson et al, N Engl J Med 1996. aumento de la SG y disminución de eventos óseos con bifosfonatos

Esquema Terapéutico MP Alexanian et al, 1969 MELFALÁN 0,25 mg/kg/día VO, días 1-4 PREDNISONA 60 mg/m2/día VO o parenteral, c/ 4-6 semanas

M.M.: TRATAMIENTO

PoliQT vs. MP: Supervivencia 10 20 30 40 50 60 70 80 90 100 – Allocated CCT (% ± SD) – Allocated MP (% ± SD) Estimated still alive (%) 24.4% 19.4% Combination chemotherapy vs MP: mortality A retrospective overview of trials assessed combination chemotherapy vs MP Survival curves were obtained for those trials that provided individual patient data Overall, no significant difference in survival was observed (P = 0.6, 2-tailed) Reference Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;3832-42. 23.0% 1.4% SD 1.4 (log-rank 2p > o.1; NS) 18.0% 1 2 3 4 5 6+ Years Deaths/person-years: CCT 642/1999 392/1456 305/1044 196/724 133/506 255/1130 MP 576/1968 407/1423 294/983 194/652 130/444 215/839 Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;3832-42. Reproduced with permission from the Am Soc Clin Oncol.

ESTUDIOS FASE III QT INTENSIVA vs. T. Convencional Pacientes CR EFS OS IFM 90 (NEJM 96) 200 + 22/5 28/18m 57/44m MRC 03 (NEJM 03) 401 44/8 31/19m 54/42m Pethema 94 (Blood 05) 185 30/11 - 42/33m 61/66m US-Intergroup (JCO 06) 516 15/17 25/21m 58/53m

ATSP: SIMPLE vs. DOBLE Patients EFs Os Ref IFM 94 400 + + NEJM 03 MAG 95 227 + Sydney 05 Bologna 220 + Sydney 05 Hovon 300 + Sydney 05 GMMG 260 + Sydney 05

OS after DOUBLE SCT Attal et al. N Engl J Med 2003;349:2495–502. Diapo dels francesos que mostra la comparació que no s’ha de fer? 399 pts <60a, random post HDT to 1 vs 2 TASPs: SINGLE VS. DOUBLE. Tassa CR+VGPR: 42% vs 50% (p NS) EFS (7a): 10 vs 20, p 0.03 OS (7a): 21 vs 42%, p 0.01 …. Però si resposta <VGPR: 11 vs 43%, p<0.001. Factors related to survival: edat, grup de ttm, beta2, LDH. CONCLUSION: As compared with a single autologous stem-cell transplantation after high-dose chemotherapy, double transplantation improves OS among patients with MM, especially those who do not have a VGPR after undergoing one transplantation. Attal et al. N Engl J Med 2003;349:2495–502.

M.M.: T. ALOGÉNICO Stem cells Trx related mortality GVM effect ADVANTAGES DISADVANTAGES Stem cells Non-contaminated No damage (chemo.) Trx related mortality >40% (8%-60%) GVM effect Age & Donor availability 10% candidates Seatle & Arkansas: 24% (<100 days), 55% (overall) Causes: infections (18%), pneumonitis (17%), acute GVHD (10%)

Treatment Through the Years 1846 1960 1970 1980 1990 2000 2003 2004 Melphalan (1958, Blokhin) Ann NY Acad Sci Mr.McBean 1948 High-dose chemo Stem cell transplantation Bisphosphonates Melphalan Glucocorticoids (1969) Combination chemo Vincristine Doxorubicin Dexamethasone Thalidomide Bortezomib ImiDs Arsenic trioxide… ……………….

Thalidomide & IMIDs X NFkB  Apoptosis Inhibitors FAS X  IL-6   Proliferation  Cytotoxicity  Adhesion  Cytokine  Angiogenesis   X VEGF IL-2 MM cells IGF-I IFN- BM Vessels TNFa T-lymph. BMSC IL-6 Intracellular level NFkB  Apoptosis Inhibitors (IAP, FLICE) Caspases 8,3 FAS MAPK PI3K antiapoptotic IL-6R X proliferation Increased Apoptosis Decreased Proliferation San Miguel J. Hematol J. 2003;4(suppl 3):201-207.

X PS-341- Bortezomib - VelcadeTM  Apoptosis Inhibitors FAS X  PI3K  Adhesion  Cytokine  Angiogenesis BMSC MM cells VEGF IGF-I TNFa IL-6 BM Vessels X  IkB/NFkB  Apoptosis Inhibitors (IAP, FLICE) Caspases 8,3 FAS MAPK PI3K Decreased Proliferation antiapoptotic Intracellular level X proliferation Increased Apoptosis IL-6, VEGF Block activation Inhibition DNA-repair effectors Disruption of unfolded protein response San Miguel J. Hematol J. 2003;4(suppl 3):201-207

PAPEL DE LAS NUEVAS DROGAS EN EL TRATAMIENTO DEL MIELOMA MÚLTIPLE TRATAMIENTO DE RESCATE TRATAMIENTO DE PRIMERA LÍNEA TRATAMIENTO DE MANTENIMIENTO

PAPEL DE LAS NUEVAS DROGAS EN EL TRATAMIENTO DEL MIELOMA MÚLTIPLE TRATAMIENTO DE RESCATE TRATAMIENTO DE PRIMERA LÍNEA TRATAMIENTO DE MANTENIMIENTO

NUEVAS DROGAS EN EL TRATAMIENTO DE RESCATE DEL MM. Response Rate ( % > PR) Single Agent +Dexamethasone + Chemotherapy . Thalidomide 29% 35 – 55% 55 – 76% . Lenalidomide 25% 60% 60 - 70% . Bortezomib 43% ---- 50 – 76%

Bortezomib vs Dexamethasone (APEX): (n = 669) Median TTP: 6.2 vs 3.5 months Median DOR: 11 m vs 7,6 m p < 0.0001 Median OS: 30 vs 24m P = 0.02 1-y OS: 80% vs 67% P = 0.0002 Bortezomib Dexamethasone P = 0.0272 Richardson NEJM 2005 TTP OS Response(>PR): 38% (9%CR) vs 18% (2% CR)

Lenalidomide+Dex vs Dexamethasone Time to Progression Overall Survival Proportion of patients 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 p < 0.001 MM-009 Dex alone (5.1 m) MM-009 Len/Dex (15.0 m) MM-010 Dex alone (4.7 m) MM-010 Len/Dex (11.3 m) 2.5 5 7.5 10 12.5 15 17.5 20 22.5 Cut-off date: June 2005. 1.00 0.75 Cumulative survival 0.50 Median OS Len/Dex Placebo/Dex MM-009 29.6 months 20.2 months p=0,01 MM-010 Not reached 20.6 months p=0.03 0.25 0.00 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 Time to tumour progression (months) Time (weeks) Weber D. Presented at ASCO Annual Meeting; 2005 May 13–17; Orlando, FL. Dimopoulos M, et al. Presented at ASH Annual Meeting; Dec 10–13, 2005; Atlanta, GA.

PAPEL DE LAS NUEVAS DROGAS EN EL TRATAMIENTO DEL MIELOMA MÚLTIPLE TRATAMIENTO DE RESCATE TRATAMIENTO DE PRIMERA LÍNEA TRATAMIENTO DE MANTENIMIENTO

Thalidomide combinations in the Up-front setting Regimen Patients, n Response, % Reference (CR + nCR) Thal-Dex vs Dex 103 vs 104 63 vs 41 *Rajkumar, JCO 2006 Thal-Dex vs VAD 100 vs 100 76 vs 52 *Cavo, Blood 2005 (10) vs (8) TAD vs VAD 200 vs 200 80 vs 63 *Goldschmith, ASH 2005 (7) vs (3) Note from Medical: I have deleted the %-signs within the table, because it is indicated in the heading of the table that you show % of Response and % of CR and nCR in between brackets. It makes your table cleaner and easier to read. Thal-Dex Peg LD 50 88 (34 + 15) Offidani, Blood 2006 *Adequate stem cell collection

Thalidomide combinations in the Up-front setting Regimen Patients % Response (CR) Reference Thal MP vs 129 vs 76 (16CR) Palumbo Lancet 2006 MP 126 47 (2 CR) Thal MP vs 191 vs 81 (15CR) Facon ASCO 2006 MP vs 124 vs 40 (2 CR) MEL 100 121 vs 72 (17 CR)

Treatment Schedules: GIMEMA* Melphalan 4 mg/m2 on days 1-7/month for 6 courses + Prednisone 40 mg/m2 days 1-7/month for 6 courses Thalidomide 100 mg/d continuously until relapse OR Melphalan 4 mg/m2 days 1-7/month for 6 courses * Palumbo et al. Lancet 2006;367:825-31.

Response Rates: GIMEMA* N (%) Patients Absolute Difference MPT (n=129) MP (n=126) MPT– MP (95% CI) CR + PR 98 (76.0) 60 (47.6) 28.3% 16.5, 39.1 CR 20 (15.5) 3 (2.4) 13.1% 6.3, 20.5 PR 78 (60.4) 57 (45.2) 15.2 3.0, 26.9 Near CR 16 (12.4) 6 (4.8) -- 90%-99% M protein ↓ 11 (8.5%) 50%-89% M protein ↓ 51 (39.5%) 45 (35.7) MR 7 (5.4) 21 (16.7) -11.2% -19.2, -3.6 Prog disease 10 (7.8) -8.9 -17.2, -0.8 * Palumbo et al. Lancet 2006;367:825-31.

Event-Free Survival: GIMEMA* 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Proportion of patients 6 12 18 24 HR 0.51 (95% CI 0.35–0.75) p=0.0006 MPT MP Months * Palumbo et al. Lancet 2006;367:825-31.

Overall Survival: GIMEMA* 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Proportion of patients HR 0.68 (95% CI 0.38–1.22) p=0.19 MPT MP Months 6 12 18 24 30 * Palumbo et al. Lancet 2006;367:825-31.

IFM 99-06 - Study protocol Newly diagnosed MM 65-75 years MP MP 1 MP 2 MP 3 MP 12 MEL100 VAD 1 VAD 2 Cyclophosphamide 3g/m2 + Granulocyte + PBSC harvest MEL 100 mg/m2 + PBSC + Granulocyte MP-T + Thalidomide  400 mg/d Clodronate was given to all patients

Survival Analyses: Median in Months (SE) MPT vs. MP vs. ASCT: IFM 99-06 Survival Analyses: Median in Months (SE) MPT (n=124) MP (n=191) ASCT (n=121) Comparisons OS Not reached at 56 months 30.3 (5.8) 38.6 (3.0) MPT v MP, p=0.0008 MPT v ASCT, p=0.014 PFS 29.5 (3.6) 17.2 (1.5) 19.0 (1.3) MPT v MP, p<0.0001 MPT v ASCT, p=0.0001 * Facon et al. J Clin Oncol 2006;24(18S):1.

MP-THAL vs MP vs MEL 100 PFS 0S Comparison HR P MP / MP-T 1.9 0.0008 MP / MEL 100 1.1 0.55 MEL100 / MP-T 1.7 0.014 Comparison HR P MP / MP-T 2.4 < 0.0001 MP / MEL 100 1.2 0.16 MEL100 / MP-T 2.0 0.0001 MP-T: 54 MEL 100: 40m MP-T: 28m MP: 32 m MEL 100: 19m MP: 17m Facon et al, ASCO2006

Lenalidomide Combinations in the Up-front setting   Lenalidomide Combinations in the Up-front setting Author Treatment schedule Patients Response Rate (%)   Reference Rajkumar Lenalidomide-Dex 34 42 91 (6CR) 86 (25CR +11nCR) Niesvizky Clarithromycin-Lenalidomide-Dex Blood 2005; 106 (11):642  

ECOG-E4A03: lenalidomide and standard- or low-dose dexamethasone in newly diagnosed MM Phase III, randomized study – dexamethasone Arm 1: lenalidomide 25 mg/day p.o., days 1–21 standard-dose dexamethasone 40 mg/day p.o., days 1–4, 9–12, 17–20 Dex/cycle 480 mg (n = 223) Arm 2: lenalidomide 25 mg/day p.o., days 1–21 lower-dose dexamethasone 40 mg/day p.o., days 1, 8, 15, 22 Dex/cycle 160 mg (n = 222) Salvage therapy: thalidomide 200 mg/day p.o., days 1–28 If PD within 4 months Four courses, every 28 days Newly diagnosed MM (N = 445) ECOG-E4A03: lenalidomide and standard- or low-dose dexamethasone in newly diagnosed MM The ECOG is conducting this randomized phase III study to compare, in terms of response rate and toxicity, lenalidomide and standard-dose dexamethasone vs lenalidomide and low-dose dexamethasone in patients with newly diagnosed untreated MM A secondary objective is to determine the response rate in patients who do not have an objective response during the first 4 courses of lenalidomide and dexamethasone and subsequently receive salvage therapy consisting of thalidomide and either standard-dose or low-dose dexamethasone Abbreviations ECOG = Eastern Cooperative Oncology Group; PD = progression of disease; p.o. = orally. References National Cancer Institute. Available from http://www.cancer.gov/clinicaltrials/ECOG-E4A03. Rajkumar SV. J Clin Oncol. 2007;25:18S [abstract LBA8025]. When CR or PR response is reached, eligible patients proceed to stem cell transplant. Rajkumar SV, et al. J Clin Oncol. 2007;25:18S [abstract LBA8025].

Survival time (months) ECOG-E4A03: superior overall survival rate with low- vs standard-dose Dex Len + std-dose Dex Len + low-dose Dex Log-rank p = 0.0001 Survival time (months) Proportion surviving ECOG-E4A03: superior overall survival rate with low- vs standard-dose Dex This figure shows the overall survival in the Len + low-dose Dex and the Len + high-dose Dex group. It clearly shows that patients on the low dose had a significantly higher overall survival (p < 0.001) Reference Rajkumar SV, et al. J Clin Oncol. 2007;25:18S [abstract LBA8025]. n Event, % (n) Censored, % (n) Median survival (95% CI) Len + std-dose Dex 223 18 (41) 82 (182) NR (23.56–NR) Len + low-dose Dex 222 6 (13) 94 (209) NR Overall survival was significantly superior in the low-dose Dex arm p < 0.001 Rajkumar SV, et al. J Clin Oncol. 2007;25:18S [abstract LBA8025].

Bortezomib combinations in the Up-front setting Treatment schedule Patients Response Rate  PR (%) Reference Bortezomib-MP Bortezomib-Dex Bortezomib1-Adria-Dex   Bortezomib2-Adria-Dex Bortezomib-Thal-Dex 60 48 47 20 21 38 86 (30CR + 13nCR) 89 (8 CR +10nCR) 83 (17 CR) 89 (11CR +5 nCR) 95 (24CR)   92 (18CR) Mateos, ASH 2005   Jagannath , ASH 2005 Harousseau, ASH 2005 Popat. ASH 2005 Oakervee BJH 2005;129:755-62 Wang, ASH 2005  

Novel drugs as induction therapy before ASCT % Complete Responses Pre-ASCT Post-ASCT (1st) Harvest Vel-Dex1 31%* 54%* OK PAD2 16% 54% 20/21 V-T-D-3 19% 31% OK V-DTPACE4 16% 80% OK 1.- Harousseau 4 Cycles/ 21d: V(1.3 mg)+ Dex (40x 4d/2pulses 2.- Popat 4 Cycles/ 21d: V(1.3-1mg), A(9mg/m2x 4 d), Dex (40 mgx 4d) 3.- Wang 2 Cycles/ 28d: V(1-1.9), Thal (100-200), Dex (20mg/m2x4x3 pulses) * It includes VGPR (10% pre ASCT and 33% post ASCT)

PAPEL DE LAS NUEVAS DROGAS EN EL TRATAMIENTO DEL MIELOMA MÚLTIPLE TRATAMIENTO DE RESCATE TRATAMIENTO DE PRIMERA LÍNEA TRATAMIENTO DE MANTENIMIENTO

in Maintenance treatment: Role of Novel drugs in Maintenance treatment: IFM 99 02 : Study Design (Inclusion: 0 or 1 Factor del 13 ; ß2m ) VAD x 3 Mel-140 + PBSC Mel 200 + PBSC Randomization Slide 7 The design of the study is illustrated on this slide: Patients without or with one adverse factor were included. They receive 3 cycles of VAD. Then a first autologous transplant prepared with Melphalan 140. Then a second autologous transplant prepared with Melphalan 200. 3 months after the Second transplant, patients were randomized to receive: No maintenance, Pamidronate or Pamidronate+Thal No maintenance Pamidronate Pamidr + Thalidom 90mg /m 100-400 mg/d Attal et al Blood 2006

IFM 99 02 : EFS & OS at 4 Years Thalid+Pamid. (87%) Thal+ Pam EFS at 3y: 52%,37%, 36%. Thal+ Pam Pamidronate (74%) Pamidr Nothing Slide 15 This result is illustrated on this slide. The PFS from randomization of patients enrolled in Arm C, enrolled in Arm A and in Arm B p < 0.003 P < 0.01 RR after Randomization: 67%, 57%, 55%. Skeletal Events : 18%, 21%, 24% Attal et al Blood 2006

MM. TOXICIDAD RELEVANTE DE LA TALIDOMIDA Astenia y Síntomas constitucionales Puede limitar la dosis Neuropatía Periférica Puede limitar la duración del tratamiento Fenómenos Tromboembólicos / TVP (s.t. cuando se emplea asociada a DXM o QT) Requiere profilaxis antitrombótica (anticoagulación o antiagregación)

Incidencia de TVP con Talidomida Percent of Patients with DVT Thalidomide Monotherapy Thalidomide + Dexamethasone Chemotherapy (especially doxorubicin) Mayo Clin Pro 2002;77:813-22 Blood 2001;98:492-4 JCO 2002;20:4319-23 Blood 2001;98:1614-5 BJH 2004;126:715-21 Haematologica 2001; 86: 404-8 Mayo Clin Pro 2002; 77:813-22

TOXICIDAD RELEVANTE POR BORTEZOMIB Astenia, Fiebre y Síntomas Constitucionales T. Gastrointestinal (anorexia, vómitos, diarrea) Neuropatía Periférica Trombocitopenia periférica Hipotension Ortostática

MIELOMA MÚLTIPLE OTROS FÁRMACOS EN DESARROLLO Bendamustina Trióxido de Arsénico Inhibidores de Farnesil-Transferasa 2-Metoxiestradiol TRIAL Fármacos anti-VEGF Inhibidores del factor de crecimiento de fibroblastos Inhibidores de histonas deacetilasas Aplindina etc…

Pönisch et al., J Cancer Res Clin Oncol 2006 Bendamustine/Prednisone (BP) versus Melphalane/Prednisone (MP) in Multiple Myeloma Therapy A: BP-schedule Bendamustine 150 mg/m² IV day 1 + 2 Prednisone 60 mg/m² IV or orally day 1 - 4 Therapy B: MP-schedule Melphalane 15 mg/m² IV day 1 Prednisone 60 mg/m² IV or orally day 1 - 4 Pönisch et al., J Cancer Res Clin Oncol 2006

BP versus MP in multiple myeloma progression-free survival 1 0,8 progression-free survival 0,6 0,4 0,2 p<0,005 BP (n=68) MP (n=63) 60 10 20 30 40 50 months Pönisch et al., J Cancer Res Clin Oncol 2006

TRATAMIENTO DEL MIELOMA MÚLTIPLE EN 2007 SUBGRUPOS DE PACIENTES RIESGO ESTÁNDAR CANDIDATOS A QT INTENSIVA NO CANDIDATOS A QT INTENSIVA ALTO RIESGO

Initial Approach to Treatment of Multiple Myeloma

TRATAMIENTO DEL MIELOMA MÚLTIPLE EN 2007 RIESGO ESTÁNDAR Y CANDIDATOS A QT INTENSIVA TRATAMIENTO DE INDUCCIÓN COMBINACIÓN DE NUEVOS FÁRMACOS (TAL-DXM; LEN-DEX; B-DXM) QT ALTERNANTE O VAD QT INTENSIVA (MEL) 2ª QT INTENSIVA (si no RC con la 1ª)

TRATAMIENTO DEL MIELOMA MÚLTIPLE EN 2007 RIESGO ESTÁNDAR Y NO CANDIDATOS A QT INTENSIVA CONSIDERAR COMORBILIDAD TRATAMIENTO: (MELFALAN-PREDNISONA) MELFALAN-PREDNISONA + NUEVO FÁRMACO

TRATAMIENTO DEL MIELOMA MÚLTIPLE EN 2007 ALTO RIESGO NINGÚN TRATAMIENTO OFRECE RESULTADOS ACEPTABLES ENSAYOS CLÍNICOS INDIVIDUALIZAR CONSIDERAR EL EMPLEO DE COMBINACIONES CON NUEVOS FÁRMACOS (B-DXM)

Mayo Stratified Myeloma and RISK-Adapted Therapy (mSMART).