Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis

Abstract

The present invention relates to a pharmaceutical combination for the treatment of diseases which involves cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis. The invention also relates to a method for the treatment of said diseases, comprising co-administration of effective amounts of specific active compounds and/or co-treatment with radiation therapy, in a ratio which provides an additive and synergistic effect, and to the combined use of these specific compounds and/or radiotherapy for the manufacture of corresponding pharmaceutical combination preparations.

1 . A pharmaceutical combination comprising effective amounts of: 
 (i) an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRα and β, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof; and    (ii) at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent;    wherein said pharmaceutical combination is optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy, in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis.    
     
     
         2 . The pharmaceutical combination in accordance with  claim 1 , wherein the antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRα and β, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is also an antagonist of a src tyrosine kinase family member, is an antagonist of src, lck, lyn or fyn.  
     
     
         3 . The pharmaceutical combination in accordance with  claim 2 , wherein the antagonist is further an antagonist of at least one complex of a cyclin dependent kinase with its specific cyclin or with a viral cyclin selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K, or an inhibitor of the paracrine IL-6 secretion.  
     
     
         4 . The pharmaceutical combination in accordance with  claim 1 , wherein the combined preparation is for use in the treatment of oncological diseases.  
     
     
         5 . The pharmaceutical combination in accordance with  claim 4 , wherein the combined preparation is for use in the treatment of oncological diseases selected from solid tumours and malignant human neoplasias.  
     
     
         6 . The pharmaceutical combination in accordance with  claim 5 , wherein the combined preparation is for use in the treatment of urogenital cancers, lung cancers, gastrointestinal cancers, head and neck cancer, malignant mesotheliomas, breast cancer, malignant melanoma, or bone and soft tissue sarcomas.  
     
     
         7 . The pharmaceutical combination in accordance with  claim 4 , wherein the combined preparation is for use in the treatment of haematologic neoplasias.  
     
     
         8 . The pharmaceutical combination in accordance with  claim 7 , wherein the combined preparation is for use in the treatment of refractory or relapsed multiple myeloma, acute or chronic myelogenous leukaemia, myelodysplastic syndrome, or acute lymphoblastic leukaemia.  
     
     
         9 . The pharmaceutical combination in accordance with  claim 3 , wherein the combined preparation is for use in the treatment of diabetic retinopathy, rheumatoid arthritis, or psoriasis.  
     
     
         10 . The pharmaceutical combination in accordance with  claim 1 , wherein the antagonist is a compound selected from 
 (A) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone;    (B) (Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1-phenyl-methylene)-2-indolinone;    (C) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-indolinone;    (D) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;    (E) (Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;    (F) (Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;    (G) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;    (H) (Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;    (I) (Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;    (J) (Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(butylcarbamoyl)-2-indolinone;    (K) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;    (L) (Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;    (M) (Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone;    (N) (Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;    (O) (Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;    (P) (Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;    (Q) (Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;    (R) (Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;    (S) (Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone;    (T) (Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone; and    (U) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-quinazoline;    or a pharmaceutically acceptable salt thereof.    
     
     
         11 . The pharmaceutical combination in accordance with  claim 10 , wherein the antagonist is 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof.  
     
     
         12 . The pharmaceutical combination in accordance with  claim 11 , wherein the antagonist is a monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.  
     
     
         13 . The pharmaceutical combination in accordance with  claim 1 , wherein the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from synthetic small molecule VEGF receptor antagonists, small molecule growth factor receptor antagonists, inhibitors of the EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents, DNA minor-groove binding compounds, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics, inhibitors of DNA transcribing enzymes selected from topoisomerase I and topoisomerase II inhibitors, chromatin modifying agents, mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome inhibitors, enzymes, hormones, hormone antagonists, hormone inhibitors, inhibitors of steroid biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines, oral and parenteral tolerance induction agents, supportive agents, chemical radiation sensitizers and protectors, photo-chemically activated drugs, synthetic poly- or oligonucleotides optionally modified or conjugated, non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, antibodies targeting the surface molecules of cancer cells, inhibitors of metalloproteinases, metals, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, complexes of rare earth elements, and photo-chemotherapeutic agents.  
     
     
         14 . The pharmaceutical combination in accordance with  claim 13 , wherein the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, gefitinib, erlotinib, CI-1033 GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006, BAY-57-9006, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a pharmaceutically acceptable salt thereof, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, propamidine, stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, colchicine or a derivative thereof, maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an epipodophyllotoxin, etoposide, teniposide, a steganacin, combretastatin, amphetinile, procarbazine, bortezomib, asparaginase, pegylated asparaginase (pegaspargase),a thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol, flutamide, casodex, anandron, cyproterone acetate, aminogluthetimide, anastrozole, formestan, letrozole leuprorelin, buserelin, goserelin, triptorelin, tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI 182,780, aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, leuprolide, prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone, triamcinolone, interferon β, IL-10, IL-12, etanercept, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone, a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a “dual-function” nitro aromatic, a nitro aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a metal complex of a nitrogen mustard, an anti-CD3 antibody, an anti-CD25 antibody, a tolerance induction agent, minodronic acid or a derivative thereof selected from YM-529, Ono-5920 and YH-529, zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate disodium, metronidazole, misonidazole, benznidazole, nimorazole, RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721, porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen, a non-steroidal anti-inflammatory drug selected from acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, lD09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a lanthanide, PUVA, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, geldanamycin or its derivative 17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate, squalamine, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukin diftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin, tamloxifen and testolactone.  
     
     
         15 . The pharmaceutical combination in accordance with  claim 14 , wherein the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide such as propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, bortezomib, vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a pharmaceutically acceptable salt thereof, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, apolizumab and lD09C3.  
     
     
         16 . The pharmaceutical combination in accordance with  claim 15 , wherein the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from the quinazoline derivative 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a pharmaceutically acceptable salt thereof.  
     
     
         17 . The pharmaceutical combination in accordance with  claim 15 , wherein the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from the di-maleic acid salt of the compound 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the tautomers or stereoisomers thereof.  
     
     
         18 . The pharmaceutical combination in accordance with  claim 15 , wherein the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A pharmaceutical combination preparation kit for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, comprising a therapeutically effective amount of an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRα and β, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof, and at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, and optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy, characterised in that the antagonist is comprised within a first compartment and the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is comprised within a second compartment, such that the administration to a patient in need thereof can be simultaneous, separate or sequential.  
     
     
         20 . The pharmaceutical combination preparation kit in accordance with  claim 19 , wherein the selected protein tyrosine kinase receptor antagonist is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.  
     
     
         21 . The pharmaceutical combination preparation kit in accordance with  claim 20 , wherein the formulation of the selected protein tyrosine kinase receptor antagonist is for oral administration.  
     
     
         22 . A method of treating diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, comprising administering to a human or non-human mammalian patient an effective amount of a pharmaceutical combination or a pharmaceutical combination preparation kit in accordance with  claim 1  or  21 , and optionally adapting the combination or kit for co-treating with radiotherapy or radio-immunotherapy.  
     
     
         23 . A method of treating diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, comprising administering to a human or non-human mammalian patient an effective amount of antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRα and β, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof, in combination with at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent and optionally adapting the combination or kit for co-treating with radiotherapy or radio-immunotherapy.  
     
     
         24 . The method in accordance with  claim 23 , wherein the antagonist is 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a polymorph, metabolite or pharmaceutically acceptable salt thereof.  
     
     
         25 . The method in accordance with  claim 23  wherein the antagonist is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.  
     
     
         26 . A method for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, which method comprises simultaneous, separate or sequential co-administration of effective amounts of: 
 (i)an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRα and β, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof; and    (ii) at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent;    in the form of a combined preparation optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy, to a patient in need of such treatment.    
     
     
         27 . A method for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, which method comprises a simultaneous, separate or sequential co-treatment with an effective amount of an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRα and β, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or with a polymorph, metabolite or pharmaceutically acceptable salt thereof, and with radiotherapy or radio-immunotherapy.  
     
     
         28 . The method in accordance with  claim 26  or  27 , wherein the selected protein tyrosine kinase antagonist is 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a polymorph, metabolite or pharmaceutically acceptable salt thereof.  
     
     
         29 . The method in accordance with  claim 26  or  27 , wherein the selected protein tyrosine kinase antagonist is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.  
     
     
         30 . The method in accordance with any one of  claims 26  to  29 , wherein the selected protein tyrosine kinase antagonist, or its polymorph, metabolite or pharmaceutically acceptable salt, is administered in a daily dosage such that the plasma level of the active substance lies between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing interval.