RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application number 63/411286, titled “CD38-B INDING FUSION PROTEIN COMBINATION THERAPY,” filed September 29, 2022, which is incorporated by reference herein in its entirety.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The contents of the electronic sequence listing (T083370024WO00-SEQ-ARM.xml; Size: 16,445 bytes; and Date of Creation: September 28, 2023) is herein incorporated by reference in its entirety.

BACKGROUND

CD38 is a 45 kDa type II transmembrane glycoprotein. It has a short N-terminal cytoplasmic tail of 20 amino acids, a single transmembrane helix and a long extracellular domain of 256 amino acids. It is expressed on the surface of many immune cells including CD4 and CD8 positive T cells, B cells, NK cells, monocytes, plasma cells, and on a significant proportion of normal bone marrow precursor cells. CD38 is expressed at high levels on various types of cancer cells, e.g., multiple myeloma cells, in most cases of T- and B-lineage acute lymphoblastic leukemias, some acute myelocytic leukemias, follicular center cell lymphomas and T lymphoblastic lymphomas. CD38 is also expressed on B-lineage chronic lymphoblastic leukemia (B-CLL) cells. Antibodies that target CD38 have been used in the treatment of CD38-expressing cancers and hematological malignancies.

Interferons, and in particular IFN-alpha, are able to increase apoptosis and decrease proliferation of certain cancer cells. IFN-alpha has been approved by the FDA for the treatment of several cancers including melanoma, renal cell carcinoma, B cell lymphoma, multiple myeloma, chronic myelogenous leukemia (CML) and hairy cell leukemia. In general, IFN may be targeted to cancer cells, for example, by linking it with a targeting antibody or targeting fragment thereof.

Fusion proteins containing anti-CD38 antibodies fused to IFN-alpha and their use in treating cancer have been described. SUMMARY

The present disclosure, in some aspects, relates to methods of treating cancer (e.g.,CD38-expressing cancer) using a CD38-binding fusion protein comprising an anti-CD38 binder, such as an-anti CD38 antibody or binding domain or fragment thereof, fused to one or more (e.g., one, two) attenuated interferon alpha-2b protein in combination with one or more (e.g., one, two, or more) agents for treating the cancer. In some embodiments, the one or more agents comprise an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide) and/or a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, the CD38-expressing cancer is multiple myeloma. In some embodiments, the multiple myeloma is Relapsed or Refractory Multiple Myeloma (RRMM). In some embodiments, the methods described herein are effective in treating RRMM: (i) in subjects who have received prior lines of therapy (e.g., one or more prior lines of therapy) for multiple myeloma, including at least one proteasome inhibitor, at least one anti-CD38 monoclonal antibody (mAb) drug, and/or at least one immunomodulatory drug (e.g., an immunomodulatory imide drug (IMiD)); (ii) in subjects who were refractory to a proteasome inhibitor, an immunomodulatory drug (e.g., an IMiD (e.g., lenalidomide or pomalidomide)), or an anti-CD38 antibody therapy regardless of prior lines of therapy; and/or (iii) in subjects who demonstrated disease progression with one or more prior lines of therapy.

Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein, an immunomodulatory drug, and a proteasome inhibitor, wherein the CD38- binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.

Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b, and wherein the subject is receiving or has received treatment with an immunomodulatory drug, and a proteasome inhibitor.

Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof an immunomodulatory drug, and a proteasome inhibitor, wherein the subject is receiving or has received treatment with a CD38-binding fusion protein, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b. Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein and an immunomodulatory drug, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b, and wherein the subject is receiving or has received treatment with a proteasome inhibitor.

Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a proteasome inhibitor, wherein the subject is receiving or has received treatment with a CD38-binding fusion protein and an immunomodulatory drug, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b.

Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein and a proteasome inhibitor, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to an attenuated interferon alpha-2b, and wherein the subject is receiving or has received treatment with and one or more immunomodulatory drug.

Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof an immunomodulatory drug, wherein the subject is receiving or has received treatment with a CD38-binding fusion protein and a proteasome inhibitor, and wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b.

In some embodiments, the proteasome inhibitor is bortezomib or carfilzomib. In some embodiments, the immunomodulatory drug is lenalidomide or pomalidomide.

In some embodiments, the anti-CD38 antibody comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD38 antibody is a full-length IgG antibody. In some embodiments, the anti-CD38 antibody comprises a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises a proline at position 228 according to the EU numbering system. In some embodiments, the anti-CD38 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

In some embodiments, the attenuated interferon alpha-2b comprises T106A and A145D mutations relative to an interferon alpha- 2b comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the attenuated interferon alpha- 2b comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the attenuated interferon alpha-2b is fused to the C-terminus of the heavy chain. In some embodiments, the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

In some embodiments, the CD38-binding fusion protein is administered once every 4 weeks during a period of administration. In some embodiments, the administrations are according to a 4-week treatment cycle during a period of administration. In some embodiments, the period of administration is up to 5 years.

In some embodiments, the subject is administered 50-250 mg of the CD38-binding fusion protein each 4-week treatment cycle. In some embodiments, the subject is administered 60 mg, 80 mg, 120 mg, or 240 mg of the CD38-binding fusion protein each 4-week treatment cycle. In some embodiments, the subject is administered the CD38-binding fusion protein at a dose of 0.5-4 mg/kg each 4-week treatment cycle. In some embodiments, the subject is administered the CD38-binding fusion protein at a dose of 0.75 mg/kg, 1 mg/kg, 2 mg/kg, or 3 mg/kg each 4-week treatment cycle. In some embodiments, administration of the CD38- binding fusion protein occurs on day 1 of each 4-week treatment cycle. In some embodiments, the CD38-binding fusion protein is administered intravenously.

In some embodiments, the immunomodulatory drug is pomalidomide. In some embodiments, the subject is administered 4 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle during the period of administration. In some embodiments, pomalidomide is administered orally.

In some embodiments, the immunomodulatory drug is lenalidomide. In some embodiments, the subject is administered 10 mg of lenalidomide daily for 28 days of each 4- week treatment cycle during the period of administration. In some embodiments, lenalidomide is administered orally. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, bortezomib is administered at a dose of 1.3 mg/m ² on days 1, 8, 15 for 8 4-week treatment cycles and on days 1 and 8 for remaining 4-week treatment cycles during the period of administration. In some embodiments, bortezomib is administered subcutaneously.

In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, carfilzomib is administered at a dose of 20 mg/m ² on day 1 of the first four- week treatment cycle, and at a dose of up to 70 mg/m ² on days 8 and 15 for remaining 4-week treatment cycles during the period of administration. In some embodiments, carfilzomib is administered intravenously.

In some embodiments, the CD38-binding fusion protein is in a composition that further comprises histidine, arginine, sucrose, and polysorbate 80 (PS80). In some embodiments, the composition comprises, histidine at a concentration of 50 nM, arginine at a concentration of 100 nM, sucrose at a concentration of 50 mg/ml, and PS80 at a concentration of 0.2 mg/ml. In some embodiments, the composition is at a pH of 6.6.

In some embodiments, the subject is receiving or has received dexamethasone.

In some embodiments, the CD38-expressing cancer is multiple myeloma. In some embodiments, multiple myeloma is refractory multiple myeloma. In some embodiments, the multiple myeloma is previously untreated multiple myeloma. In some embodiments, the administration results in tumor regression.

In some embodiments, the subject is human. In some embodiments, the subject is a rodent.

Some aspects of the present disclosure provide CD38-binding fusion proteins for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof, an immunomodulatory drug, and a proteasome inhibitor, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.

Some aspects of the present disclosure provide CD38-binding fusion proteins for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b, and wherein the subject is receiving or has received treatment with an immunomodulatory drug and a proteasome inhibitor.

Some aspects of the present disclosure provide lenalidomide or pomalidomide, and a proteasome inhibitor for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof an immunomodulatory drug and a proteasome inhibitor, wherein the subject is receiving or has received treatment with a CD38- binding fusion protein, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.

Some aspects of the present disclosure provide CD38-binding fusion proteins and lenalidomide or pomalidomide for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein and an immunomodulatory drug, wherein the CD38-binding fusion protein comprises an anti- CD38 antibody fused to one or more attenuated interferon alpha-2b, and wherein the subject is receiving or has received treatment with a proteasome inhibitor.

Some aspects of the present disclosure provide proteasome inhibitor for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a proteasome inhibitor, wherein the subject is receiving or has received treatment with a CD38-binding fusion protein and an immunomodulatory drug, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.

Some aspects of the present disclosure provide CD38-binding fusion proteins and a proteasome inhibitor for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein and a proteasome inhibitor, wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b, and wherein the subject is receiving or has received treatment with and an immunomodulatory drug.

Some aspects of the present disclosure provide an immunomodulatory drug for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof the immunomodulatory drug, wherein the subject is receiving or has received treatment with a CD38-binding fusion protein and a proteasome inhibitor, and wherein the CD38-binding fusion protein comprises an anti-CD38 antibody fused to one or more attenuated interferon alpha-2b.

In some embodiments, the proteasome inhibitor is bortezomib or carfilzomib. In some embodiments, the immunomodulatory drug is lenalidomide or pomalidomide.

Some aspects of the present disclosure provide a method of treating a subject having multiple myeloma, the method comprising administering to the subject: (i) 60-240 mg of CD38-binding fusion protein once during a 4-week treatment cycle; and (ii) 2-4 mg of pomalidomide daily for up to the first 21 days of the 4-week treatment cycle. In some embodiments, 2 mg of pomalidomide is administered to the subject. In some embodiments, 3 mg of pomalidomide is administered to the subject. In some embodiments, 4 mg of pomalidomide is administered to the subject.

Some aspects of the present disclosure provide a method of treating a subject having multiple myeloma, the method comprising administering to the subject: (i) 60-240 mg of CD38-binding fusion protein once during a 4-week treatment cycle; and (ii) 10 mg of lenalidomide daily for up to 28 days during the 4-week treatment cycle.

In some embodiments, 15 mg lenalidomide is administered to the subject after the 4- week treatment cycle.

Some aspects of the present disclosure provide a method of treating a subject having multiple myeloma, the method comprising administering to the subject: (i) 60-240 mg of CD38-binding fusion protein once during a 4-week treatment cycle; and (ii) 1.3 mg/m2 of bortezomib on days 8, 15 and 22 for up to the first eight 4-week treatment cycles.

In some embodiments, 1.3 mg/m2 of bortezomib is administered on days 8 and 22 at least one 4-week treatment cycle that occurs after the first eight 4-week treatment cycles.

In some embodiments, 60 mg of the CD38-binding fusion protein is administered. In some embodiments, 80 mg of the CD38-binding fusion protein is administered. In some embodiments, 120 mg of the CD38-binding fusion protein is administered. In some embodiments, 240 mg of the CD38-binding fusion protein is administered.

In some embodiments, the CD38-binding fusion protein comprises: (i) a first anti-CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; and (ii) an attenuated interferon alpha-2b comprising an amino acid sequence of SEQ ID NO: 12.

BRIEF DESCRIPTION OF DRAWINGS

The drawings are for illustration purposes only, not for limitation.

FIGs. 1A-1B show the tumor inhibition activity of CD38-binding fusion protein combined with lenalidomide (FIG.1A) and bortezomib (FIG. IB) in NCI-H929 multiple myeloma (MM) xenograft tumor model. Mice bearing subcutaneous NCI-H929 tumors were randomized and treated with vehicle (PBS, twice a week (BIW) for 3 weeks), a CD38-binding fusion protein (amino acid sequences shown in Table 1, 2.5 mg/kg, BIW for 3 weeks), lenalidomide (25 mg/kg, BIW for 3 weeks), or bortezomib (1.0 mg/kg, BIW for 3 weeks), or the combination of a CD38-binding fusion protein and lenalidomide, or the combination of a CD38-binding fusion protein and bortezomib (at the same dosing amounts and schedules as the single doses). Individual tumor volumes were measured BIW and the graphs show median tumor volume per treatment arm.

DETAILED DESCRIPTION

Various terms relating to aspects of disclosure are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.

As used herein, the singular forms “a,” “an,” and “the” include plural referents unless expressly stated otherwise.

The present disclosure, in some aspects, relates to methods of treating cancer (e.g., CD38-expressing cancer) using a CD38-binding fusion protein comprising an anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b protein in combination with one or more (e.g., one, two, or more) agents for treating the cancer. In some embodiments, the one or more agents comprise an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide) and/or a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, the CD38-expressing cancer is multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma. In some embodiments, the methods described herein are effective in treating relapsed or refractory multiple myeloma: (i) in subjects who have received prior lines of therapy (e.g., one or more prior lines of therapy) for multiple myeloma, including at least one proteasome inhibitor, at least one anti-CD38 monoclonal antibody (mAb) drug, and/or at least one immunomodulatory drug (e.g., an IMiD); (ii) in subject who were refractory to a proteasome inhibitor, an immunomodulatory drug (e.g., an ImiD), or an anti-CD38 antibody therapy regardless of prior lines of therapy; and/or (iii) in subjects who demonstrated disease progression with one or more prior lines of therapy.

Accordingly, provided herein are methods of treating cancer (e.g., CD38-expressing cancer such as multiple myeloma) using a CD38-binding fusion protein comprising an anti- CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b protein in combination with an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide) and a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, the subject being treated in a method described herein is not also receiving treatments with an anti-CD38 antibody (e.g., daratumumab). However, the subject being treated in a method described herein may have previously received treatments with an anti- CD38 antibody (e.g., daratumumab), and maybe refractory to such treatment and/or has experienced disease progress or relapse after such treatment.

In some embodiments, a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide), and a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, pomalidomide, and bortezomib. In some embodiments, a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, pomalidomide, and carfilzomib.

In some embodiments, a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, wherein the subject is receiving or has received treatment with an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide) and a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, a method described herein comprises administering to a subject in need thereof an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide) and a proteasome inhibitor (e.g., bortezomib or carfilzomib), wherein the subject is receiving or has received treatment with a CD38-binding fusion protein described herein.

In some embodiments, a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein and an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide), wherein the subject is receiving or has received treatment with a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, a method described herein comprises administering to a subject in need thereof a proteasome inhibitor (e.g., bortezomib or carfilzomib), wherein the subject is receiving or has received treatment with a CD38-binding fusion protein described herein and an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide).

In some embodiments, a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein and a proteasome inhibitor (e.g., bortezomib or carfilzomib), wherein the subject is receiving or has received treatment with an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide). In some embodiments, a method described herein comprises administering to a subject in need thereof an immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide), wherein the subject is receiving or has received treatment with a CD38-binding fusion protein described herein and a proteasome inhibitor (e.g., bortezomib or carfilzomib). A “CD38-binding fusion protein,” as used herein, refers to a fusion protein comprising a CD38 binder, such as an anti-CD38 antibody or binding domain or fragment thereof fused to one or more (e.g., one, two) attenuated interferon alpha-2b proteins. A “fusion protein” refers to a polypeptide comprising two or more proteinaceous components associated by at least one covalent bond which is a peptide bond, regardless of whether the peptide bond involves the participation of a carbon atom of a carboxyl acid group or involves another carbon atom. The term “fuse” refers to the act of creating a fused molecule as described above, such as, e.g., a fusion protein generated from the recombinant fusion of genetic regions which when translated produces a single proteinaceous molecule. CD38-binding fusion proteins that may be used in the compositions described herein are described in the art, e.g., in US Patent No. 10544199B2, incorporated herein by reference. The amino acid sequences of an example of an anti-CD38 antibody are provided in Table 1 herein.

A CD38-binding fusion protein used in a method described herein comprises an anti- CD38 binder, such as an anti-CD38 antibody or binding domain or fragment thereof. The term “antibody,” as used herein includes, for example, an intact immunoglobulin or an antigen binding portion of an immunoglobulin or an antigen binding protein related or derived from an immunoglobulin. Intact antibody structural units often comprise a tetrameric protein. Each tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one “light” chain (typically having a molecular weight of about 25 kDa) and one “heavy” chain (typically having a molecular weight of about 50- to 70 kDa). Human immunoglobulin light chains may be classified as having kappa or lambda light chains. In some embodiments, the antibodies described herein comprise antigen binding domains (e.g., antibody heavy and/or light chains) that generally are based on the IgG class, which has several subclasses, including, but not limited to IgGl, IgG2, IgG3, and IgG4. In general, IgGl has different allotypes with polymorphisms at 356 (D or E), IgG2 and 358 (L or M). The sequences depicted herein use the 356D/358M allotype; however any allotype is included herein and can be used in accordance with the present disclosure. For example, any sequence inclusive of an IgGl Fc domain included herein can have 356E/358L replacing the 356D/358M allotype.

The anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising a heavy chain variable domain (VH) and a light chain comprising a light chain variable domain (VL). A “variable domain,” as used herein, refers to the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the VK(V.kappa), Vk (V. lambda), and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively. In the variable domains, three loops are gathered for each of the V domains of the heavy chain and light chain to form an antigen-binding site. Each of the loops is referred to as a complementarity-determining region (hereinafter referred to as a “CDR”). Additionally, the variable domains also contain relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by CDRs. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1-CDR1- FR2-CDR2-FR3-CDR3-FR4. In some embodiments, an “antibody molecule” refers to two- chain and multi-chain immunoglobulin proteins and glycoproteins. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein is an antibody fragment or antigen binding fragment of an antibody, including, for example, Fab, Fab', F(ab')2, and Fv fragments.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a VH comprising a CDRH1 comprising the amino acid sequence of SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 3; and a VE comprising a CDRE1 comprising the amino acid sequence of SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a set of 6 CDRs that collectively contain up to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid modifications, relative to the 6 CDRs of the anti-CD38 antibody provided in Table 1. For example, in some embodiments, the CDRs can be modified in any fashion, as long as the total number of changes in the set of 6 CDRs does not exceed 10 amino acid modifications, with any combination of CDRs being changed; e.g., there may be one change in CDRL1, two in CDRH2, none in CDRH3, etc. In some embodiments, each CDR has no more than a single amino acid substitution relative to the corresponding CDR of the anti-CD38 antibody provided in Table 1. In some embodiments, amino acid modifications in the CDRH3 are avoided.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 7 and a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 8.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein is a full-length IgG antibody. In a full-length IgG antibody, each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. In some embodiments, the immunoglobulin molecules are IgG class IgG4, or a subclass thereof.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises an IgG4 constant region (e.g., a human IgG4 constant region comprising the amino acid sequence of SEQ ID NO: 14). As used herein, the term “IgG4 constant region” refers to a wild-type IgG4 constant region (e.g., a wild-type human IgG4 constant region) or an IgG4 constant region variant (e.g., a human IgG4 constant region variant) or fragment thereof. IgG4 constant region variants (e.g., human IgG4 constant region variants) that may be used in the anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein may, in some embodiments, comprise one or more mutations, e.g., mutations that stabilize the hinge region and/or reduce the toxicity of the antibody. For example, a mutation at position 228 of the IgG4 according to the EU numbering system stabilizes the hinge of IgG4. In some embodiments, a mutation at position 228 of the IgG4 constant region according to the EU numbering system results in a proline at position 228.

In some embodiments, modifications, such as mutations in the IgG4 constant region decrease antibody dependent cell cytotoxicity (ADCC). “Antibody dependent cell-mediated cytotoxicity (ADCC),” as used herein, refers to a cell-mediated reaction wherein nonspecific cytotoxic cells that express Fc gamma receptors (FcyRs) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. For example, such mutations include, without limitation, mutations at one or more of positions 252, 254, and 256 of the IgG4 constant region according to the EU numbering system. In some embodiments, a mutation at position 252 of the IgG4 constant region according to the EU numbering system results in a tyrosine at position 252. In some embodiments, a mutation at position 254 of the IgG4 constant region according to the EU numbering system results in a threonine at position 254. In some embodiments, a mutation at position 256 of the IgG4 constant region according to the EU numbering system results in a glutamic acid at position 256.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises an IgG4 constant region comprising a mutation at position 228 of the IgG4 constant region according to the EU numbering system. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises an IgG4 constant region comprising the amino acid sequence of SEQ ID NO: 15.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising a VH and a human IgG4 constant region, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7 and the IgG4 constant region comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

9. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 9.

In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a light chain comprising a VL and a kappa light constant region, wherein the VL comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:

10. In some embodiments, an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a light chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 10.

In some embodiments, a CD38-binding fusion protein used in a method described herein further comprises an anti-CD38 antibody (e.g., the anti-CD38 antibody provided in Table 1) fused to one or more (e.g., one, two) attenuated interferon alpha- 2b protein (e.g., the attenuated interferon alpha- 2b protein is fused to the heavy chain of the anti-CD38 antibody). It has been observed that interferon- alpha-2b can be attenuated in its biologic activity, which is mediated through the interferon binding to an interferon receptor on a cell surface, by introducing certain amino acid changes into the protein sequence. In some embodiments, an attenuated interferon alpha- 2b protein comprises mutations that reduce its potency (e.g., A145D) and/or eliminate O-linked glycosylation of the interferon alpha- 2b protein (e.g., T106A) (in both instances, numbering is relative to the wild type sequence of human interferon-alpha-2b). The potency (e.g., anti-proliferative activity) of attenuated interferon alpha-2b fused to a CD38 binding protein can be determined relative to a non-attenuated IFN- alpha2b (e.g., a wildtype IFN-alpha2b) using an on target (Daudi) assay, as described in USP 11,319,356. An attenuated interferon molecule can be fused to antibodies that specifically bind to CD38 (e.g., an anti-CD38 antibody), as described herein, such that the anti-CD38 antibody may serve as a delivery vehicle for the attenuated interferon to CD38-positive cells with a resulting diminution of off target interferon activity caused by the attenuated interferon molecule.

In some embodiments, the attenuated interferon alpha-2b protein is fused to the heavy chain of the anti-CD38 antibody. In some embodiments, the attenuated interferon alpha-2b protein is fused to the C-terminus of the heavy chain of the anti-CD38 antibody. As such, in some embodiments, the CD38-binding fusion protein used in a method described herein comprises a heavy chain and a light chain, wherein the heavy chain comprises the heavy chain of an anti-CD38 antibody fused to an attenuated interferon alpha- 2b protein and wherein the light chain is the light chain of the anti-CD38 antibody. In some embodiments, the CD38- binding fusion protein used in a method described herein comprises two heavy chains and two light chains, wherein each heavy chain comprises the heavy chain of an anti-CD38 antibody fused to an attenuated interferon alpha- 2b protein and wherein each light chain is the light chain of the anti-CD38 antibody.

In some embodiments, the attenuated interferon alpha-2b comprises T106A and A145D mutations relative to a wild type human interferon alpha-2b (e.g., a human interferon alpha- 2b comprising the amino acid sequence of SEQ ID NO: 11). In some embodiments, the attenuated interferon alpha- 2b comprises the amino acid of SEQ ID NO: 12. In some embodiments, the attenuated interferon alpha- 2b comprises an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid of SEQ ID NO: 12.

In some embodiments, a CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid of SEQ ID NO: 13 and a light chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid of SEQ ID NO: 10. In some embodiments, a CD38-binding fusion protein used in a method described herein comprises the amino acid of SEQ ID NO: 13 and a light chain comprising the amino acid of SEQ ID NO: 10. In some embodiments, a CD38-binding fusion protein used in a method described herein comprises two heavy chains and two light chains, wherein each heavy comprises the amino acid sequence of SEQ ID NO: 13 and each light chain comprises the amino acid sequence of SEQ ID NO: 10.

Table 1. CD38-binding fusion protein amino acid sequences

“Pomalidomide” refers to a thalidomide analog with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of pomalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. Pomalidomide inhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines. Pomalidomide has been shown to enhance T cell- and NK cell-mediated immunity and inhibit production of pro-inflammatory cytokines by monocytes (POMALYST® (pomalidomide) Capsules). Pomalidomide is approved in combination with dexamethasone for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, and had demonstrated disease progression on or within 60 days of completion of the last therapy.

“Lenalidomide” refers to a thalidomide analog which inhibits tumor angiogenesis, tumor- secreted cytokines, and tumor proliferation through inhibition of proteasome activity and induction of apoptosis. Lenalidomide (REVLAMID®) has been shown to have direct antitumor effect, activity in inhibition of angiogenesis, and immunomodulation activity.

Lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti- angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

A “proteasome inhibitor,” as used herein, refers to a compound that blocks the action of proteasomes, cellular complexes that break down proteins. Proteasome inhibitors have been used in the treatment of cancer. Examples of approved proteasome inhibitors for use in treating multiple myeloma include bortezomib and carfilzomib, which are used as the standard of care treatment for multiple myeloma.

Bortezomib has been described, e.g., in US Patent Nos. 6,713,446 and 6,958,319. Bortezomib (VELCADE®) is a proteasome inhibitor that is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Bortezomib is indicated for treatment of adult patients with multiple myeloma and in combination with other antimyeloma agents.

Carfilzomib has been described, e.g., in US Patent No. 7,232,818. Carfilzomib (KYPROLIS®) covalently irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome. Carfilzomib displays minimal interactions with non-proteasomal targets, thereby improving safety profiles over bortezomib. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquitinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered once every 4 weeks during a period of administration.

In some embodiments, in a method described herein, agents (e.g., the CD38-binding fusion protein described herein, the immunomodulatory drug (e.g., an IMiD such as lenalidomide or pomalidomide), and/or the proteasome inhibitor (e.g., bortezomib or carfilzomib)) are administered according to treatment cycles (e.g., one or more treatment cycles) during a period of administration. In some embodiments, each treatment cycle is 4 weeks (i.e., 28 days). In some embodiments, a period of administration is up to 5 years (e.g., up to 5 years, up to 4.5 years, up to 4 years, up to 3.5 years, up to 3 years, up to 2.5 years, up to 2 years, up to 23 months, up to 22 months, up to 21 months, up to 20 months, up to 19 months, up to 18 months, up to 17 months, up to 16 months, up to 15 months, up to 14 months, up to 13 months, up to 12 months, up to 11 months, up to 10 months, up to 9 months, up to 8 months, up to 7 months, up to 6 months, up to 5 months, up to 4 months, up to 3 months, up to 2 months, or up to 1 month). In some embodiments, a period of administration is more than 2 years (e.g., 2-5, 3-5, 4-5, 2-4, 3-4, or 2-3 years). In some embodiments, a period of administration is until the subject exhibits disease progression. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.

In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at 0.5-4 mg/kg (e.g., 0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 1-4, 1- 3.5, 1-3, 1-2.5, 1-2, 1-1.5, 1.5-4, 1.4-3.5, 1.5-3, 1.5-2.5, 1.5-2, 2-4, 2-3.5, 2-3, 2-2.5, 2.5-4, 2.5- 3.5, 2.5-3, 3-4, 3-3.5, or 3.5-4 mg/kg) of the subject. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at 0.75-3 mg/kg (e.g., 0.75- 3, 1-3, 1.2-2.8, 1.4-2.6, 1.6-2.4, 1.8-2.2, or 1.9-2.1 mg/kg) of the subject. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at about 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, or 4 mg/kg of the subject. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at about 1 mg/kg of the subject.

In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at a dose of 50-250 mg (e.g., 50-250, 50-200, 50-150, 50-100, 60-250, 60-200, 60-150, 60-100, 100-250, 100-200, 100-150, 150-250, 150-200, or 200-250 mg) to the subject regardless of the subject’s weight. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at a dose of 60-240 mg (e.g., 60-240, 80-240, 100-200, or 120-160 mg) to the subject regardless of the subject’s weight. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at a dose of about 60 mg, 80 mg, 120 mg, or 240 mg to the subject regardless of the subject’s weight. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at a dose of about 80 mg to the subject regardless of the subject’s weight.

In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at 0.75-3 mg/kg (e.g., about 0.75, 1, 1.5, 2, 2.5, or 3 mg/kg) of the subject or at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg regardless of the subject’s weight) according to treatment cycles (e.g., 4-week (i.e., 28-day) treatment cycles) during a period of administration (e.g., any one of the period of administration described herein). In some embodiments, during a period of administration, the CD38-binding fusion protein is administered at 0.75-3 mg/kg (e.g., about 0.75, 1, 1.5, 2, 2.5, or 3 mg/kg) of the subject or at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg regardless of the subject’s weight) once in each 4-week treatment cycle (e.g., on day 1 of each treatment cycle).

In some embodiments, in a method described herein, the CD38-binding fusion protein is administered intravenously (e.g., via intravenous injection or infusion).

In some embodiments, in a method described herein, the immunomodulatory drug administered to the subject is pomalidomide (e.g., according to any known dose and dosing regimen for pomalidomide). In some embodiments, in a method described herein, the subject is administered 2-6 mg (e.g., 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, or 5-6 mg) of pomalidomide daily. In some embodiments, in a method described herein, the subject is administered 2, 3, 4, 5, or 6 mg of pomalidomide daily. In some embodiments, in a method described herein, the subject is administered 4 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle during a period of administration. In some embodiments, in a method described herein, pomalidomide is administered orally (e.g., as a capsule).

In some embodiments, a method described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject having multiple myeloma the CD38-binding fusion protein described herein, and the immunomodulatory drug pomalidomide, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, pomalidomide is administered (e.g., orally as a capsule) at a dose of 2-4 mg daily for the first 21 days of each 4-week treatment cycle during a period of administration. In some embodiments, the method comprises administering 2-3 mg of pomalidomide. In some embodiments, the method comprises administering 3-4 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments, the method comprises administering 2 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments, the method comprises administering 3 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments, the method comprises administering 4 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime. In some embodiments, in a method described herein, the immunomodulatory drug administered to the subject is lenalidomide (e.g., according to any known dose and dosing regimen for lenalidomide). In some embodiments, in a method described herein, the subject is administered 5-15 mg (e.g., 5-15, 5-12, 5-9, 5-6, 8-15, 8-12, 8-9, 9-15, 9-12, or 12-15 mg) of lenalidomide daily. In some embodiments, in a method described herein, the subject is administered about 5, 6, 7, 8, 9, 10, 11, 12, 13 ,14, or 15 mg of lenalidomide daily. In some embodiments, the method comprises administering lenalidomide at a dose of 5-15 mg (e.g., 10 mg) up to daily for a 4-week treatment cycle. In some embodiments, the method comprises administering lenalidomide at a dose of 5-15 mg (e.g., 10 mg) daily for a 4-week treatment cycle. In some embodiments, in a method described herein, the subject is administered 10 mg of lenalidomide daily for 28 days of each 4-week treatment cycle during a period of administration (i.e., lenalidomide is administered every day of each 4-week treatment cycle). In some embodiments, in a method described herein, lenalidomide is administered orally (e.g., as a capsule).

In some embodiments, a method described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject having multiple myeloma the CD38-binding fusion protein described herein, and the immunomodulatory drug lenalidomide, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, lenalidomide is administered (e.g., orally as a capsule) at a dose of 10 mg daily for the first 28 days of each 4-week treatment cycle during a period of administration. In some embodiments, after 3 cycles of maintenance therapy, the dose of lenalidomide is increased to 15 mg daily if tolerated. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.

In some embodiments, in a method described herein, the proteasome inhibitor administered to the subject is bortezomib. In some embodiments, bortezomib is administered according to any known dose and dosing regimen for bortezomib. In some embodiments, in a method described herein, bortezomib is administered at a dose based on the subject’s body surface area. In some embodiments, in a method described herein, bortezomib is administered at a dose of 1-1.5 mg/m ² (e.g., 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1-1.1, 1.1-1.5, 1.1-1.4, 1.1-1.3, 1.1- 1.2, 1.2-1.5, 1.2-1.4, 1.2-1.3, 1.3-1.5, 1.3-1.4, or 1.4-1.5 mg/m ² ). In some embodiments, in a method described herein, bortezomib is administered at a dose of about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 mg/m ² . In some embodiments, the method comprises administering bortezomib at a dose of 1-2 mg/m ² weekly for a 4-week treatment cycle for 1, 2, 3, 4, 5, 6, 7, 8, or 10 treatments cycles and then administering bortezomib at a dose of 1-2 mg/m ² every two weeks for any remaining treatment cycles. In some embodiments, in a method described herein, bortezomib is administered at a dose of about 1.3 mg/m ² on days 1, 8, 15 for eight 4-week treatment cycles and on days 1 and 8 for remaining 4-week treatment cycles during a period of administration. In some embodiments, in a method described herein, bortezomib is administered subcutaneously (e.g., via subcutaneous injection).

In some embodiments, a method described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject having multiple myeloma the CD38-binding fusion protein described herein, and the proteasome inhibitor bortezomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, and bortezomib is administered (e.g., via subcutaneous injection) at a dose of about 1-2 mg/m ² on days 8, 15 and 22 for eight 4-week treatment cycles and on days 8 and 22 for remaining 4-week treatment cycles during a period of administration. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.

In some embodiments, a method described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject having multiple myeloma the CD38-binding fusion protein described herein, and the proteasome inhibitor bortezomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, and bortezomib is administered (e.g., via subcutaneous injection) at a dose of about 1.3 mg/m ² on days 8, 15 and 22 for eight 4-week treatment cycles and on days 8 and 22 for remaining 4-week treatment cycles during a period of administration. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.

In some embodiments, in a method described herein, the proteasome inhibitor administered to the subject is carfilzomib. In some embodiments, carfilzomib is administered according to any known dose and dosing regimen for carfilzomib. In some embodiments, in a method described herein, carfilzomib is administered at a dose based on the subject’s body surface area. In some embodiments, in a method described herein, bortezomib is administered at a dose of 10-30 mg/m ² (e.g., 10-30, 10-25, 10-20, 10-15, 15-30, 15-25, 15-20, 20-30, 20-25, or 25-30 mg/m ² ). In some embodiments, in a method described herein, carfilzomib is administered at a dose of about 10, 15, 20, 25, 30 mg/m ² . In some embodiments, in a method described herein, carfilzomib is administered at a dose of up to 70 mg/m ² (e.g., up to 70, up to 60, or up to 50 mg/m ² ). In some embodiments, in a method described herein, carfilzomib is administered at a dose of about 70 mg/m ² . In some embodiments, in a method described herein, carfilzomib is administered at a dose of about 20 mg/m ² on day 1 of cycle 1 (i.e., the first 4-week treatment cycle during a period of administration), and at a dose of up to 70 mg/m ² on days 8 and 15 for remaining 4-week treatment cycles during a period of administration. In some embodiments, in a method described herein, carfilzomib is administered intravenously (e.g., intravenous injection or infusion).

In some embodiments, a method described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject having multiple myeloma the CD38-binding fusion protein described herein, and the proteasome inhibitor carfilzomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, carfilzomib is administered (e.g., via intravenous infusion) at a dose of about 20 mg/m ² on day 1 and at a dose of up to 70 mg/m ² on days 8 and 15 of cycle 1 (i.e., the first 4- week treatment cycle during a period of administration), and at a dose of up to 70 mg/m ² for remaining 4-week treatment cycles during a period of administration. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.

In some embodiments, a method of treating a CD38-expressing cancer described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject in need thereof a CD38-binding fusion protein described herein, pomalidomide, and bortezomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, pomalidomide is administered (e.g., orally as a capsule) at a dose of 4 mg daily for up to the first 21 days of each 4-week treatment cycle (e.g., depending on adverse patient side effects), and bortezomib is administered (e.g., via subcutaneous injection) at a dose of 1-2 mg/m ² (e.g., 1.3 mg/m ² ) on days 1, 8, 15 for eight 4-week treatment cycles and on days 1 and 8 for remaining 4-week treatment cycles during a period of administration.

In some embodiments, a method described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject having multiple myeloma the CD38-binding fusion protein described herein, pomalidomide, and bortezomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, pomalidomide is administered (e.g., orally as a capsule) at a dose of 2-4 mg daily for the first 21 days of each 4-week treatment cycle, and bortezomib is administered (e.g., via subcutaneous injection) at a dose of about 1.3 mg/m ² on days 8, 15 and 22 for eight 4-week treatment cycles and on days 8 and 22 for remaining 4-week treatment cycles during a period of administration. In some embodiments, the method comprises administering 2-3 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments daily for the first 21 days of each 4-week treatment cycle, the method comprises administering 2 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments, the method comprises administering 3 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle. In some embodiments, a period of administration is until the subject exhibits disease progression. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.

In some embodiments, the method comprises administering an CD38-binding fusion protein comprising: (i) a first anti-CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; and (ii) an attenuated interferon alpha- 2b comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, a method of treating a CD38-expressing cancer described herein comprises administering, according to a 4-week treatment cycle during a period of administration, to a subject in need thereof a CD38-binding fusion protein described herein, pomalidomide, and carfilzomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, pomalidomide is administered (e.g., orally as a capsule) at a dose of 4 mg daily for the first 21 days of each 4-week treatment cycle, and carfilzomib is administered at a dose of about 20 mg/m ² on day 1 of cycle 1 (i.e., the first 4-week treatment cycle during a period of administration), and at a dose of up to 70 mg/m ² on days 8 and 15 for remaining 4-week treatment cycles during a period of administration.

In some embodiments, in any one of the methods described herein, the subject is receiving or has received treatment with a steroid, e.g., dexamethasone.

In some embodiments, in any one of the methods described herein, the subject is not receiving or has not received treatment with a steroid, e.g., dexamethasone.

In some embodiments, in any one of the methods described herein, the CD38-binding fusion protein is formulated in a composition for administration. In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a buffer (e.g., a histidine/histidine-HCl buffer), a tonicity agent (e.g., arginine- HCL), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80). In some embodiments, a composition described herein has a pH between 6.1-7.1 (e.g., 6.6) and comprises a CD38-binding fusion protein at a concentration of 8-12 mg/mL (e.g., 10 mg/ml), histidine/histidine-HCl at a concentration of 40-60 mM (e.g., 50 mM), arginine-HCL at a concentration of 75-125 mM (e.g., 100 mM), sucrose at a concentration of 30-80 mg/ml (e.g., 50 mg/ml), and polysorbate 80 at a 0.1-0.3 mg/ml (e.g., 0.2 mg/ml).

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration that does not exceed 100 mg/ml. In some embodiments, a composition comprising the CD38- binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration of 8-12 mg/ml. For example, a composition comprising the CD38- binding fusion protein used in a method described herein may comprise a CD38-binding fusion protein at a concentration of 8-12 mg/ml, 8-11.5 mg/ml, 8-11 mg/ml, 8-10.5 mg/ml, 8-10 mg/ml, 8-9.5 mg/ml, 8-9 mg/ml, 8-8.5 mg/ml, 8.5-12 mg/ml, 8.5-11.5 mg/ml, 8.5-11 mg/ml, 8.5-10.5 mg/ml, 8.5-10 mg/ml, 8.5-9.5 mg/ml, 8.5-9 mg/ml, 9-12 mg/ml, 9-11.5 mg/ml, 9-11 mg/ml, 9-10.5 mg/ml, 9-10 mg/ml, 9-9.5 mg/ml, 9.5-12 mg/ml, 9.5-11.5 mg/ml, 9.5-11 mg/ml, 9.5-10.5 mg/ml, 9.5-10 mg/ml, 10-12 mg/ml, 10-11.5 mg/ml, 10-11 mg/ml, 10-10.5 mg/ml,

10.5-12 mg/ml, 10.5-11.5 mg/ml, 10.5-11 mg/ml, 11-12 mg/ml, 11-11.5 mg/ml, or 11.5-12 mg/ml. In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration of about 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12 mg/ml. In some embodiments, a composition comprising the CD38- binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration of about 10 mg/ml.

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein has a pH of 5.5-7.5. For example, a composition comprising the CD38-binding fusion protein used in a method described herein may have a pH of 5.5-7.5, 5.5- 7, 5.5-6.5, 5.5-6, 6-7.5, 6-7, 6-6.5, 6.5-7.5, 6.5-7, or 7-7.5. In some embodiments, a composition described herein has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5. In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein has a pH of about 6.1-7.1 (e.g., 6.1-7.1, 6.2-7, 6.3-6.9, 6.4-6.8, or 6.5-6.7). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein has a pH of about 6.6.

A composition comprising the CD38-binding fusion protein used in a method as described herein further comprises a buffer (e.g., a histidine/histidine-HCl buffer), a tonicity agent (e.g., arginine-HCL), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80).

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a buffer comprising histidine and histidine-HCL. In some embodiments, the histidine and histidine-HCL balance results in a final histidine concentration in the composition of 10-120 mM (e.g., 10-120 mM, 20-110 mM, 30-100 mM, 40-90 mM, 50-80 mM, or 60-70 mM). In some embodiments, the histidine and histidine-HCL balance results in a final histidine concentration in the composition of 12.5-107.5 mM. In some embodiments, the histidine and histidine-HCL balance results in a final histidine concentration in the composition of 15-50 mM (e.g., about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, or about 50 mM). In some embodiments, the histidine and histidine-HCL balance results in a final histidine concentration in the composition of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,

58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,

83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105,

106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 mM of histidine.

The relative amount of histidine and histidine-HCL may be adjusted, e.g., to achieve a desired pH, while maintaining the histidine concentration in the composition, as described herein. In some embodiments, the histidine and histidine-HCL balance results in a final histidine concentration in the composition of about 15 mM (e.g., when the composition comprises a buffer comprising histidine at a concentration of 7.5 mM and histidine-HCL at a concentration of 7.5 mM). In some embodiments, the histidine and histidine-HCL balance results in a final histidine concentration in the composition of about 50 mM (e.g., when the composition comprises a buffer comprising histidine at a concentration of 40 mM and histidine-HCL at a concentration of 10 mM).

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a tonicity agent comprising arginine-HCL. In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises arginine-HCL at a concentration of 50-125 mM (e.g., 50-125 mM, 60-120 mM, 70-110 mM, or 80-100 mM, 75-125 mM, 95-105 mM, or 97.5-102.5 mM). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises arginine-HCL at a concentration of about 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, or 120 mM. In some embodiments, a composition comprising the CD38- binding fusion protein used in a method described herein comprises arginine-HCL at a concentration of about 100 mM.

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a stabilizer. In some embodiments, the stabilizer is a sugar. In some embodiments, the stabilizer is sucrose. In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of 3-10 % w/v (equivalent to 30-100 mg/ml). For example, a composition described herein may comprise sucrose at a concentration of 3-10 % w/v, 3-9 % w/v, 3-8 % w/v, 3-7 % w/v, 3-6 % w/v, 3-5 % w/v, 3-4 % w/v, 3-10 % w/v, 3-9 % w/v, 3-8 % w/v, 3-7 % w/v, 3-6 % w/v, 3-5 % w/v, 3-4 % w/v, 4-10 % w/v, 4-9 % w/v, 4-8 % w/v, 4-7 % w/v, 4-6 % w/v, 4-5 % w/v, 5-10 % w/v, 5-9 % w/v, 5-8 % w/v, 5-7 % w/v, 5-6 % w/v, 6-10 % w/v, 6-9 % w/v, 6-8 % w/v, 5-7 % w/v, 7-10 % w/v, 7-9 % w/v, 7-8 % w/v, 8-10 % w/v, 8-9 % w/v. or 9-10 % w/v (equivalent to 30-100 mg/ml, 30-90 mg/ml, 30-80 mg/ml, 30-70 mg/ml, 30-60 mg/ml, 30-50 mg/ml, 30-40 mg/ml, 40-100 mg/ml, 40-90 mg/ml, 40-80 mg/ml, 40-70 mg/ml, 40-60 mg/ml, 40-50 mg/ml, 50-100 mg/ml, 50-90 mg/ml, 50-80 mg/ml, 50-70 mg/ml, 50-60 mg/ml, 60-100 mg/ml, 60-90 mg/ml, 60-80 mg/ml, 60-70 mg/ml, 70-100 mg/ml, 70-90 mg/ml, 60-80 mg/ml, 80-100 mg/ml, 80-90 mg/ml, or 90-100 mg/ml, respectively).

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 3% w/v (equivalent to 30 mg/mL), 3.5% w/v (equivalent to 35 mg/mL), 4% w/v (equivalent to 40 mg/mL), 4.5% w/v (equivalent to 45 mg/mL), 5% w/v (equivalent to 50 mg/mL), 5.5% w/v (equivalent to 55 mg/mL), 6% w/v (equivalent to 60 mg/mL), 6.5% w/v (equivalent to 65 mg/mL), 7% w/v (equivalent to 70 mg/mL), 7.5% w/v (equivalent to 75 mg/mL), 8% w/v (equivalent to 80 mg/mL), 8.5% w/v (equivalent to 85 mg/mL), 9w/v (equivalent to 90 mg/mL), 9.5% w/v (equivalent to 95 mg/mL), or 10% w/v (equivalent to 100 mg/ml). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4%-8% w/v (equivalent to 40-80 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4%-7% w/v (equivalent to 40-70 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4%- 6% w/v (equivalent to 40-60 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4.5%-5.5% w/v (equivalent to 45-55 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4% w/v, 5% w/v, 6% w/v, 7% w/v, or 8 % w/v (equivalent to 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml or 80 mg/ml, respectively). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 5% w/v (equivalent to 50 mg/ml).

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a surfactant. In some embodiments, the surfactant is a polysorbate. In some embodiments, the surfactant is a polysorbate 80 (PS 80). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS80 at a concentration of 0.005-0.03 % w/v (equivalent to 0.05- 0.3 mg/ml). For example, a composition comprising the CD38-binding fusion protein used in a method described herein may comprise PS80 at a concentration of 0.005-0.03 % w/v, 0.005- 0.025 % w/v, 0.005-0.02 % w/v, 0.005-0.015 % w/v, 0.005-0.01% w/v, 0.01-0.03 % w/v, 0.01- 0.025 % w/v, 0.01-0.02 % w/v, 0.01-0.015 % w/v, 0.015-0.03 % w/v, 0.015-0.025 % w/v, 0.015-0.02 % w/v, 0.02-0.03 % w/v, 0.02-0.025 % w/v, 0.02-0.03 % w/v, 0.02-0.025 % w/v, or 0.025-0.03% w/v (equivalent to 0.05-0.3 mg/ml, 0.05-0.25 mg/ml, 0.05-0.2 mg/ml, 0.05-0.15 mg/ml, 0.05-0.1 mg/ml, 0.1-0.3 mg/ml, 0.1-0.25 mg/ml, 0.1-0.2 mg/ml, 0.1-0.15 mg/ml, 0.15- 0.3 mg/ml, 0.15-0.25 mg/ml, 0.15-0.2 mg/ml, 0.2-0.3 mg/ml, 0.2-0.25 mg/ml, or 0.25-0.3 mg/ml, respectively). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS 80 at a concentration of about 0.007% w/v (equivalent to 0.07 mg/mL), 0.008% w/v (equivalent to 0.08 mg/mL), 0.009% w/v (equivalent to 0.09 mg/mL), 0.01% w/v (equivalent to 0.1 mg/mL), 0.011% w/v (equivalent to 0.11 mg/mL), 0.012% w/v (equivalent to 0.12 mg/mL), 0.013% w/v (equivalent to 0.13 mg/mL), 0.014% w/v (equivalent to 0.14 mg/mL), 0.015% w/v (equivalent to 0.15 mg/mL), 0.016% w/v (equivalent to 0.16 mg/mL), 0.017% w/v (equivalent to 0.17 mg/mL), 0.018% w/v (equivalent to 0.18 mg/mL), 0.019w/v (equivalent to 0.19 mg/mL), or 0.02% w/v (equivalent to 0.2 mg/mL). In some embodiments, a composition described herein comprises PS80 at a concentration of about 0.01%-0.03% w/v (equivalent to 0.1-0.3 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS80 at a concentration of about 0.015%-0.025% w/v (equivalent to 0.15-0.25 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS 80 at a concentration of about 0.02% w/v (equivalent to 0.2 mg/ml).

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein (e.g., a CD38-binding fusion protein as provided in Table 1) at a concentration of 8.5-11.5 mg/ml (e.g., 10 mg/ml), histidine (e.g., composed of histidine and histidine-HCL) at a concentration of 15-60 mM (e.g., 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM), arginine-HCL at a concentration of 80-120 mM (e.g., 100 mM), sucrose at a concentration of 3-8% w/v (e.g., 5% w/v), and PS80 at a concentration of 0.01-0.03% w/v (e.g., 0.02% w/v), and wherein the composition is at a pH of 5.5-7.5 (e.g., 5.5, 6, 6.5, or 6.6). In some embodiments, the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein (e.g., a CD38-binding fusion protein as provided in Table 1) at a concentration of 10 mg/ml, histidine (e.g., composed of histidine and histidine-HCL) at a concentration of 50 mM, arginine-HCL at a concentration of 100 mM, sucrose at a concentration of 5% w/v, and PS80 at a concentration of 0.02% w/v, and wherein the composition is at a pH of 6.6. In some embodiments, the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein (e.g., a CD38-binding fusion protein as provided in Table 1) at a concentration of 10 mg/ml, histidine (e.g., composed of histidine and histidine-HCL) at a concentration of 15 mM, arginine-HCL at a concentration of 100 mM, sucrose at a concentration of 5% w/v, and PS80 at a concentration of 0.02% w/v, and wherein the composition is at a pH of 6. In some embodiments, the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein is an aqueous solution.

In some embodiments, a composition described herein (e.g., in a form of aqueous solution or in lyophilized form) is stored in dosage unit form. In some embodiments, a lyophilized form of a composition described herein is stored for at least 2 months, at least 4 months, at least 6 months, at least 1 year, at least 2 years, or at least 3 years. In some embodiments, a composition described herein (e.g., in a form of aqueous solution or in lyophilized form) is stored frozen.

In some embodiments, a method described herein is effective in treating a cancer in a patient. Treating may include, for example, inhibiting or reducing proliferation of CD38- positive cells in the cancer and/or inducing apoptosis of CD38-positive cells in the cancer.

The terms “subject” and “patient” are used interchangeably and include any mammals, including companion and farm mammals, as well as rodents, including mice, rabbits, and rats, and other rodents. Non-human primates, such as Cynomolgus monkeys, are more preferred, and human beings are highly preferred. In some embodiments, the subject is a human. In some embodiments, the subject is a human adult (e.g., more than 18 years old, including 18 years old). In some embodiments, the subject is a non-adult human (e.g., less than 18 years old).

The terms “treatment”, “treating”, “treat”, and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof or reducing the likelihood of a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “Treatment”, as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development or progression; and (c) relieving the disease, i.e., causing regression of the disease and/or relieving one or more disease symptoms. “Treatment” is also meant to encompass delivery of an agent in order to provide for a pharmacologic effect, even in the absence of a disease or condition.

Any one of the methods described herein is suitable for treating cancer. In some embodiments, the cancer is a CD38-expressing cancer. In some embodiments, the cancer is not a CD38-expressing cancer. In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the subject has not received any prior lines of MM therapy. In some embodiments, the subject has not received any prior anti-CD38-based therapies (e.g., using daratumumab). In some embodiments, the subject has received prior lines of therapy (e.g., one or more prior lines of therapy) for multiple myeloma, including at least one proteasome inhibitor, at least one anti-CD38 monoclonal antibody (mAb) drug, and/or at least one immunomodulatory drug (e.g., an IMiD). In some embodiments, the subject is refractory to a proteasome inhibitor, an immunomodulatory drug (e.g., an IMiD), or an anti-CD38 antibody therapy regardless of prior lines of therapy. In some embodiments, the subject demonstrated disease progression with the one or more prior lines of therapy.

In some embodiments, the subject has undergone standard of care (SOC) treatment for MM. In some embodiments, subject has undergone autologous stem cell transplant (ASCT) and is responsive to such treatment.

In some embodiments, the subject suffers from Relapsed or Refractory Multiple Myeloma (RRMM). In some embodiments, the subject with RRMM has failed treatment with, is intolerant to, or is not a candidate for available therapies that are known to confer clinical benefit in RRMM patients.

In some embodiments, the RRMM subject has received at least three prior lines of MM therapy and is refractory or intolerant to at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy. The prior lines of MM therapy can include one or more anti-CD38 therapy, including but not limited to daratumumab. In some embodiments, the RRMM subject has received at least three prior lines of MM therapy including daratumumab, and is relapsed or refractory to daratumumab, at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy.

In some embodiments, the RRMM subject has received at least three prior lines of MM therapy, and is refractory to at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid- based therapy. The prior lines of MM therapy do not include any anti-CD38 therapy.

In some embodiments, the RRMM subject has received at least two prior lines of MM therapy, wherein one of these two lines includes a combination of a PI based therapy and an immunomodulatory drug (e.g., an IMiD) based therapy, and the subject is refractory to at least one PI based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy. One or more of the prior lines of MM therapy can include an anti-CD38 therapy, including but not limited to daratumumab.

In some embodiments, the RRMM subject has received at least two prior lines of MM therapy, wherein one of these two lines includes a combination of a PI based therapy and an immunomodulatory drug (e.g., an IMiD) based therapy, and the other line includes daratumumab, and the subject is relapsed or refractory to daratumumab, at least one PI based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy.

In some embodiments, the RRMM subject has received at least two prior lines of MM therapy, wherein one of these two lines includes a combination of a PI based therapy and an immunomodulatory drug (e.g., an IMiD) based therapy, and the subject is refractory to at least one PI based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy. The prior lines of MM therapy do not include any anti-CD38 therapy.

In some embodiments, the RRMM subject has received prior lines of anti-CD38 therapy, including but not limited to daratumumab, and the subject is relapsed or refractory to the anti-CD38 therapy at any time during treatment with the methods described herein.

EXAMPLES

Example 1: A Phase lb Open-label Study to Evaluate the Safety and Tolerability of Intravenous CD 38 -binding fusion protein as Part of Combination Therapy in Adult Patients With Multiple Myeloma This study aims to determine proper dosing and administration approaches of a CD38- binding fusion protein in combination with other compounds for treating multiple myeloma.

CD38 is a multifunctional ectoenzyme involved in cell adhesion and transmembrane signaling. It is overexpressed in various tumor types and is believed to play a role in tumor cell migration and metastasis. CD38 is an approximately 45 kDa transmembrane glycoprotein expressed by immature hematopoietic cells, downregulated in mature cells, and re-expressed at higher levels by activated lymphocytes, such as T cells, B cells, dendritic cells, and natural killer (NK) cells.

The CD38-binding fusion protein evaluated in this study is a recombinant humanized immunoglobulin (Ig) G4 anti-CD38 monoclonal antibody fused to 2 attenuated interferonalpha 2b (IFNa2b) moieties. The amino acid sequences of the CD38-binding fusion protein are provided in Table 1 (heavy chain fused to attenuated interferon alpha-2b, i.e., SEQ ID NO: 13, and light chain, i.e., SEQ ID NO: 10). The CD38-binding fusion protein was produced by recombinant DNA technology in a mammalian cell expression system and was purified by a process that included specific viral inactivation and removal steps. The CD38 antibody portion of CD38-binding fusion protein directs the attenuated IFNa2b portion to CD38-expressing (CD38+) cells, thus achieving a high local concentration of IFNa2b at the surface of these target cells. On CD38-negative cells, the attenuation resulted is approximately 130,000-fold reduced potency compared with IFNa2b.

The CD38-binding fusion protein has a high binding affinity (dissociation constant [KD]) for human and cynomolgus CD38, with a KD of 168 pM and 1.25 nM, respectively. CD38-binding fusion protein potently inhibits proliferation of CD38+ multiple myeloma (MM) cells (half-maximal inhibitory concentration [IC50] 19.9 pM), whereas potency on CD38- negative cells is approximately 2500-fold lower. The antibody portion of CD38-binding fusion protein is an IgG4 isotype and therefore has limited effector capacity to induce antibodydependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, or complement activation against normal CD38+ cells. CD38-binding fusion protein does not modulate the adenosine dipho sphate-ribosyl cyclase activity of CD38.

Study Design

The main aims of this study are to evaluate side effects, safety, and tolerability of a CD38-binding fusion protein in combination therapy and to determine the recommended phase 2 dose (RP2D) of combination therapy with the CD38-binding fusion protein and how often administration occurs. The dose of the CD38-binding fusion protein is increased incrementally over time until the highest dose that does not cause harmful side effects is found. Participants are given the CD38-binding fusion protein through intravenous infusion.

The study determines the safety, tolerability, and the recommended dose of CD38- binding fusion protein in combination with lenalidomide in participants with newly diagnosed multiple myeloma (NDMM), and in combination with pomalidomide, or bortezomib, or carfilzomib in participants with relap sed/refractory multiple myeloma (RRMM).

The study consists of 3 groups: Group 1 corresponds to newly diagnosed multiple myeloma (NDMM) patients in maintenance therapy. Group 2 corresponds to RRMM patients who have received at least 2 prior lines of therapy, including at least 1 proteasome inhibitor (PI), at least 1 CD38 monoclonal antibody (mAb) drug, and at least 1 immunomodulatory drug (IMiD), and/or who were refractory to a PI, an IMiD, and a CD38 therapy regardless of prior lines of therapy; and who demonstrated disease progression with the last therapy. Group 3 corresponds to RRMM patients who have received 1 to 3 prior lines of antimyeloma therapy including at least 1 PI, 1 IMiD, and 1 anti-CD38 mAb and who are not refractory to the combination partners.

Inclusion criteria for the study:

In Group 1, all of the following must apply to the study participants. Participants must have/show:

1) newly diagnosed multiple myeloma based on standard International Myeloma Working Group (IMWG) diagnostic criteria;

2) a history of measurable disease documented at time of diagnosis (before induction and ASCT).

3) undergone ASCT within the 12 months of the start of induction therapy and completed ASCT within 180 days before enrollment. Time to initiation of maintenance therapy: participants may start maintenance therapy as early as 60 days after transplant and up to 180 days after transplant. Consolidation cycles are allowed.

4) Post ASCT MRD positive (IO ^-5 threshold by local SOC methods or central assessment, if a prior local MRD assessment had not been performed).;

5) no prior progression after initial therapy (at any time before starting maintenance). Participants whose induction therapy was changed due to suboptimal response or toxicity will be eligible if they do not meet criteria for progression. In addition, no more than 2 regimens will be allowed before ASCT, excluding dexamethasone alone.

6) no prior allogeneic hematopoietic stem cell transplant or solid organ transplant; and

7) recovered to Grade <1 ASCT-related toxicities from the reversible effects of ASCT (except for alopecia and amenorrhea).

In Groups 2 and 3, all of the following must apply to the study participants. Participants:

1) must have/show measurable disease defined as serum M-protein > 0.5 g/dL (> 5 g/dL) on serum protein electrophoresis (SPEP) or urine M-protein >200 mg/24 hours on urine protein electrophoresis (UPEP) or Serum free light chain (FLC) assay result with an involved FLC level >10 mg/dL, provided the serum FLC ratio is abnormal (per IMWG criteria);

2) must have/show confirmed diagnosis of multiple myeloma according to IMWG criteria with documented disease progression in need of additional therapy as determined by the investigator;

3) cannot be currently participating in another Multiple Myeloma interventional study;

4) Cannot have received previous treatment with the CD38-fusion binding protein as described in Table 1 herein;

5) cannot have a diagnosis of primary amyloidosis, Waldenstrom disease, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma per IMWG criteria or standard diagnostic criteria, plasma cell leukemia (according to the World Health Organization criterion: >20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 x 109/L), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or lymphoplasmacytic lymphoma;

6) cannot have had another malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the patient is not on active anticancer therapy and that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years; and

7) cannot have evidence of central nervous system involvement and/or meningeal involvement due to multiple myeloma exhibited during screening;

8) For Group 2 RRMM doublet arms only: Participants must have received at least 2 prior lines of therapy, including at least 1 PI, at least 1 CD38 monoclonal antibody (mAb) drug, and at least 1 immunomodulatory drug (IMiD), or who are triple refractory to a PI, and IMiD, and an anti-CD38 mAb drug regardless of the number of prior line(s) of therapy.

9) For Group 3 RRMM triplet arms only: Participants must have received 1 to 3 prior lines of antimyeloma therapy including at least 1 PI, 1 IMiD, and who are not refractory to the combination partners.

10) For carfilzomib arms, baseline echocardiogram with left ventricular ejection fraction >=50%.

For all groups, all of the following must apply to the study participants. Participants:

1) Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at screening

2) Has adequate organ function at screening as determined by the laboratory values required for enrollment: Absolute neutrophil count (ANC) >=1000 per cubic millimeter (/mm ^A 3) (or >=l*10 ^A 9/L); Platelets >=75,000/mm ^A 3 (>=75*10 ^A 9/L); Hemoglobin >=8.0 g/dL; Serum creatinine or estimated creatinine clearance <=2.0 mg/dL or >=30 mL/min (Cockcroft- Gault formula); Total serum bilirubin <=2.0*Upper limit of normal (ULN); an exception for participants with Gilbert’s syndrome may be granted after discussion with the sponsor; Liver transaminases (alanine aminotransferase [ALT])/aspartate aminotransferase [AST]) <=3.0*ULN.

3) Has recovered from adverse reactions to prior myeloma treatment or procedures (example, chemotherapy, immunotherapy, radiation therapy) to NCI CTCAE Version 5.0 Grade <=1 or baseline treatment or have the toxicity established as sequela, except for sensory or motor neuropathy, which should have recovered to Grade <=2 or baseline; Grade 1 for bortezomib arm.

Exclusion criteria for the study

Participants must:

1) currently be participating in another MM interventional study, including other clinical trials with investigational agents (including investigational vaccines or investigational medical device for disease under study) throughout the duration of this study;

2) have received previous treatment with CD38-binding fusion protein;

3) have a diagnosis of primary amyloidosis, Waldenstrom disease, monoclonal gammopathy of undetermined significance or smoldering MM per IMWG criteria or standard diagnostic criteria, plasma cell leukemia POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or lymphoplasmacytic lymphoma;

4) have had another malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy and that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years;

5) have evidence of CNS involvement and/or meningeal involvement due to MM exhibited during screening;

6) have a known severe allergic or anaphylactic reactions to human recombinant proteins or excipients used in the CD38-binding fusion protein formulation or to the study combination agents, the study medications, their analogs, or excipients in the various formulations of any agent per the prescribing information;

7) be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]) (participants with resolved infection (that is, participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels; those who are PCR positive will be excluded; an exception to this applies to participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR);

8) have a known history of seropositivity for HIV;

9) be seropositive for hepatitis C (anti-hepatitis C virus antibody positive or antihepatitis C virus-RNA quantitation positive). An exception to this applies to participants with a sustained virologic response (negative viremia is defined as undetectable HCV RNA level at least 12 weeks after completion of antiviral therapy);

10) for bortezomib arms: have received a strong cytochromes P450 (CYP3A4) inducer within 5 half-lives prior to randomization;

11) has a chronic condition requiring the use of systemic corticosteroids > 10 mg/dL of prednisone or equivalent, in addition to any required corticosteroids for the treatment of MM; and

12) has QT interval corrected with Fridericia correction method (QTcF) >480 millisecond (ms) (Grade >=2). The maximum treatment duration in this study for Group 1 is up to 2 years or until disease progression or unacceptable toxicity, or up to 2 years for minimal/measurable residual disease (MRD) negative participants, whichever occurs first. Participants with clinical benefit after 2 years may continue treatment after sponsor approval and overall time to participate in the study is approximately up to 5 years. The maximum treatment duration in this study for Group 2 and Group 3 is until disease progression or unacceptable toxicity, whichever occurs first. Overall time to participate in the study is approximately up to 5 years.

The study groups receive administration regimens as described below in Table 2.

Table 2. Study Design

§ Lenalidomide §

§ CD38-binding fusion protein, infusion intravenously (IV), once on Day 1, once every 4 §

§ weeks (Q4W), in combination with Lenalidomide capsules orally once daily §

§ continuously on Days 1 to 28, in a 28-day (4-week) treatment cycle until disease §

§ progression, unacceptable toxicity, any other discontinuation criterion is met, or to a

§ maximum of 2 years for MRD-negative participants, whichever occurs first. §

§ Experimental: Group 2 (RRMM Doublets) Arm 2: CD38-binding fusion protein + §

§ Pomalidomide

§ CD38-binding fusion protein, infusion IV, once on Day 1, Q4W in combination with §

§ Pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment^ cycle until disease progression, unacceptable toxicity, or until any other discontinuation § § criterion is met, whichever occurs first. §

§ Experimental: Group 2 (RRMM Doublets) Arm 3: CD38-binding fusion protein + §

Bortezomib §

§ CD38-binding fusion protein, infusion IV, once on Day 1, Q4W in combination with §

§ Bortezomib injection subcutaneously on Days 1, 8 and 15 for the first 8 cycles and §

§ subsequently on Days 1 and 8 of treatment cycle until disease progression, unacceptable §

§ toxicity, or until any other discontinuation criterion is met, whichever occurs first. §

§ Experimental: Grou

§ Carfilzomib §

§ CD38-binding fusion protein, infusion IV, once on Day 1, Q4W in combination with §

Carfilzomib IV, on Day 1, 8 and 15 of treatment cycle until disease progression, § § unacceptable toxicity, or until any other discontinuation criterion is met, whichever § s occurs Erst. §

§ Experimental: Group 3 (RRMM Triplets) Arm A: CD38-binding fusion protein +

§ Pomalidomide + Bortezomib

§ CD38-binding fusion protein, infusion IV, once on Day 1, Q4W in combination with § Pomalidomide capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment^

§ cycle along with Bortezomib injection subcutaneously on Days 1, 8 and 15 for the first 8 §

§ cycles and subsequently on Days 1 and 8 of treatment cycle until disease progression, §

§ unacceptable toxicity, or until any other discontinuation criterion is met, whichever

§ occurs first. §

§ Experimental: Group 3 (RRMM Triplets) Arm B: CD38-binding fusion protein + §

§ Carfilzomib + Pomalidomide

§ CD38-binding fusion protein, infusion IV, once on Day 1, Q4W in combination with §

§ Carfilzomib IV, on Days 1, 8 and 15 of treatment cycle along with Pomalidomide §

§ capsules orally once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle until §

§ disease progression, unacceptable toxicity, or until any other discontinuation criterion is §

§ met whichever occurs first. §

Primary outcome measures of the study include:

1) the number of participants with dose-limiting toxicities (DLTs) in cycle 1 (28 days in length). DLT will be defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0) as follows:

• Grade 5 adverse events (AE)

• hematologic toxicity: nonfebrile grade 4 neutropenia/grade greater than or equal to (>) 3 febrile neutropenia;

• Grade 4 thrombocytopenia lasting more than 14 consecutive days

• Grade 3 thrombocytopenia as well any other grade 4 with exceptions

• nonhematologic grade 3 or higher toxicities unrelated to the underlying disease with exceptions

• delay in Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities; and

2) number of participants reporting one or more treatment emergent adverse events (TEAEs) up to approximately 5 years.

Secondary outcome measures of the study include:

1) Progression Free Survival (PFS) of up to approximately 5 years. PFS is defined as the time from the date of the first dose administration to the date of first documentation of confirmed progression of disease (PD) or death due to any cause, whichever occurs first. PD is determined by International Myeloma Working Group (IMWG) criteria. PD may be defined by an increase of >25 percent (%) from lowest response value in any one or more of the following: serum M-component increase >0.5 gram per deciliter (g/dL) or urine M-component increase >200 milligram (mg)/24-hour; difference between involved and uninvolved free light chains (FLC) levels increase must be greater than (>) 10 milligram per deciliter (mg/dL); bone marrow plasma cell >10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; or development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.

2) Overall response rate (ORR) of up to approximately 5 years. ORR is defined as the percentage of participants who achieved a partial response rate (PR) or better during the study as defined by IMWG Uniform Response Criteria. PR may be determined by >50% reduction of serum M-protein and >90% reduction in urine M-protein or less than (<) 200 mg/24 hour, or >50% decrease in uninvolved FLC or >50% reduction in plasma cells. At baseline, a >50% decrease in size of soft tissue plasmacytomas is required.

3) Duration of response (DOR) of up to approximately 5 years. DOR is defined as the time from the date of first documentation of response PR or better to the date of first documentation of PD or death due to any cause. PR may be determined by >50% reduction of serum M-protein and >90% reduction in urine M-protein or <200 mg/24 hour, or >50% decrease in uninvolved FLC or >50% reduction in plasma cells. At baseline, a >50% decrease in size of soft tissue plasmacytomas is required. PD may be determined by an increase of >25% from lowest response value in any one or more of the following: serum M-component increase >0.5 g/dL or urine M-component increase >200 mg/24-hour; difference between involved and uninvolved FLC levels increase must be >10 mg/dL; bone marrow plasma cell >10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.

4) Overall survival (OS) rates in Groups 2 and 3 of up to approximately 5 years. OS is defined as the time from the first dose of administration to the date of death, due to any cause. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.

5) Time to progression (TTP) of up to approximately 5 years. TTP is defined as the time from the date of the first dose until the earliest date of confirmed PD per IMWG, or death due to PD. PD may be determined by an increase of >25% from lowest response value in any one or more of the following: serum M-component increase >0.5 g/dL or urine M-component increase >200 mg/24-hour; difference between involved and uninvolved FLC levels increase must be >10 mg/dL; bone marrow plasma cell >10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.

6) Time to next treatment (TTNT) in Groups 2 and 3 over a 5-year time frame. TTNT is defined as the time from the date of first dose administration to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason.

7) Disease control rate (DCR) in Groups 2 and 3 over a 5-year time frame. DCR is defined as the percentage of participants who achieved a stable disease (SD) or better during the study as defined by IMWG Uniform Response Criteria. SD is defined as no known evidence of progressive disease or new bone lesions.

8) Clinical benefit rate (CBR) in Groups 2 and 3 over a 5-year time frame. CBR is defined as percentage of participants with measurable disease who had stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response per IMWG criteria. CR may be determined by negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required. sCR may be determined by CR + normal FLC ratio, absence of clonal plasma cells (determined by immunohistochemistry) or 2-to 4-color flow cytometry. VGPR may be determined by serum, urine M-protein detectable by immunofixation, not by electrophoresis, >90% reduction, or <100mg/24hrs (in those with only measurable disease by serum FLC levels, r >90% decrease in involved-uninvolved FLC level difference). PR may be determined by >50% reduction of serum M-protein; >90% reduction in urine M-protein or <200 mg/24 hour, or >0% decrease in uninvolved FLC or >50% reduction in plasma cells. At baseline, >50% decrease in size of soft tissue plasmacytomas is required.

9) Time to response (TTR) in Groups 2 and 3 over a 5-year time frame. TTR is defined as the time from the date of the first dose administration to the date of the first documentation of objective response as defined by IMWG criteria.

10) Percentage of participants in Group 1 with MRD Negativity Status at a Sensitivity of IO ⁵ in Participants Achieving CR in a 5-year time frame. MRD negativity at a sensitivity of IO ⁵ is defined as the percentage of participants who have achieved MRD negative status in participants achieving suspected CR. CR is defined as negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5 % plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required.

11) Group 3: Percentage of Participants with MRD Negativity Status at a Sensitivity of IO ⁵ in Participants Achieving CR in a 5-year time frame. MRD negativity at a sensitivity of IO ⁵ is defined as the percentage of participants who have achieved MRD negative status in participants achieving suspected CR. CR is defined as negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in participants for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is required.

12). Group 1: Duration of MRD Negativity Status at a Sensitivity of 10’ ⁵ in Participants Achieving MRD Negativity up to approximately 2 years after treatment. Duration of MRD negativity (IO ^-5 ) is defined as the duration from the start of MRD negative status to the time of reappearance of detectable MRD, PD, or death. PD: increase of >=25% from lowest response value in any one or more of the following: serum M-component increase >=0.5 g/dL or urine M-component increase >=200 mg/24-hour; difference between involved and uninvolved FLC levels increase must be >10 mg/dL; bone marrow plasma cell >=10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.

13) Duration of MRD negativity status in Group 1 and Group 3 at a sensitivity of 10’ ⁵ in participants achieving MRD negativity in a 5-year time frame. Duration of MRD negativity (IO ^-5 ) is defined as the duration from the start of MRD negative status to the time of reappearance of detectable MRD, PD, or death. PD may be determined by increase of >25% from lowest response value in any one or more of the following: serum M-component increase >0.5 g/dL or urine M-component increase >200 mg/24-hour; difference between involved and uninvolved FLC levels increase must be >10 mg/dL; bone marrow plasma cell >10%; definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; or development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder.

14) Number of participants with positive anti-drug antibodies (ADA) and neutralizing antibody (NAb) in a 5-year time frame.

Initial results from these studies indicate that the CD38-binding fusion protein and carfilzomib drug combination is associated with adverse side effects in human patients that may limit applicability of this combination therapy for use in humans. Example 2: Synergistic effect in tumor inhibition with a combination of CD38-binding fusion protein, immunomodulatory drugs and proteasome inhibitors in a mouse model

For this study, the effects of CD38-binding fusion protein combination therapies were measured immunodeficient mice implanted with human multiple myeloma cells (NCI-H929). NCI-H929 is a differentiated, highly secretory human plasma cell line established from a malignant effusion obtained from a patient with IgAK myeloma.

Four different groups of therapies or controls were tested: PBS vehicle, CD38-binding- attenuated IFN a2b fusion protein, lenalidomide, bortezomib, and a combined solution of CD38-binding fusion protein and lenalidomide, or CD38-binding fusion protein and bortezomib.

In each combination, Group 1 received the PBS vehicle twice weekly (BIW) for three weeks. Group 2 received the CD38-binding fusion protein at 2.5 mg/kg BIW for three weeks. Group 3 received lenalidomide at 25 mg/kg, BIW for 3 weeks, or bortezomib at 1.0 mg/kg, BIW for 3 weeks. Group 4 received a combination of a CD38-binding fusion protein and lenalidomide, or the combination of a CD38-binding fusion protein and bortezomib (at the same dosing amounts and schedules as the single doses).

The treatment effects on mice models are demonstrated in FIG. 1A and FIG. IB. The results show that more significant reduction in tumor median volume was achieved in groups treated with a combination therapy, compared to groups treated with the CD38-binding fusion protein or lenalidomide or bortezomib alone.