 synergistic combination
专利摘要:
SYNERGIC COMBINATION. The present disclosure describes a pharmaceutical combination of an anti-CD38 antibody and lenalidomi and a pharmaceutical combination of an anti-CD38 antibody and bortezomib. 公开号:BR112013006769B1 申请号:R112013006769-1 申请日:2011-09-26 公开日:2021-02-02 发明作者:Christofer Samuelsson；Mark Winderlich；Jan Endell；Rainer BOXHAMMER；Lisa Rojkjaer 申请人:Morphosys Ag； IPC主号:
专利说明:
CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of provisional application serial number US 61 / 486,814 filed on May 17, 2011, provisional application serial number US 61 / 468,607 filed on March 29, 2011, provisional application serial number US 61 / 437,696 filed on January 31, 2011 and provisional application serial number US 61 / 386,619 deposited on September 27, 2010, all of which are incorporated by reference in their entirety. BACKGROUND Multiple myeloma is a B-cell malignancy characterized by the latent accumulation in the bone marrow of secreting plasma cells with a low proliferative index and an extended life span. The disease ultimately attacks bones and bone marrow, resulting in multiple tumors and injuries throughout the skeletal system. Approximately 1% of all cancers and slightly more than 10% of all malignancies can be attributed to multiple myeloma (MM). The incidence of MM increases in the aging population with the average age at the time of diagnosis, around 61 years. Currently available therapies for multiple myeloma include chemotherapy, stem cell transplantation, Thalomid (R) (thalidomide), Velcade (R) (bortezomib), Aredia (R) (pamidronate) and Zometa (R) (zoledronic acid). Current treatment protocols that include a combination of chemotherapeutic agents, such as vincristine, BCNU, melphalan, cyclophosphamide, adriamycin and prednisone or dexamethasone, yield a complete remission rate of only about 5% and average survival is approximately 36 to 48 months from the moment of diagnosis. Recent advances in the use of high-dose chemotherapy followed by peripheral mononuclear or autologous bone marrow blood cell transplantation have increased the rate of complete remission and the duration of remission. Even so, overall survival has been prolonged only slightly and no evidence for a cure has been obtained. Ultimately, MM patients often relapse, even on maintenance therapy with interferon-alpha (IFN-a) alone or in combination with steroids. Non-Hodgkin's lymphoma is a broad classification of lymphomas that are cancers originating from the lymphatic system when lymphocytes (B cells or T cells) become malignant and proliferate uncontrollably to form a tumor mass. In total, NHL encompasses about 30 different lymphoma subtypes, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The incidence of NHL will reach over 140,000 in major markets in 2019. Treatment options available include Rituxan / MabThera, combinations of them such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), R-CVP (Rituxan, cyclophosphamide) , vincristine and prednisone), and chemotherapy. In addition, after remission or after relapse, hematopoietic stem cell transplantation can be reconsidered. Despite current treatment options, however, survival rates in high-risk groups for aggressive NHL can be as low as 30% in the 5-year period. Therefore, there remains a great unmet need for treatments and effective treatment combinations. CD38 is an example of an antigen expressed on such malignant cells in plasma and other lymphocytes. Functions attributed to CD38 include both receptor mediation in adhesion and signaling events and (ecto-) enzymatic activity. As an ectoenzyme, CD3 8 uses NAD + as a substrate for the formation of cyclic ADP (cADPR) and ADPR ribose, but also nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to act as second messengers for Ca2 + mobilization. When converting NAD + to cADPR, CD3 8 regulates the concentration of extracellular NAD + and, therefore, cell survival by modulating NAD-induced cell death (NCID). In addition to Ca2 + signaling, CD38 signaling occurs via cross-line with antigen receptor complexes in B and T cells or other types of receptor complexes, for example, MHC molecules and is thus involved in various cellular responses, but also in IgG switching and secretion. Antibodies specific for CD38 are described in WO No. 1999/62526 (Mayo Foundation); WO 200206347 (Crucell Holland); U.S. 2002164788 (Jonathan Ellis) which are incorporated by reference in their entirety; WO 2005/103083 (MorphoSys AG), serial number US 10 / 588,568 which are incorporated by reference in their entirety, WO 2006/125640 (MorphoSys AG), Serial number US 1 1 / 920,830 which are incorporated as a reference reference in its entirety and W02007 / 042309 (MorphoSys AG), serial number US 12 / 089.806 which are incorporated by reference in their entirety; WO 2006099875 (Genmab), U.S. serial number 1 1 / 886,932 which are incorporated by reference in their entirety; and WO 08/047242 (Sanofi-Aventis), U.S. serial number 12 / 441,466 which are incorporated by reference in their entirety. The combinations of antibodies specific for CD38 and other agents are described in documents No. WO 200040265 (Research Development Foundation); WO 2006099875 and WO 2008037257 (Genmab); and WO 2010061360, WO 2010061359, WO 2010061358 and WO 2010061357 (Sanofi Aventis), which are all incorporated by reference in their entirety. It is evident that, despite recent progress in the recognition and development of anticancer agents, many forms of cancer involving CD38-expressing tumors still have a poor prognosis. Thus, there is a demand for methods to treat such forms of cancer. SUMMARY In one aspect, the present disclosure relates to a synergistic combination of an antibody specific for CD38 and thalidomide or an analogue thereof, for example, lenalidomide. In another aspect, the present disclosure relates to a synergistic combination comprising an antibody specific for CD38 and bortezomib or another proteasome inhibitor. Such combinations are useful in the treatment of cancers, such as multiple myeloma and / or non-Hodgkin's lymphoma. In vitro and in vivo models are considered indicators of how a certain compound or combination of compounds would behave in humans. Here, combinations of an antibody specific for CD38 and lenalidomide were tested on human multiple myeloma cell lines and synergy was identified. In addition, the combination of an antibody specific for CD3 8 and lenalidomide and a combination of an antibody specific for CD38 and bortezomib was tested in mouse models against both multiple myeloma cells and Burkitt's lymphoma cells (a form of NHL) and synergy has been identified. Therefore, the combinations will be effective in treating humans with multiple myeloma and / or non-Hodgkin's lymphoma. In addition, the CD38-specific antibody exemplified in this specification is currently undergoing clinical trials, in which such combinations can be confirmed in humans. When compounds are combined either in vitro or in vivo, the combination is expected to have only additive effects. Quite unexpectedly, the inventors found that the combination of a particular anti-CD38 antibody and lenalidomide mediated a synergistic level of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in both AMO-1 and NCI- multiple myeloma cell lines. H929. In addition, and also unexpectedly, a particular anti-CD38 antibody, when combined with lenalidomide or when combined with bortezomib, mediated a synergistic level of reduction in bone lysis in the SCID mouse model NCI-H929 and, synergistically, increased median survival days in the SCID RAMOS mouse model. Therefore, both the combination of the specific antibody exemplified for CD38 and lenalidomide and the specific antibody exemplified for CD38 and bortezomib behaved synergistically in the in vitro and / or in vivo models relevant to multiple myeloma and / or non-Hodgkin's lymphoma. One aspect of the present disclosure comprises a combination in which the CD38 specific antibody comprises an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6) and thalidomide or an analog thereof is lenalidomide. In preferred aspects, the combination is used to treat multiple myeloma and / or non-Hodgkin's lymphoma. One aspect of the present disclosure comprises a combination in which the CD38 specific antibody comprises an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6) and the proteasome inhibitor is bortezomib. In preferred aspects, the combination is used to treat multiple myeloma and / or non-Hodgkin's lymphoma. DESCRIPTION OF THE DRAWINGS Figure 1 shows the effects of lenalidomide only on CD38 expression in AMO-1 cells. Figure 2 shows the effects of lenalidomide only on cell proliferation in various multiple myeloma cell lines. This measure represents the relative cytotoxicity of lenalidomide in each cell line. Figure 3 shows the mediation of ADCC in AMO-1 cells by the combination of MOR03087 and lenalidomide. PBMCs and AMO-1 cells were treated with lenalidomide before treatment with MOR03087. MOR03207 alloys lysozyme and is used as an isotype control, as well as IgGl. LEN stands for lenalidomide. "Theoretical" represents the addition of the MOR03087 value only and the LEN value only. The data shown are the average of Table 3b. Figure 4 shows the mediation of ADCC in AMO-1 cells by the combination of MOR03087 and lenalidomide. Only PBMCs were treated with lenalidomide before treatment with MOR03087. MOR03207 alloys lysozyme and is used as an isotype control, as well as IgGl. LEN stands for lenalidomide. "Theoretical" represents the addition of the MOR03087 value only and the LEN value only. The data shown are the average of Table 4b. Figure 5 shows the effects of lenalidomide only on CD38 expression in NCI-H929 cells. Figure 6 shows the mediation of ADCC in NCI-H929 cells by the combination of MOR03087 and lenalidomide. PBMCs and NCI-H929 cells were treated with lenalidomide before treatment with MOR03087. Theoretical represents the combination calculated using the fractional product concept by Chou et al. The data shown are the average of Table 7b. Figure 7 shows the mediation of ADCC in NCI-H929 cells by the combination of MOR03087 and lenalidomide. Only PBMCs were treated with lenalidomide before treatment with MOR03087. Theoretical represents the combination calculated using the fractional product concept by Chou et al. The data shown are the average of Table 8b. Figure 8 shows the growth inhibition of several multiple myeloma cell lines caused by bortezomib alone. The IC50 in AMO-1 cells was 3.9 nM. The IC50 in LP-1 cells was 6.1 nM. The IC50 in NCI-H929 cells was 3.3 nM. The IC50 in RPMI-8226 cells was 9.0 nM. Figure 9 shows the mediation of ADCC in NCI-H929 cells by combining MOR03087 at 15 μg / ml and Velcade (R) (bortezomib). The two graphs represent two different donors. Figure 10 shows the mediation of ADCC in LP-1 cells by combining MOR202 at 15 μg / ml and Velcade (R) (bortezomib). The two graphs represent two different donors. Figure 11 shows the amino acid sequence of MOR202. Figure 12 shows the Best Fit curve, as described in Chou et al. , of the combination of lenalidomide and MOR202 in ADCC mediation in AMO-1 cells and is also representative for the Best Fit curve generated for the analysis of ADCC mediation in NCI-H929 cells. Figures 13 to 18 show the Chou factor synergy analysis for six separate experiments using the combination of MOR202 and lenalidomide in the mediation of ADCC in AMO-1 cells. Figure 13 shows experiment 1. Figure 14 shows experiment 2. Figure 15 shows experiment 3. Figure 16 shows experiment 4. Figure 17 shows experiment 5. Figure 18 shows experiment 6. Figures 13 to 15 were derived from from the three experiments shown in Tables 3a ace Figure 3. Figures 16 to 18 were derived from the three experiments shown in Tables 4a ace Figure 4. Figure 19 shows the average total bone volume of MicroCT Scan for each of the study groups described in Example 7, where the results are shown in Table 11. Figure 20 shows the average total bone volume of MicroCT Scan for each of the study groups described in Example 11, where the results are shown in Table 17. DETAILED DESCRIPTION OF THE INVENTION "Synergy", "synergism" or "synergistic" means more than the expected additive effect of a combination. The "synergy", "synergism" or "synergistic" effect of a combination is determined in this document by the methods of Chou et al. and / or Clarke et al. See Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58: 621 to 681 (2006), which is incorporated by reference in its entirety. In Chou et al. , multiple methods of determining synergism are revealed and at least one of these methods is used in this document. See also Clarke et al. , Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46: 255-278 (1997), which is incorporated by reference in its entirety. The term "antibody" means monoclonal antibodies that include any isotype such as IgG, IgM, IgA, IgD and IgE. An IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called "complementarity determining regions" ("CDRs") or "hypervariable regions" that are primarily responsible for binding an epitope to an antigen are referred to as CDR1, CDR2, and CDR3, numbered sequentially from of the N-terminal. The most highly conserved portions of the variable regions outside the CDRs are called "structure regions". An "antibody fragment" means an Fv, scFv, dsFv, Fab, Fab 'F (ab') 2 fragment or other fragment that contains at least one variable heavy or variable light chain, each containing CDRs and structure regions . THALOMID (R) (thalidomide) in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma and is marketed by Celgene. A "thalidomide analogue" includes, but is not limited to, thalidomide itself, lenalidomide (CC-5013, Revlimid (TM)), Pomalidomide (CC4047, Actimid (TM)) and the compounds disclosed in WO 2002068414 and WO 2005016326 , which are incorporated by reference in their entirety. The term refers to a synthetic chemical compound that uses the thalidomide structure as a backbone (for example, side groups have been added or such groups have been excluded from the parent structure). The analog differs in structure from thalidomide and its metabolite compounds as by a difference in the length of an alkyl chain, a molecular fragment, by one or more functional groups, or a change in ionization. The term "thalidomide analog" also includes thalidomide metabolites. Thalidomide analogs include the racemic mixture of the S enantiomer and the R of a respective compound and the S enantiomer or for the R enantiomer individually. The racemic mixture is preferred. Thalidomide analogs include compounds of the following structures: (A) Lenalidomide (B) Thalidomide where R21, R22, R23 and R24 are (each) independently H, alkoxy, amine or alkylamine and where R21, R22, R23 and R24 are (each) independently H, alkoxy, amine or alkyl Lenalidomide is currently marketed as Revlimid (R) by Celgene for the treatment of multiple myeloma. Lenalidomide is described as having at least the following properties in relation to the treatment of tumors, a) cytotoxic to tumor cells, Gandhi et al. , Lenalidomide inhibits the proliferation of Namalwa CSN.70 cells and interferes with Gabl phosphorylation and assembly of an adapter protein complex, Leuk Res., 30 (7): 849 to 858 (2006), which is incorporated by reference in its totality; b) activates natural killer cells (Nk), Gandhi et al. , Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T cell and NK function, Curr Cancer Drug Targets, 1; 10 (2): 155 to 167 (March 2010), which it is incorporated by reference in its entirety; and c) upwardly regulates CD38 expression in tumor cells, see Lapalombella et al. , Lenalidomide downwardly regulates the CD20 antigen and antagonizes rituxima.be antibody-dependent and direct cell cytotoxicity in primary chronic lymphocytic leukemia cells, Blood, 112: 13, 5180 to 5189 (December 15, 2008), which is incorporated as a reference in its entirety. "LEN" is used to describe lenalidomide. As described, thalidomide analogs up-regulate CD38 expression in tumor cells. Other agents that upwardly regulate the expression of CD38 on the surface of tumor cells are described in documents No. WO 00/40265, serial number US 09 / 226.895, which are incorporated by reference in their entirety (Research Development Foundation ). A "proteasome inhibitor" refers to a compound that blocks the action of proteasomes, that is, cell complexes that break down proteins, such as the p53 protein. Several classes of proteasome inhibitors are known. The class of peptide boronates includes bortezomib (INN, PS-341; Velcade (R)), a compound that is approved in the USA for the treatment of relapsed multiple myeloma. Another peptide boronate is CEP-18770. Other classes of proteasome inhibitors include peptide aldehydes (for example, MG132), vinyl sulfone peptide, peptide epoxyketones (for example, epoxomycin, carfilzomib), β lactone inhibitors (for example, lactacistin, MLN 519, NPI-0052, Salinosporamide A), compounds that create dithiocarbamate complexes with metals (for example, Disulfiram, a drug that is also used to treat chronic alcoholism) and certain antioxidants (for example, Epigallocatechin-3-gallate) catechin-3-gallate, and Salinosporamide A. "VH" refers to the variable region of an immunoglobulin heavy chain of an antibody or antibody fragment. "VL" refers to the variable region of the immunoglobulin light chain of an antibody or antibody fragment. The term "CD38" refers to the protein known as CD38 which has the following synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, Ribose cyclic ADP hydrolase 1, TIO. Human CD38 has the amino acid sequence: MANCEFS PVSGDKPCCRLSRRAQLCLGVSILVLILVWLAVWPRWRQQWS GPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKL GTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSC PDWRKDCSNNPVSVFWKTVSRRFAEAACDWHVMLNGSRSKIFDKNSTFGSVEVHNLQPEK VQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSS CTSEI (SEQ ID NO: 7). "MOR202" is an anti-CD38 antibody whose amino acid sequence is provided in Figure 11. "MOR202" and "MOR03087" are used interchangeably to describe the antibody shown in Figure 11. The DNA sequence encodifica heavy domain MOR202 variable is: CAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGCAGC CTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGAATTGGGTGC GCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATCTCTGGTGATCCTAGCAATAC CTATTATGCGGATAGCGTGAAAGGCCGTTTTACCATTTCACGTGATAATTCGAAAAACACC CTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCCGTGTATTATTGCGCGCGTG ATCTTCCTCTTGTTTATACTGGTTTTGCTTATTGGGGCCAAGGCACCCTGGTGACGGTTAG CTCA (SEQ ID NO: 12) DNA sequence encodifica Domain Light MOR202 variable is: GATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAGACC GCGCGTATCTCGTGTAGCGGCGATAATCTTCGTCATTATTATGTTTATTGGTACCAGCAGA AACCCGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCGTCCCTCAGGCATCCC GGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGACCCTGACCATTAGCGGCACTCAG GCGGAAGACGAAGCGGATTATTATTGCCAGACTTATACTGGTGGTGCTTCTCTTGTGTTTG GCGGCGGCACGAAGTTAACCGTTCTTGGCCAG (SEQ ID NO: 13) Antibody "Ref mAB5" is an anti-CD38 antibody whose amino acid sequence is provided below (CDRs are in bold and su blinhadas): VH: QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTI YPGDGDTGYAQKFQGKATLTADKSS KTVYMHLS SLAs EDSAVYYCARGDYYGSNSLDYWGQ GTSVTVSS (SEQ ID NO: 21) VL: DIVMTQSHLSMSTSLGDPVSITCKASQDVSTWAWYQQKPGQSPRRLIYSASYRYIGVPDR FTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKRT (SEQ ID NO: 22) Ref mAB5 CDRs are defined by Kabat et al. and an antibody that has the same CDRs as Ref mAB5 is described in WO 2008/047242, U.S. 12 / 441,466, which are incorporated by reference in their entirety. "Fc Region" means the constant region of an antibody that in humans can be one of the subclasses of IgGl, 2, 3, 4 or others. Human Fc region sequences are available at IMGT, Human IGH REGIONS c, http://www.imgt.org/lMGTrepertoire/Proteins/protein/human/IGH /IGHC/Hu_IGHCallgenes.html (taken May 16, 2011 ). "Intensifies ADCC activity" means an increase in the mediation of antibody-dependent cell-mediated cytotoxicity. Amino acid modifications in the Fc region that result in an intensification of ADCC activity are disclosed in WO 200042072 Genentech, WO 2004029207A2 Xencor and WO 2004063351 A2 Macrogenics, which are all incorporated by reference in their entirety. "MOR03207" is an antibody whose amino acid sequence is: VH: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWSWIRQSPGRGLEWLG RIYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARLDHRYHEDTVY PGMDVWGQGTLVTVSS (SEQ ID NO: 8) VL: DIELTQPPSVSVAPGQTARISCSGDNLPAYTVTWYQQKPGQAPVLVIYDDS DRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCASWDPSSGWFGGGTKLTVLGQ (SEQ ID NO: 9). MOR03207 alloys lysozyme and is used as an isotype control, as well as IgGl. A "combination" means more than one item, for example, a compound such as an antibody and lenalidomide. The present disclosure also relates to combinations, pharmaceuticals and pharmaceutical compositions that contain the described combinations. The two components of the synergistic combination of the present invention, for example, the specific antibody to CD38 and lenalidomide, can be administered together or separately. When administered together, the two components can be formulated together in a pharmaceutical composition that can include a pharmaceutically acceptable carrier or excipient. Alternatively, the two components can also be formulated in different pharmaceutical compositions. In that case, the two components can be administered simultaneously or subsequently. In one embodiment, thalidomide or an analogue thereof, for example, lenalidomide, is administered before and / or separately from the administration of the specific antibody to CD38, for example, MOR202. In an additional embodiment, lenalidomide, is administered at least 72 hours before administration of the CD38 specific antibody, for example, MOR202. This time period allows mediated upward regulation of CD38 lenalidomide in the target cells. A pharmaceutical composition includes an active agent, for example, an antibody for therapeutic use in humans. A pharmaceutical composition can include acceptable carriers or excipients. "Administered" or "administration" includes, but is not limited to, delivery via an injectable form such as an intravenous, intramuscular, intradermal or subcutaneous route or mucous route, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution, capsule or tablet. A "therapeutically effective amount" of a compound or combination refers to an amount sufficient to cure, alleviate or partially retain the clinical manifestations of a given disease or condition and its complications. The amount that is effective for a particular therapeutic purpose will depend on the seriousness of the disease or injury, as well as the individual's weight and general condition. It will be understood that the determination of an appropriate dosage can be achieved, with the use of routine experimentation, by building a matrix of values and by testing different points in the matrix, all of which are within the common skills of a trained physician. or clinical scientist. Surprisingly, the combination of a particular anti-CD38 antibody and lenalidomide was found to mediate a synergistic level of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in both AMO-1 and NCI-H929 multiple myeloma cells. Furthermore, and also unexpectedly, a particular anti-CD38 antibody when combined with lenalidomide mediated a synergistic level of reduction in bone lysis in the SCID mouse model NCI-H929 and synergistically increased median survival days in the model of mouse SCID RAMOS. Therefore, the combination of the specific antibody exemplified for CD38 and lenalidomide behaved synergistically in both in vitro and in vivo models relevant to multiple myeloma and / or non-Hodgkin's lymphoma. Therefore, this combination yields synergistic results in the treatment of multiple myeloma and / or non-Hodgkin's lymphoma in humans. Lenalidomide is a thalidomide analogue, so other thalidomide analogs such as pomalidomide or thalidomide itself are also expected to lead to synergistic effects when used in combination with an anti-CD38 antibody. In addition, according to thalidomide or an analogue of the same regulating upwardly the expression of CD3 8 in multiple myeloma cell lines, therefore, it is expected that synergism should result when other agents that upwardly regulate the expression of CD38 on the surface of tumor cells, for example, transretinoic acid and anti-CD38 antibodies are used in combination. Surprisingly, it was found that the combination of a particular anti-CD38 antibody and bortezomib mediated a high level of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in NCI-H929 and LP-1 multiple myeloma cell lines. In addition, and also surprisingly, it was found that the combination of a particular anti-CD38 antibody and bortezomib mediated a synergistic level of reduction in bone lysis in the SCID mouse model NCI-H929 and synergistically increased median survival days in the mouse model SCID RAMOS. Therefore, the combination of the specific antibody exemplified for CD38 and bortezomib behaved synergistically in the in vivo models relevant to multiple myeloma and / or non-Hodgkin's lymphoma. Therefore, this combination yields synergistic results in the treatment of multiple myeloma and / or non-Hodgkin's lymphoma in humans. It is expected that other proteasome inhibitors such as Disulfiram, Epigallocatechin-3-gaiate and Salinosporamide will lead to similar effects when used in combination with an anti-CD38 antibody. The "CDRs" in this document are defined either by Chothia et al. , Rabat et al. or by an internal numbering convention. See Chothia C, Lesk AM. (1987) Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol., 196 (4): 901 to 917, which is incorporated by reference in its entirety. See Rabat E.A, Wu T.T., Perry H.M., Gottesman K.S. and Foeller C. (1991). Sequences of Proteins of Immunological Interest. 5th edition, NIH Publication No. 91-3242, United States Department of Health and Human Services, Washington, DC, which is incorporated by reference in its entirety. MODALITIES One aspect of the present disclosure comprises a synergistic combination of an antibody specific for CD38 and (a) thalidomide or an analogue thereof or (b) a proteasome inhibitor for use in the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. One aspect of the present disclosure comprises a combination of an antibody specific for CD38 and thalidomide or an analogue thereof. In modalities, the combination is synergistic. In embodiments, the CD38-specific antibody comprises an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a region DLPLVYTGFAY sequence HCDR3 (SEQ ID NO: 3), SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and QTYTGGASL sequence LCDR3 region (SEQ ID NO : 6). In embodiments, the CD38 specific antibody comprises a HCDR1 region of DYWMQ sequence (SEQ ID NO: 15), a HCDR2 region of TIYPGDGDTGYAQKFQG (SEQ ID NO: 16), a HCDR3 region of GDYYGSNSLDY sequence (SEQ ID NO: 17) , an LCDR1 sequence of KASQDVSTWA sequence (SEQ ID NO: 18), an LCDR2 region of SASYRYI sequence (SEQ ID NO: 19) and an LCDR3 region of QQHYSPPYT sequence (SEQ ID NO: 20). In one aspect, the combination is used to treat multiple myeloma and / or non-Hodgkin's lymphoma. The modalities comprise a combination in which the thalidomide analog is lenalidomide. One aspect concerns pharmaceutical compositions that comprise the combinations. In embodiments, the composition comprises an acceptable carrier. In embodiments, the composition is administered in an effective amount. One aspect of the present disclosure comprises a synergistic combination of an antibody specific for CD38 comprising an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 1) or sequence SYYMN (SEQ ID NO: 14), an HCDR2 region of sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a region LCDR3 of QTYTGGASL sequence (SEQ ID NO: 6) and lenalidomide for the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. A further embodiment comprises a combination in which the antibody comprises a variable heavy chain sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 10) and a variable light chain sequence DIELTQP PSVSVAPGQTARIS CSGDNLRHYYVYWYQQKPGQAPVLVIYGDS KRPSGIPERF SGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 11) • One aspect of the present disclosure comprises a synergistic combination of a CD38-specific antibody comprising a DYWMQ sequence HCDR1 region (SEQ ID NO: 15), a TIYPGDGDTGYAQKFQG sequence (SEQ ID NO: 16), a sequence HCDR3 region GDYYGSNSLDY (SEQ ID NO: 17), an LCDR1 region of KASQDVSTWA sequence (SEQ ID NO: 18), an LCDR2 region of SASYRYI sequence (SEQ ID NO: 19) and an LCDR3 region of QQHYSPPYT sequence (SEQ ID NO: 20) and lenalidomide for the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. A further embodiment comprises a combination in which the antibody comprises a variable heavy chain sequence QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYA QKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSS (SEQ ID NO: 21) and a variable light chain sequence DIVMTQSHLSMSTSLGDPVSITCKASQDVSTWAWYQQKPGQSPRRLIYSASYRYIGVPDR FTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKRT (SEQ ID NO: 22). In embodiments, the antibody has an IgGl Fc region. In embodiments, the antibody comprises a modified Fc region in which said modification enhances ADCC activity. In another aspect, the components of the combination, the specific antibody to CD38 and lenalidomide are administered separately. In one embodiment, lenalidomide is administered prior to administration of the CD38 specific antibody. In an additional embodiment, lenalidomide is administered at least 72 hours before administration of the CD38 specific antibody. In another aspect, the synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO : 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6) and lenalidomide have the ability to mediate extermination of AMO-1 cells and / or NCI-H929 cells of CD38 expression by ADCC in the presence of isolated human PBMCs with at least two efficacy , three times, four times or five times greater than lenalidomide alone. In another aspect, the synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO : 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6) and lenalidomide has the ability to reduce bone lysis with an efficacy at least twice, three times, four times or five times greater than lenalidomide alone. Another aspect comprises a method of treating multiple myeloma and / or non-Hodgkin's lymphoma in an individual in need of it, which method includes administration of an antibody specific for CD38 which comprises an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 1) or SYYMN sequence (SEQ ID NO: 14), an HCDR2 sequence of GISGDPSNTYYADSVKG (SEQ ID NO: 2), an HCDR3 sequence of DLPLVYTGFAY (SEQ ID NO: 3), an LCDR1 region of SGDNLRHYYVY sequence (SEQ ID NO : 4), an LCDR2 region of GDSKRPS sequence (SEQ ID NO: 5) and an LCDR3 region of QTYTGGASL sequence (SEQ ID NO: 6) and lenalidomide to an individual who has multiple myeloma or non-Hodgkin's lymphoma. In modalities, the combination is administered in an effective amount. Another aspect comprises a combination comprising an antibody specific for CD38 comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a sequence LCDR3 region QTYTGGASL (SEQ ID NO: 6) and lenalidomide. In one embodiment, the combination is used to treat cancer. In an additional modality, the cancer is selected from multiple myeloma and non-Hodgkin's lymphoma. Another aspect comprises a combination of a CD38 specific antibody and a proteasome inhibitor. In modalities, the combination is synergistic. In embodiments, the CD38-specific antibody comprises an HCDR1 region of GFTFSSYYMN sequence (SEQ ID NO: 1) or SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a region DLPLVYTGFAY sequence HCDR3 (SEQ ID NO: 3), SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and QTYTGGASL sequence LCDR3 region (SEQ ID NO : 6). In one aspect, the combination is used to treat multiple myeloma and / or non-Hodgkin's lymphoma. In embodiments, the combination comprises a proteasome inhibitor that is bortezomib. One aspect concerns pharmaceutical compositions that comprise the combinations. In embodiments, the composition comprises an acceptable carrier. In embodiments, the composition is administered in an effective amount. One aspect of the present disclosure comprises a synergistic combination of an antibody specific for CD38 comprising an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 1) or sequence SYYMN (SEQ ID NO: 14), an HCDR2 region of sequence GISGDPSNTYYADSVKG (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a region LCDR3 of QTYTGGASL sequence (SEQ ID NO: 6) and bortezomib for the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. A further embodiment comprises a combination in which the antibody comprises a variable heavy chain QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVS S sequence (SEQ ID NO: 10) and a variable light chain sequence DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERF SGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 11). In embodiments, the antibody has an IgGl Fc region. In embodiments, the antibody comprises a modified Fc region in which said modification enhances ADCC activity. In one embodiment, the combination is used to treat cancer. In an additional modality, the cancer is selected from multiple myeloma and non-Hodgkin's lymphoma. In another aspect, the components of the combination, the antibody and the proteasome inhibitor are administered separately. In another aspect, the synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO : 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6) and bortezomib has the capacity to mediate the extermination of LP-1 cells and / or CD38 expression NCI-H929 cells by ADCC in the presence of isolated human PBMCs with at least two efficacy, three times, four times or five times greater than bortezomib alone. In another aspect, the synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO : 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and an LCDR3 region of sequence QTYTGGASL (SEQ ID NO: 6) and bortezomib has the ability to reduce bone lysis with an efficacy at least twice, three times, four times or five times greater than bortezomib only. In another aspect, the present disclosure comprises a method of treating multiple myeloma and / or non-Hodgkin's lymphoma in an individual in need thereof, which method comprises administration of a specific antibody to CD38 which comprises a HCDR1 region of GFTFSSYYMN sequence (SEQ ID NO: 1) or SYYMN sequence (SEQ ID NO: 14), a GISGDPSNTYYADSVKG sequence HCDR2 region (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a sequence LCDR1 region SGDNLRHYYVY (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a QTYTGGASL sequence LCDR3 region (SEQ ID NO: 6) and bortezomib to an individual who has multiple myeloma or non-Hodgkin's lymphoma . In modalities, the combination is administered in an effective amount. Another aspect comprises a combination comprising an antibody specific for CD38 comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a sequence LCDR3 region QTYTGGASL (SEQ ID NO: 6) and bortezomib. One aspect comprises a synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a QTYTGGASL sequence LCDR3 region (SEQ ID NO: 6) and (a) thalidomide or an analogue thereof or (b) a proteasome inhibitor, for use in the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. The methods comprise a combination wherein the antibody comprises a variable heavy chain sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS (SEQ ID NO: 10) and a variable light chain sequence DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERF SGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ ID NO: 11) • The modalities comprise a combination in which the antibody comprises an IgGl Fc region. The embodiments comprise a combination in which the antibody comprises a modified Fc region in which said modification enhances ADCC activity. The modalities comprise a combination, wherein said CD38-specific antibody and said thalidomide or an analogue thereof or proteasome inhibitor are administered separately. The modalities comprise a combination that has the ability to reduce bone lysis with an efficacy at least twice as high as lenalidomide and / or bortezomib only. The modalities comprise a combination in which said CD38 specific antibody is combined with thalidomide or an analogue thereof. The modalities comprise a combination in which the thalidomide analog comprises lenalidomide. The modalities comprise a combination in which lenalidomide is administered prior to administration of the CD38 specific antibody. The modalities comprise a combination in which lenalidomide is administered at least 72 hours before the administration of the specific antibody to CD3 8. The modalities comprise a combination of an antibody specific for CD38 and lenalidomide which has the ability to mediate the extermination of NCI-H929 and / or AMO1 cells of CD3 8 expression by ADCC in the presence of isolated human PBMCs with at least an efficacy twice as long as lenalidomide only. The embodiments comprise a combination comprising said CD38 specific antibody and a proteasome inhibitor. In some embodiments, the proteasome inhibitor is bortezomib. The modalities comprise a combination of an antibody specific for CD38 and bortezomib which has the ability to mediate the extermination of NCI-H929 and / or LP38 cells of CD38 expression by ADCC in the presence of isolated human PBMCs with an efficacy by less than twice as large as bortezomib only. One aspect comprises a synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a sequence LCDR3 region QTYTGGASL (SEQ ID NO: 6) and lenalidomide or another thalidomide analog for use in the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. One aspect comprises a synergistic combination of a CD38-specific antibody comprising an HCDR1 region of the GFTFSSYYMN sequence (SEQ ID NO: 1) or of the SYYMN sequence (SEQ ID NO: 14), an HCDR2 region of the GISGDPSNTYYADSVKG sequence (SEQ ID NO: 2), a DLPLVYTGFAY sequence HCDR3 region (SEQ ID NO: 3), a SGDNLRHYYVY sequence LCDR1 region (SEQ ID NO: 4), a GDSKRPS sequence LCDR2 region (SEQ ID NO: 5) and a sequence LCDR3 region OTYTGGASL (SEQ ID NO: 6) and bortezomib or another proteasome inhibitor for use in the treatment of multiple myeloma and / or non-Hodgkin's lymphoma. EXAMPLES Example 1: Expression of CD38 on the surface of several cell lines The cell lines in Table 1 were tested for CD38 expression level. Table 1 Bone marrow samples (4 to 10 ml aspirated) from patients with multiple myeloma and extramedullary tumor plasmacytoma samples were obtained after 10 informed consent from Klinikum rechts der Isar ("KrdI") (Munich, Germany). The samples were subjected to organic transistor centrifugation and additionally the plasma cell enrichment was achieved through magnetically activated cell classification. 15 The cells were stained with a CD38-PE antibody QuantiBRITETM directly identified (Becton Dickinson GmbH, Clone HB7, CAT No. 342371) which is specific for CD38. The "Cell-Linked Antibodies" (ABCs) were determined using flow cytometry based on the 20 QuantiBRITETM system that measures geometric mean (GeoMean) per cell. The conversion of GeoMean measured in a corresponding amount of ABC per cell was performed with GraphPad PRISMTM software. The ABC values are assumed to be added to the number of CD3 8 molecules per cell, since CD3 8-PE Quant iBRITE <TM> carries one PE molecule per antibody. The results are shown in Table 2. Example 2: Evaluation of the effect of Lenalidomide on the upward regulation of CD38 in several cell lines In order to determine whether lenalidomide induced upward regulation of CD38 in multiple myeloma and plasmacytoma cells in Table 1, cell lines were incubated with 100 μm lenalidomide and subsequently CD38 surface expression was analyzed by FACS. Materials and methods About 2x105 cells from each of the cell lines in Table 1 were plated in 48-well plates in standard RPMI medium. Lenalidomide, purchased from Selleck Chemicals (LLC S1029, CAS No. 191732-6; Lot: S10290), was applied to the respective wells at a final concentration of 100μrn in a volume of 750 μl containing 20% FCS and 0.1 % DMSO. As a negative control, 0.1% DMSO in medium supplemented with FCS was used and plates were incubated for 24 hours, 48 hours and 72 hours at 37 ° C and 5% CO2 in a humidified incubator. The cells were resuspended by gentle pipetting and 250 μl of cell suspension per incubation period was transferred to a well of a 96-well round bottom plate. The cells were washed by centrifugation for 1 min at 700 X g and resuspended in 150 μl of cold FACS buffer (1 x PBS supplemented with 3% FCS). The cells were pelleted again by centrifugation and were resuspended in 150 μl of FACS buffer that contains 15 μg / ml of anti-CD38 antibody (MOR202, IgGl) or controls the MORO3207 antibody and incubated for 1 hour on ice. The cells were washed 3 times by centrifugation and resuspended in FACS buffer supplemented with secondary antibody identified as PE (PE-Fab2 fragment, goat anti-human IgG, Fc fragment specific; Jackson Immuno Research; CAT: 109-1 16-098; Lot: 80938). The cells were incubated for 45 minutes on ice, then washed 3 times by centrifugation and resuspended in FACS buffer. The cell suspensions were then subjected to FACS analysis using a FACS arrangement device. The baseline CD38 expression of each cell line and the affect of lenalidomide on CD38 expression are shown in Table 2. Additionally, the affect of lenalidomide on CD38 expression of AMO-1 cells is shown in Figure 1 and the affect of lenalidomide in CD3 8 expression of NCI-H929 cells is shown in Figure 5. Table 2 Example 3: Inhibition of cell proliferation of AMO-1 using Lenalidomide only The cytotoxicity of Lenalidomide was tested on AMO-1 cells. The cells were collected and distributed in 96-well plates with 5000 cells per well. Increasing amounts of Lenalidomide were added to the wells and the plates were incubated for 24 hours, 48 hours and 72 hours at 37 ° C in a humidified incubator (5% CO2). After incubation, the plates were analyzed for cell proliferation in an assay based on quantitative colorimetric XTT using the cell proliferation kit II (ROCHE, Cell Proliferation Kit II, Cat. No: 11465015001). For subsequent measurements, the plates were subjected to Tecan Gênios Reader and absorbance at 492 nM was detected. The results were shown in Figure 2. Example 4: Synergistic combination of MOR0202 and Lenalidomide in AMO-1 cells AMO-1 cells were selected for testing with the combination of MOR202 and lenalidomide. AMO-1 cells are similar to plasmacytoma cells in humans in which both have a low baseline CD3 8 expression and CD3 8 is significantly upwardly regulated in both after treatment with lenalidomide as shown in Table 2. PBMCs were isolated by recently isolated human blood density gradient centrifugation. The blood isolated from different donors was layered in a defined volume of Biocoll (Biochrome AG; CAT #: L61 15; LOT #: 1050T) in a Falcon tube and centrifuged at 380g. PBMCs were isolated and supplemented with RPMI medium. After 72 hours, cells were counted and PBMCs were adjusted to a concentration of 6.6 x 10 6 / ml, while AMO-1 cells were adjusted to a final concentration of 2.5 x 10 5 / ml. For further identification in flow cytometry, AMO-1 cells were stained for 3 min with 0.1 μg / ml of CalceinAM (Calcein: 1 mg / ml of stock solution, Invitrogen, Cat #: C3099) and washed three times by gentle centrifugation. 100 μl of target cell suspension was mixed with 100 μl of PBMCs to achieve a 1:30 ratio. The MOR202 antibody or MOR03207 antibody (negative control) was added to a final concentration of 15 μg / ml. The cell suspensions were further incubated for 4 h at 37 ° C. In order to detect dead AMO-1 cells, the cell suspensions were stimulated with propidium iodide (PI) and subsequently analyzed by flow cytometry. The target cells were separated by closing CalceinAM positive cell populations and cells exterminated by ADCC were quantified. In total, six experiments were carried out in order to determine the mediation of ADCC in AMO-1 cells by the combination of MOR202 and lenalidomide. In three experiments, PBMCs and AMO-1 cells were treated with lenalidomide before treatment with MOR202, the results are shown in Tables 3a to 3c and Figure 3. In three additional experiments, only PBMCs were treated with lenalidomide before treatment with MOR202, the results are shown in Tables 4a ace Figure 4. Table 3 Both Efetor cells and AMO-1 cells were treated with Lenalidomide before treatment with MOR202. Single and combination doses of 10 μm LEN and 15 μg / ml of MOR03207 and MOR202 were used. Data are presented in the following three ways as a) raw data (% dead cells), b) normalized specific extermination data where the MOR202 treatment group is set to 1 (100%) and c) normalized specific extermination data where the theoretical combination is set to 1 (100%). Table 3a represents raw data. Table 3a dead. The groups of DMSO, MOR03207, MOR03207 + DMSO, LENO, LEN10 without PBMCs and DMSO without PBMCs are controls. Table 3b represents the data in Table 3a, but normalized where the MOR202 treatment group is set to 1 (100%). Table 3b represents the addition of MOR202 values only and LEN values only. The normalized data in Table 3b are calculated as follows. Table 3a represents the number of dead cells. Therefore, the specific extermination values in Table 3b are calculated by subtracting the values from the controls. Then, the specific extermination values are compared to the MOR202 group which is set to 1. The averages of the results in Table 3b are shown in Figure 3. 1. Determination of synergism 1.1 Chou et al. The Chou-Talalay methods were used to determine synergism. See Chou TC, Talalay P, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27 to 55 (1984) which is incorporated by reference in its entirety. Synergism analysis is performed using the Cl-isobol method. Medium effect equation The average effect equation models of the effect of an inhibitor (such as a drug) such as Fa / Fu = (D / D50) "m where D is the dose, Fa and Fu are the fractions of the system affected and not affected by the dose D (Fa + Fu = 1); D50 is the dose that produces the average effect (for example, IC50, ED50, LD5 0). The constant m determines the shape of the dose effect curve. Excel Fit software was used to perform a linear regression calculation to estimate parameters m and D50. The effects of the combination on AMO-1 cells are measured in% of cell death as described above. The Fu fraction is defined as the ratio of% cell death of the treated cell line to% cell death of the cell line exposed to a control. That is: Fu =% cell death (treated cell line) /% cell death (untreated cell line) So the% cell death of a cell line is the constant D50 in the medium effect equation that can be estimated by the linear regression described above. Cl-isobol method The Cl-isobol method provides a quantitative assessment of synergism between drugs. A Combination Index (Cl) is estimated from treatment dose data for single and combined drugs. A Cl value less than 1 indicates synergism; Cl = 1 indicates an additive effect; and Cl> 1 indicates antagonism. The synergistic ranges are further defined by Chou and Talahay for values of Cl <0.1 as very strong synergism, Cl values between 0.1 and 0.3 as strong synergism, Cl values of 0.3 to 0.7 as synergism, Cl values from 0.7 to 0.9 as moderate to mild synergism. The drug interaction (synergism or antagonism) is more pronounced the further away a Cl value is 1. Formally, the Combination Index (Cl) of a combined drug treatment is defined as CI = Di / Dxl + D2 / DX2 Here Di and D2 are the doses of drug 1 and drug 2, respectively, in the combination; DX1 and Dx2 (each) represent the dose of a treatment with only drug 1 and drug 2 that would confer the same effect as that of the combination, respectively. The DX1 and Dx2 doses need to be estimated from the dose effect data of treatments per single drug. Essentially, a medium-effect equation is fitted to the data for each drug. From the equation of average effect of a drug, it is possible to estimate the dose (that is, D) necessary to produce an effect (that is, Fa, Fu). The farther a point is from the additive line, the greater the difference between 1 and its Cl, thus, the stronger the effect (synergistic or antagonistic). The above method is described in Chou TC, Talalay P, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27 to 55 (1984), which is incorporated by reference in its entirety. An additional review of the Chou method above is also provided in Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58: 621 to 681 (2006) which is incorporated by title reference in its entirety. The curves generated for the Chou-based synergy calculations are shown in Figures 12 to 18. In Figure 12, the best fit curve was determined by removing the data points a) in which the concentration of MOR202 was too low to have any effect and b) in which the concentration was close to saturation. At the appropriate data point, approximately 80% cell extermination, the Cl value is less than 1, supporting clear synergy. Figures 13 to 18 represent the six experiments from Tables 3 and 4, and, in each, the DX1 (dose of MOR202) necessary to achieve 100% effect of the combination of MOR 202 and lenalidomide reaches infinity; therefore, the DÍ / DXÍ is less than 1 and as lenalidomide has no effect on AMO-1 cells in relation to cell extermination, the Dx2 value also approximates infinite, thus, the D2 / DX2 approaches 0, therefore, the Cl values for each of the six experiments are less than 1, supporting clear synergy. Table 3c represents the normalization of data in which the theoretical combination is established as 1 (100%) and includes the Chou de Cl calculations. Table 3c The data shown in Table 3c differ from Tables 3a and 3b. Table 3c is based on raw data points other than those shown in Table 3a, as the concentrations chosen in Table 3c are closest to the EC50 of the antibody (raw data not shown). "Theoretical combination" represents the addition of MOR202 values only and LEN values only. Table 4 Effector cells only treated with Lenalidomide before treatment with MOR202. Single and combination doses of 10 μm LEN and 15 μg / ml of MOR03207 and MOR202 were used. Data are presented in the following three modes, such as a) raw data (% of dead cells), b) normalized specific extermination data where the MOR202 treatment group is set to 1 (100%), and c) normalized data specific extermination in which the theoretical combination is established as 1 (100%). Table 4a represents raw data. Table 4a The units of values listed are% of dead cells. The DMSO, MOR03207, MOR03207 + DMSO, LENO, LEN10 without PBMCs and DMSO without PBMCs are controls. Table 4b Table 4b represents the data in Table 4a, but normalized where the MOR202 treatment group is set to 1 (100%). For Tables 4b to 4c, "Theoretical combination" represents the MOR202 values only plus the LEN values only. The normalization of the data as shown in Table 4b is calculated as described in Table 3b by subtracting the controls. The averages of the results in Table 4b are shown in Figure 4. Table 4c Table 4c represents the normalization of data in which the theoretical combination is established as 1 (100%) and includes the calculations by Chou et al. of Cl using the methodology described above in Example 4. Table 4c differs from Tables 4a and 4b. Table 4c is based on raw data points other than those shown in Table 4a, as the concentrations chosen in Table 4c are closer to the EC50 of the antibody (raw data not shown). 1. Determination of synergism 1.2 Synergism by Clarke et al. Where a drug has low activity, as here where Lenalidomide has only low cytotoxicity against AMO-1 cells, the synergy can also be determined by statistical evidence that the combination is significantly different from the inhibitory drug alone. See Clarke et al., Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46: 255-278 (1997), which is incorporated by reference in its entirety. Here both Chou et al. as shown above regarding the methods of Clarke et al. were used to determine synergism. The data were analyzed in the following ways: Antagonist (AB) / C <(A / C) x (B / C) Additive (AB) / C - (A / C) x (B / C) Synergistic (AB) / C > (A / C) x (B / C) where A is LEN treatment only; B is treatment with MOR202 only; C is the response to the treatment vehicle; AB is the combination of treatments A and B. Table 5: The raw data values shown in this table are the same as those shown in Table 3a, as they come from the same three experiments in which both effector cells and cells of AMO-1 were treated with Lenalidomide before treatment with MOR202 and single and combination doses of 10 μm LEN and 15 μg / ml of MOR03207 and MOR202 were used. The only difference is that the data are analyzed using Clarke et al. instead of Chou et al. Experiment 1 Experiment 2 Experiment 3 A = response to treatment with LEN only B = response to treatment with MOR202 only C = response to treatment with control AB = combination of treatments A and B The values of A, B, C and AB represent% cell extermination. In each experiment (AB) / C is greater than (A / C) x (B / C), showing clear synergy. Table 6: The raw data values shown in this table are the same as those shown in Table 4a, as they come from the same three experiments in which only Efetor cells were treated with Lenalidomide before treatment with MOR202 and single doses and a combination of 10 μm LEN and 15 μg / ml of MOR03207 and MOR202 were used. The only difference is that the data are analyzed using Clarke et al. instead of Chou et al. A = response to treatment with LEN only B = response to treatment with MOR202 only C = response to treatment with control AB = combination of treatments A and B In each experiment (AB) / C is greater than (A / C) x (B / C), showing clear synergy. Results of Analysis application by Clarke et al. , LEN synergistically enhanced the ADCC activity of MOR202 in AMO-1 cells in all 6 experiments. The application of the analysis by Chou et al., LEN synergistically enhanced the ADCC activity of MOR202 in AMO-1 cells in 6 of 6 experiments. This intensification of activity was identified, by several mechanisms that include direct cytotoxicity, to be the activation of Efetor cells and upward regulation of CD38 expression levels in MM cells. The experiments according to example 4 are also carried out with other antibodies specific for CD38, for example, the antibody "Ref mAB5". Example 5: Inhibition of NCI-H929 cell proliferation using Lenalidomide only The cytotoxicity of Lenalidomide was tested on NCI-H929 using the methods described in Example 3. The results were shown in Figure 2. In summary, the stimulation with Lenalidomide only significantly inhibited cell proliferation in NCI-H929 cells. Example 6: Synergistic combination of MOR202 and Lenalidomide in NCI-H929 cells NCI-H929 cells were selected for testing with the combination of MOR202 and lenalidomide. NCI-H929 cells express higher levels of CD38 than AMO-1 cells, therefore, they are representative of certain cell types found in human patients with multiple myeloma or non-Hodgkin's lymphoma. In total, six experiments were performed using the methods described in Example 4 in order to determine the mediation of ADCC in NCI-H929 cells by the combination of MOR202 and lenalidomide. In three experiments, PBMCs and NCI-H929 cells were treated with lenalidomide before treatment with MOR202, the results are shown in Tables 7a to 7b and Figure 6. In three additional experiments, only PBMCs were treated with lenalidomide before treatment with MOR202, the results are shown in Tables 8a to 8b and Figure 7. Table 7 Both Efetor cells and NCI-H929 cells were treated with Lenalidomide prior to MOR202 treatment. Single and combination doses of 5 μm LEN and 15 μ g / ml of MOR03207 and 0.2 or 0.07 μg / ml of MOR202 were used. The data are presented in the following ways, such as a) raw data (% of dead cells) and b) normalized data for specific extermination in which fractional product combination is set to 1 (100%). Table 7a represents raw data. Table 7a The units of values listed are% of dead cells. The DMSO, MOR03207, MOR03207 + DMSO, LENO, LEN10 without PBMCs and DMSO without PBMCs are controls. Table 7b represents normalized data in which the fractional product combination is set to 1 (100%). The fractional product combination is calculated using the following formula 1 - [(1 - A) * (1 - B)] = fpc (%) as described in Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58: 621 to 681 (2006) which is incorporated by reference in its entirety. Table 7b is based on the raw data shown in Table 7a. The normalization of the data as shown in Table 7b is calculated as described in Table 3b by subtracting the controls. In Table 7b where the combination of LEN and MOR202 is greater than the combination based on the fractional product concept, then clear synergy exists. In addition, the Combination index values were calculated using the methods of Chou et al. as described in Example 4. The averages of the results in Table 7b are shown in Figure 6. Table 8 Effector cells treated with Lenalidomide only before treatment with MOR202. Single and combination doses of 5 μm LEN and 15 μg / ml of MOR03207 and 0.2 * or 0.07 μg / m of MOR202 were used. The data are presented in the following ways, such as a) raw data (% of dead cells) and b) normalized data for specific extermination in which the fractional product combination is set to 1 (100%). Table 8a represents raw data. Table 8a The units of values listed are% of cells killed. The DMSO, MOR03207, MOR03207 + DMSO, LENO, LEN10 without PBMCs and DMSO without PBMCs are controls. Table 8b represents the normalized data in which fractional product combination is set to 1 (100%). Table 8b Table 8b is based on the raw data shown in Table 8a. The normalization of the data as shown in Table 8a is calculated as described in Table 3b by subtracting the controls. In Table 8b where the combination of LEN and MOR202 is greater than the combination based on the fractional product concept, then clear synergy exists. In addition, the Combination index values were calculated using the methods of Chou et al. as described in Example 4. The averages of the results in Table 8b 20 are shown in Figure 7. Determination of synergism 1.3 Fractional Product Concept The evaluation of the data in this example differs from that used in analyzing the effect of the combination of MOR2 02 and LEN on AMO-1 cells in example 4. Here the NCI-H929 cells are tested and LEN only has a significant effect on cell proliferation. of NCI-H929 as shown in example 5, therefore, the fractional product concept is used. The fractional product concept has been described in Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58: 621 to 681 (2006) which is incorporated by reference in its wholeness. In that document Chou et al. declare: If A and B (each) inhibits 60%, then it is an oversimplification to say that the additive effect is 84% inhibition. Based on the rationalization by Webb (1963), this type of problem can be solved by (1 - 0.6) (1 - 0.6) = 0.16, 1 - 0.16 = 0.84. Chou and Talalay (1984) called this the fractional product method. This method will never lead to a combination effect that exceeds 100% inhibition. Chou and Talalay (1984), however, also proved that this method has limited validity because it takes into account the potency (for example, fractional inhibition), but ignores the shape of the dose effect curve (for example, hyperbolic or sigmoid) . The importance of "format" in a dose-effect analysis is shown in Figure 1. Chou and Talalay (1984) indicated that Webb's method is valid only when both drugs have hyperbolic curves (that is, in Michaelis-Menten kinetics simple, when the dose effect curves are hyperbolic, that is, m = 1 in the medium effect plot) and is not valid when m does not equal 1, such as sigmoid (m> 1) or flat sigmoid (m < 1) . Furthermore, the Webb method is valid when the effects of two drugs are mutually non-exclusive (for example, totally independent) and is not valid for mutually exclusive (for example, similar mechanisms or modes of action, as assumed for the classic isobologram) , see below). Clarke et al. it has not been used since Clarke is more suitable when monotherapy has a low effect. See Figure 12, the best fit curve was determined by removing the data points a) where the concentration of MOR202 was too low to have any effect and b) where the concentration was close to saturation. At the appropriate data point, approximately 80% cell extermination, the Cl value is less than 1, supporting clear synergy. Results of Application of the Fractional Product Concept analysis, LEN synergistically enhanced MOR202 activity in NCI-H929 cells in 6 of 6 experiments. The application of the analysis by Chou et al., LEN synergistically enhanced the activity of MOR202 in NCI-H929 cells in 6 of 6 experiments. See Tables 7a to 7b and 8a to 8b. Example 7: MOR2 02 and LEN only and in combination in a mouse model of SCID mouse from bone lysis of NCI-H929 Materials Lenalidomide (SYNthesis med chetn; Shanghai, China; Lot #: ZHM-066-051). MOR202 (MorphoSys AG, Lot 100706- 5KLE18). Vehicle control: Ora-Plus: Ora-Sweet SF (Paddock Laboratories, Minneapolis, MN, USA, Lot n ° 9499528). SCID mice (University of Adelaide, Waite Campus, Urrbaraie, SA, Australia, Cepa C. B. -17-Igh-lb -Prkdcscld). NCI-H929 human multiple myeloma cells (see Table 1). RPMI 1640 cell culture medium, Bovine Fetal Serum (FBS), Mercaptoethanol, Hank's Balanced Salt Solution (HBSS) and penicillin-streptomycin from Invitrogen Australia (Mt Waverley, VIC, Australia); and Trypan Blue and glucose from Sigma-Aldrich (Castle Hill, NSW, Australia). Methods 63 SCID mice were inoculated on Day (-7) orthotopically in the right tibia with 2.5 x 10s MM cells of NCI-H929 (in 5 μl) in order to induce bone lysis. Three days after inoculation (Day -4), 60 of the SCID mice were randomized by body weight in the groups shown in Table 10, 10 mice per group. The dosage regimen is provided in Table 9. Lenalidomide treatments (Groups A and D) and vehicle control (Group C) were started on Day (-1). MOR202 treatments (Groups B and D) were started on Day 0. Treatment continued for 6 weeks. Table 9: Dosing regimen and Groups Compound Group Treatment Program MicroCT Scan was used to assess bone lysis and included a three-dimensional analysis comprising Total Bone Volume (TBV), Trabecular Bone Volume (Tb.BV), Trabecular Pattern Factor (Tb.Pf) and Structure Model index 20 ( SMI). Table 10 defines each of these parameters. The results for each of the MicroCT Scan parameters are shown in Table 11. The Total Bone Volume (TBV) results are shown in Figure 19. Table 10: MicroCT Scan parameters The analysis of each parameter in relation to synergistic activity was performed according to al. Table 12 shows the calculations made to determine the synergy of the combination of MOR202 and lenalidomide. Table 12 The numerical values shown in Table 12 are taken directly from the averages shown in Table 11 for each of the parameters in each of the Groups. The Groups described as A, B, C and AB are the same treatment groups in Tables 9, 11 and 12. In Total Bone Volume (AB) / C is greater than (A / C) X (B / C) showing clear synergism. In the Trabecular Pattern Factor and Structural Model Index, as described in Table 10, a lower value represents less bone lysis (treatment efficacy), therefore, (AB) / C less than (A / C) X (B / C), shows clear synergism in the parameters. Results of Inoculation of NCI-H929 multiple myeloma cells induced significant bone lysis in the tibiae of female SCID mice in this study, as indicated by measurement of bone lysis using a MicroCT scan. The degree of bone lysis was significantly decreased in the tibia of mice treated with the combination of MOR202 and lenalidomide as shown by the MicroCT scan. In each of the MicroCT Scan parameters: Total Bone Volume (TBV), Trabecular Bone Volume (Tb.BV), Trabecular Pattern Factor (Tb.Pf) and Structure Model Index (SMI) the combination of MOR202 and lenalidomide ( Group AB) showed clear synergy in the reduction of bone lysis caused by NCI-H929 multiple myeloma cells. When the values in Table 11 are adjusted so that the Control Group (Contralateral Tibia without Non-inoculated Tumor) is considered to be 0% bone lysis and Group C (Vehicle Control (0.9% Sodium Chloride Injection) ) is considered 100% bone lysis, so MOR202 only dose-reduced bone lysis by up to 55% at 12 mg / kg compared to vehicle control. LEN only 50 mg / kg inhibited bone lysis in 20%. The combination of 3mg / kg of MOR202 and 50mg / kg of LEN has completely abolished bone lysis. These findings support a synergistic effect of combination therapy. protein M in the combination group, indicating a significant decrease in tumor burden. Example 8 MOR202 and lenalidomide alone and in combination against human non-Hodgkin's BRANCH tumor in female SCID mice, survival model Materials Cyclophosphamide (Fluka, Buchs, Switzerland, Lot n ° 07551661). Lenalidomide (SYNthesis Med Chem; Shanghai, China; Lot No. ZHM-066-051). MOR202 (MorphoSys AG, Lot 100706- 5KLE18). Vehicle control: Ora-Plus: Ora-Sweet SF, 1: 1, v / v (SYNthesis Med Chem, Shanghai, China). SCID mice (University of Adelaide, Waite Campus, Urrbaraie, SA, Australia, Cepa C. B. -17 - Igh-lb -Prkdcscld). RAMOS cells (Oncodesign, Dijon Cedex, France) were grown in RPMI1640 + 20% alternating inactivated heat source FBS + 1% Glutamax (Medium # 2). Reagents for non-Hodgkin's lymphoma RAMOS cell culture were obtained from the following suppliers: RPMI 1640 cell culture medium, FBS, Glutamax, HEPES, sodium pyruvate, HBSS and penicillin-streptomycin from Invitrogen Australia (Mt Waverley, VIC, Australia); and Trypan Blue and glucose from Sigma-Aldrich (Castle Hill, NSW, Australia). Methods Sixty-eight female SCID mice were pretreated with cyclophosphamide (75 mg / kg, ip, twice a day) for two days before inoculation of RAMOS cells (Day -5 and -4). On the day of inoculation (Day -3), all mice were inoculated with 1 x 10 6 RAMO cells (each) intravenously into the tail vein. Sixty-four of the mice were randomized by body weight 10 in eight groups of eight. The dosing regimen for each group is shown in Table 13. Table 13: Dosing regimen The study continued for 98 days and the end point measured was survival. The results for each Group are 15 shown in Table 14. Table 14: Number of Survival and time period for each group Analysis for synergistic activity was performed according to the theorem by Clarke et al. , as described in example 4. Table 15 shows the calculations made in determining the synergy of the combination of MOR202 and lenalidomide. Table 15 The numerical values shown in Table 15 are taken directly from the median survival days shown in Table 14 for each of the Groups. The Groups described as A, B, C and AB are the same treatment groups as Tables 13 to 15. Inoculation with RAMOS cells was lethal in a median time of 20 days in the Control Group. The combination of MOR202 and lenalidomide, however, showed a clear synergy 15 in the increase in median survival days. Example 9: Bortezomib only inhibits the proliferation of several multiple myeloma cell lines. The inhibitory effect of Bortezomib on the proliferation of multiple myeloma cells was analyzed in relation to 20 multiple cell lines. Increasing amounts of Bortezomibe (Velcade (R), Lot: n °: n ° 9AZSY00) were applied to AMO-1, LP-1, NCI-H929 and RPMI-8226 cells and incubated for 24 hours, 48 hours and 72 hours. After the incubation period, the plates were analyzed for cell proliferation in an assay based on quantitative colorimetric XTT using the cell proliferation kit II (ROCHE, Cell proliferation kit II, Cat. No: 1 1465015001). For subsequent measurement, the plates were subjected to Tecan Génios Reader and absorbance at 492nm was detected. The proliferation of cells from all tested cell lines was inhibited by Bortezomib with an IC 50 concentration of 3.9 nM for AMO-1 cells, 6.1 nM for LP-1 cells, 3.3 nM for NCI- H929 and 9.0 nM for RPMI-8226 cells respectively, as shown in Figure 8. Example 10: ADCC using a combination of MOR2 02 and Bortezomibe Using the methods described in example 4, the ADCC effect of bortezomib and MOR202 combined was analyzed. Here, the target cells were treated with bortezomib before treatment with MOR202. The target cells, LP-1 and NCI-H929 cells, were tested. The results were shown in Figures 9 and 10. The intensification of MOR202 activity by bortezomib was mediated through a direct cytotoxic effect on MM cells. Example 11: MOR202 and BOR only and in combination in a SCID mouse model of human multiple myeloma NCI-H929 bone lysis Bortezomibe materials (SYNthesis med chem., Shanghai, China, Lot n ° ZHM-066 - 054). Bortezomib was formulated in sterile 0.9% sodium chloride solution for dosing. MOR202 (MorphoSys AG, Lot 100706-5KLE18). Vehicle control: 0.9% sodium chloride injection. SCID mice (University of Adelaide, Waite Campus, Urrbaraie, SA, Australia, strain CB-17-Igh-lb-Prkdcsoid). Methods 63 SCID mice were inoculated on Day (-7) intratibially with 2.5 x 106 MM cells of NCI-H929 in order to induce bone lysis. Three days after inoculation (Day - 4) 6 0 of the SCID mice were randomized by body weight in the groups shown in Table 16, 10 mice per group. The dosage regimen is provided in Table 16. Bortezomibe (Groups A and AB) and Vehicle Control (Group C) were started on Day (-1). MOR202 treatments (Groups B and AB) were started on Day 0. Treatment continued for 6 weeks. Table 16: Dosing regimen and Groups MicroCT Scan was used to assess bone lysis and included a three-dimensional analysis comprising Total Bone Volume (TBV), Trabecular Bone Volume (Tb.BV), Trabecular Pattern Factor (Tb.Pf) and Structure Model Index (SMI) . Table 10 above defines each of these parameters. The results for each of the MicroCT Scan parameters are shown in Table 17. The Total Bone Volume (TBV) results are shown in Figure 20. Table 17: MicroCT Scan Results: Total Bone Volume (TBV), Trabecular Bone Volume ( Tb.BV), Trabecular Pattern Factor (Tb.Pf) and Structure Model Index (SMI). The analysis of each parameter in relation to synergistic activity was performed according to the theorem by Clarke et al. , as described in example 4. Table 18 shows the The numerical values shown in Table 18 are taken directly from the averages shown in Table 17 for each of the parameters in each of the Groups. The 5 Groups described as A, B, C and AB are the same treatment groups in Tables 16 to 18. In Total Bone Volume and Trabecular Bone Volume, (AB) / C is greater than (A / C) X (B / C) showing clear synergism. In Trabecular Pattern Factor and Structural Model Index, 10 as described in Table 10, a lower value represents less bone lysis (treatment efficacy), therefore, (AB) / C less than (A / C) X (B / C), supports clear synergism in the parameters. Results of Inoculation of NCI-H929 multiple myeloma cells induced significant bone lysis in the tibiae of female SCID mice in this study, as indicated by measurement of bone lysis using MicroCT scanning. The degree of bone lysis was significantly decreased in the tibia of mice treated with the combination of MOR202 and bortezomib as shown by MicroCT scanning. In each of the MicroCT Scan parameters: Total Bone Volume (TBV), Trabecular Bone Volume (Tb.BV), Trabecular Pattern Factor (Tb.Pf) and Structure Model Index (SMI) the combination of MOR202 and bortezomib ( Group AB) showed clear synergy in the reduction of bone lysis caused by NCI-H929 multiple myeloma cells. When the values in Table 17 are adjusted so that the Control Group (Contralateral Tibia without Non-inoculated Tumor) is considered to be 0% bone lysis and Group C (Vehicle Control (0.9% Sodium Chloride Injection) be considered 100% bone lysis, then MOR202 only dose-reduced bone lysis by up to 55% at 12 mg / kg compared to vehicle control, BOR only 0.6 mg / kg inhibited bone lysis in 40% and the combination of a lower dose of 3mg / kg MOR202 and 0.6mg / kg BOR has completely abolished bone lysis. These findings support a synergistic effect of combination therapy. In addition, there was a reduction (> 90%) of serum protein M levels in the combination group, indicating a significant decrease in tumor burden Example 12 MOR202 and bortezomib only and in combination against human non-Hodgkin's BRANCH tumor in female SCID mice, survival model Materials Cyclophosphamide (Fluka, Buchs, Switzerland, WB10468). Bortezomibe (SYNthesis med chem., Shanghai, China, Lot n ° ZHM-066 - 054). Bortezomib was formulated in sterile 0.9% sodium chloride solution for dosing. MOR202 (MorphoSys AG, Lot 100706-5KLE18). Vehicle control: 0.9% sodium chloride injection. SCID mice (University of Adelaide, Waite Campus, Urrbaraie, SA, Australia, strain CB-17-lgh-lb-Prkdcscid). RAMOS cells (Oncodesign, Dijon Cedex, France) were cultured in RPMI1640 + 20% inactivated alternating heat source FBS + 1% Glutamax (Medium no. 2). Reagents 5 for non-Hodgkin's lymphoma RAMOS cell culture were obtained from the following suppliers: RPMI 1640 cell culture medium, FBS, Glutamax, HEPES, sodium pyruvate, HBSS, and penicillin-streptomycin from Invitrogen Australia (Mt Waverley, VIC, Australia); and Trypan Blue and 10 glucose from Sigma-Aldrich (Castle Hill, NSW, Australia). Methods Fifty-five female SCID mice were pretreated with cyclophosphamide (75 mg / kg, ip, twice daily) for two days before inoculation of 15 BRANCH cells (Day -5 and -4). On the day of inoculation (Day -3), all fifty-five mice were inoculated with 1 x 106 RAMOS cells (each) (in 100 μl) intravenously into the tail vein. Forty-eight of the mice were randomized by body weight into six groups of eight. The 20 dosing regimen for each group is shown in Table 19. Table 19: Dosing regimen The study continued for 98 days and the end point measured was survival. The results of each Group are shown in Table 20. Table 20: Number of Survival and time period for each group Analysis for synergistic activity was performed according to the theorem by Clarke et al. Table 21 shows the calculations made in determining the synergy of the combination of MOR202 and bortezomib. Table 21 The numerical values shown in Table 21 are taken directly from the median survival days shown in Table 20 for each of the Groups. Groups 10 described as A, B, C and AB are the same treatment groups in Tables 19-21. Inoculation with RAMOS Cells was lethal in a median time of 20.5 days in the Control Group. The combination of MOR202 and bortezomib, however, showed clear synergy in the increase in median survival days. Importantly, with the combination of MOR202 and bortezomib (Group AB), 2 of 5 mice survived for the duration of the study. This strongly supports a synergistic finding of the combination of MOR202 and bortezomib. It is understood that the description, specific examples and data, while indicating exemplary modalities, are presented by way of illustration and are not intended to limit the present invention. Several changes and modifications to the present invention will become apparent to persons skilled in the art from the discussion, disclosure and data contained in this document, and are thus considered part of the invention.
权利要求:
Claims (21) [0001] 1. SYNERGIC COMBINATION, characterized by: (i) MOR202 + thalidomide antibody, MOR202 + lenalidomide antibody, MOR202 + pomalidomide antibody, (ii) MOR202 + bortezomib antibody, for use in the treatment of multiple myeloma and / or non-lymphoma Hodgkin, in which the MOR202 antibody is defined by its variable regions of the heavy chain (SEQ ID NO: 10) and variable regions of the light chain (SEQ ID NO: 11). [0002] COMBINATION according to claim 1, characterized in that the antibody comprises an HCDR1 region of SYYMN sequence (SEQ ID NO: 14). [0003] COMBINATION according to claim 1, characterized in that the antibody comprises an HCDR1 region of sequence GFTFSSYYMN (SEQ ID NO: 1). [0004] 4. COMBINATION, according to claim 1, characterized in that the antibody comprises a variable heavy chain of the sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGI SGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYCGTLGTLQTGYLGNGGG and a variable light chain of the sequence: DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERF SGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ (SEQ). [0005] COMBINATION, according to claim 1, characterized in that said antibody is an IgG antibody [0006] COMBINATION according to claim 5, characterized in that said antibody comprises an IgG1 Fc region. [0007] 7. COMBINATION according to claim 1, characterized in that the antibody comprises a modified Fc region, wherein said modification enhances ADCC activity. [0008] COMBINATION according to claim 1, characterized in that said CD38 specific antibody and said thalidomide, thalidomide analog, lenalidomide, pomalidomide or a proteasome inhibitor, are administered separately. [0009] COMBINATION according to claim 8, characterized in that said thalidomide, thalidomide analog, lenalidomide, pomalidomide or a proteasome inhibitor, are administered before the administration of the specific antibody to CD38. [0010] COMBINATION according to claim 9, characterized in that said thalidomide, thalidomide analog, lenalidomide, pomalidomide or a proteasome inhibitor are administered for at least 72 hours before administration of the specific antibody to CD38. [0011] COMBINATION according to claim 1, characterized in that said CD38 specific antibody and said thalidomide, thalidomide analog, lenalidomide, pomalidomide or a proteasome inhibitor are subsequently administered. [0012] 12. COMBINATION, according to claim 1, characterized in that said combination has the capacity to reduce bone lysis with an efficiency at least twice greater than lenalidomide and / or bortezomib only. [0013] COMBINATION according to any one of claims 1 to 12, characterized in that the combination comprises thalidomide. [0014] COMBINATION according to any one of claims 1 to 12, characterized in that the combination comprises a thalidomide analog. [0015] COMBINATION according to any one of claims 1 to 12, characterized in that the combination comprises lenalidomide. [0016] 16. COMBINATION according to claim 15, characterized in that said combination has the ability to mediate the extermination of CD38 expression AMO-1 and / or NCI-H929 cells by ADCC in the presence of isolated human PBMCs with an efficacy of at least twice as high as with lenalidomide alone. [0017] COMBINATION according to any one of claims 1 to 12, characterized in that the combination comprises a pomalidomide. [0018] COMBINATION according to any one of claims 1 to 12, characterized in that the combination comprises a proteasome inhibitor. [0019] 19. COMBINATION according to claim 18, characterized in that said proteasome inhibitor is bortezomib. [0020] 20. COMBINATION according to claim 19, characterized in that said combination has the ability to mediate the extermination of LP-1 of CD38 expression and / or NCI-H929 cells by ADCC in the presence of isolated human PBMCs with an efficacy of at least twice as high as with bortezomib alone. [0021] 21. COMBINATION according to claim 18, characterized in that said proteasome inhibitor is carfilzomib.
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公开号 | 公开日 US9765152B2|2017-09-19| DK2621531T3|2017-02-27| EP2621531A1|2013-08-07| EP2621531B1|2016-11-30| US20150017160A1|2015-01-15| RU2013113933A|2014-11-10| JP2017048208A|2017-03-09| MX350540B|2017-09-08| HUE031956T2|2017-08-28| SI2621531T1|2017-06-30| US20160222127A1|2016-08-04| KR101912957B1|2018-10-29| KR20140045288A|2014-04-16| WO2012041800A1|2012-04-05| MX2013003304A|2013-09-26| JP2013542191A|2013-11-21| US8877899B2|2014-11-04| JP6087283B2|2017-03-01| IL224915A|2017-05-29| CN103118706B|2016-05-18| CA2812631A1|2012-04-05| RU2595839C2|2016-08-27| NZ607473A|2014-11-28| AU2011310696A1|2013-03-07| EP2621531B8|2017-01-18| PL2621531T3|2017-07-31| AU2011310696B2|2016-06-02| US10308722B2|2019-06-04| CA2812631C|2020-12-29| US9289490B2|2016-03-22| US20180022823A1|2018-01-25| ZA201301232B|2016-05-25| CN103118706A|2013-05-22| ES2617446T3|2017-06-19| BR112013006769A2|2016-07-05| JP6231642B2|2017-11-15| LT2621531T|2017-04-10| SG188345A1|2013-04-30| US20130302318A1|2013-11-14| PT2621531T|2017-03-13|
引用文献:
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法律状态:
2016-07-12| B15I| Others concerning applications: loss of priority|Free format text: PERDA DAS PRIORIDADES US 61/386,619 DE 27/09/2010 E US 61/486,814 DE 17/05/2011, CONFORME AS DISPOSICOES PREVISTAS NA LEI 9.279 DE 14/05/1996 (LPI) ART. 167O E NO ART. 28 DO ATO NORMATIVO 128/1997, POR NAO ATENDER AO DISPOSTO NO ART. 27 DO ATO NORMATIVO 128/1997, POIS NAO FOI APRESENTADA CESSAO DAS REFERIDAS PRIORIDADES, QUE POSSUEM DEPOSITANTES DIFERENTES DO DEPOSITANTE DA FASE NACIONAL. | 2016-08-23| B12F| Appeal: other appeals| 2017-10-03| B25G| Requested change of headquarter approved|Owner name: MORPHOSYS AG (DE) | 2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2019-12-03| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]| 2020-03-31| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]| 2020-07-21| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2020-10-13| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2021-02-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 26/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |
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申请号 | 申请日 | 专利标题 US38661910P| true| 2010-09-27|2010-09-27| EP10180485.4|2010-09-27| US61/386,619|2010-09-27| EP10180485|2010-09-27| US201161437696P| true| 2011-01-31|2011-01-31| US61/437,696|2011-01-31| US201161468607P| true| 2011-03-29|2011-03-29| US61/468,607|2011-03-29| US201161486814P| true| 2011-05-17|2011-05-17| US61/486,814|2011-05-17| PCT/EP2011/066648|WO2012041800A1|2010-09-27|2011-09-26|Anti-cd38 antibody and lenalidomide or bortezomib for the treatment of multiple myeloma and nhl| 相关专利
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