A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma

Inclusion Criteria:

* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Male or female who is at least 18 years of age or older.
* Histologically confirmed diagnosis of secretory MM (must have measurable M protein in serum or urine) with one or more of the following:

Serum M-protein count greater than or equal to 1 g/dL Urinary M-protein greater than or equal to 200 mg/24 hours Serum free light chain (FLC) assay: involved FLC level greater than or equal to 10 mg/dL (greater than or equal to 100 mg/L) and a serum FLC ratio outside of normal range. Biopsy proven plasmacytoma

* Relapsed after 2 or more lines of systemic therapy including at least one proteasome inhibitor (i.e., bortezomib, carfilzomib) and at least one immunomodulatory agent (i.e., lenalidomide, pomalidomide) AND refractory to proteasome inhibitor therapy. Subjects will be considered refractory to proteasome inhibitor therapy if they experienced stable disease or progressive disease as the best response on their last proteasome inhibitor containing therapy OR progressed within 60 days following two or more cycles of proteasome inhibitor therapy. A line of therapy is generally separated by disease progression from a preceding line of therapy; therefore, the preparative regimen (with or without total body irradiation) and subsequent autologous stem cell rescue used for an autologous stem cell transplant are considered as one line of therapy.
* Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:

Transplant was more than 100 days prior to study enrolment No active infection Subject meets the remainder of the eligibility criteria

* Performance status score of 0 to 2 according to Eastern Cooperative Oncology Group (ECOG).
* Able to swallow and retain oral medication.
* Fasting serum glucose less than126 mg/dL (\<7 mmol/L). Subjects diagnosed previously with diabetes mellitus type 2 must also meet the additional following criteria:

Diagnosis of diabetes greater than 6 months prior to enrollment Glycosylated hemoglobin A1c (HbA1c) less than 8% at screening

* A female subject is eligible to participate if she is of the following:

Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone greater than 40 MlU/ml and estradiol less than 40 pg/ml (less than 147 pmol/L) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed in the protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Childbearing potential, has a negative serum pregnancy test during the screening period, and agrees to use adequate contraception (methods listed in the protocol) from screening until four weeks after the last dose of GSK2110183. Note: Oral contraceptives are not reliable due to potential drug-drug interaction.

* Male subjects with female partners of childbearing potential must have had a prior vasectomy or agree to use adequate contraception from the time of the first dose of GSK2110183 until 3 months after the last dose of GSK2110183.
* Adequate organ function as defined by laboratory results within specific value ranges listed in the protocol.

Inclusion criteria: Salvage Therapy with GSK2110183 and Bortezomib:

* Platelet count greater than or equal to 70 X 10\^9/L
* A subject whose ANC is greater than 1000/mm\^3 before GSK2110183 monotherapy but whose ANC decreases below 1000/mm\^3 at the time of transitioning to the salvage therapy is allowed up to 14 days following interruption of GSK2110183 dosing for ANC to recover to greater than or equal to 1000/mm\^3.

Exclusion Criteria:

* Chemotherapy, radiotherapy, immunotherapy, or other anti-myeloma therapy within 14 days prior to the first dose of GSK2110183. In addition, any drug-related toxicity, except for alopecia, should have recovered to Grade 1 or less.
* Use of an investigational drug within 14 days or 5 half-lives, whichever is longer, preceding the first dose of GSK2110183.
* History of an allogeneic stem cell transplant. Subjects with a history of an autologous stem cell transplant are NOT excluded if they meet Inclusion Criterion 5 (Subjects with a history of autologous stem cell transplant are eligible for...).
* Current use of a prohibited medication.
* Current use of oral corticosteroids, with the exception of inhaled or topical corticosteroids.
* Anticoagulants (e.g., warfarin, low molecular weight heparin, direct thrombin inhibitors) at therapeutic doses or at low doses (e.g., prophylactic) are permitted only if the subject meets the partial thromboplastin time (PTT) and international normalization ratio (INR) entry criteria. Anticoagulant use must be monitored in accordance with local institutional practice.
* Presence of active GI disease or other condition that could affect GI absorption (e.g., malabsorption syndrome) or predispose subject to GI ulceration.
* Any major surgery within the last 14 days.
* Unresolved toxicity (except alopecia) greater than or equal to Grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v4) from previous anticancer therapy.
* Presence of greater than Grade 1 peripheral neuropathy.
* Type 1 diabetes mellitus.
* Any serious or unstable pre-existing medical, psychiatric, or other condition (including laboratory abnormalities) that could interfere with subject's safety or providing informed consent.
* Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease, unstable hypertension).
* History of known human immunodeficiency virus infection.
* Subjects with a positive test for hepatitis B surface antigen or a positive test for hepatitis C antibody are excluded, regardless of the viral load. If hepatitis C antibody is positive, a confirmatory RIBA test may be performed. If the RIBA test is negative, the subject is eligible for the study.
* Primary or metastatic malignancy of the central nervous system.
* Diagnosis of or treatment for another malignancy within 2 years of enrollment, with the exception of complete resection of basal carcinoma or squamous cell carcinoma of the skin, or an in situ malignancy.
* QTC interval greater than or equal to 470 msec. NOTE: If initial result is prolonged, eligibility will be based on the average of manually calculated QTcF value from 3 ECGs (e.g., obtain 2 more ECGs at least 5 minutes apart and calculate the average of triplicate ECGs).
* Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular block.
* History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within the past 6 months.
* Class III or IV heart failure as defined by the New York Heart Association \[NYHA, 1994\] functional classification system.
* Known hypersensitivity to GSK2110183, bortezomib, boron, and/or mannitol.
* Pregnant or lactating female.