The study will evaluate if the N-methyl-pyrrolidone (NMP) can be safely administered to humans at doses, which induce measurable immunological and anti-tumour effects in patients with myeloma who are resistant to or intolerant of lenalidomide and bortezomib.

N-Methyl-2-pyrrolidone (NMP) is a small molecule acetyl-lysine mimetic compound with potent (low micromolar range) immunomodulatory and direct anti-myeloma activity attributable to BETbromodomain inhibition at higher concentrations. NMP is nontoxic, stable and already in use as a solvent in biomedical applications. It has been the subject of numerous toxicity studies in humans and been demonstrated to have few adverse effects. The study is proposing an empiric starting dose of 50mg daily, 50% of that seen in healthy volunteers with no observable toxicity. Dose escalation will follow a rule based on accelerated trial design in order to minimise the number of patients treated at sub-therapeutic doses and minimise the length of the study. During the accelerated dose-escalation phase, one patient will be entered per cohort with a dose escalation increment of 100%, with up to 6 dose escalation and up to two dose de-escalation levels.The accelerated phase ends when one patient experiences DLT during the first cycle of treatment or when a total of two patients have experienced moderate toxicity during the first cycle of treatment regardless of the dose level; or the most recent patient has been treated at the highest dose level in the first cycle. If 1 patient experiences a DLT in the first cycle at any dose level, the cohort will be further expanded to a total of 6 patients treated at the same dose level. The maximum tolerated dose (MTD) in the study will be defined as the highest dose in which the incidence of DLT was less than 33%.

Inclusion Criteria:

1. Histologically confirmed diagnosis of plasma cell myeloma defined by WHO 2008 criteria

2. Measurable disease as defined by at least one of:

   • serum M protein ≥5g/L
   • urine M protein ≥ 200mg/24hrs
   • involved serum free light chain ≥ 100mg/L
   • measurable (by imaging at the discretion of the investigator) soft tissue plasmacytoma

3. Relapsed, refractory or intolerant of both bortezomib and lenalidomide

Definitions:

• refractory at least 4 weeks of therapy administered, with less than a partial response by IMWG criteria

• relapsed from previous response (PR or greater) to therapy, with subsequent disease progression as defined as development of bone marrow dysfunction (fall in Hb of 20g/L or platelet count <100 x 109/L) due to increased bone marrow plasmacytosis

• OR new lytic bone lesions

• OR increase in serum M protein of 5g/L

• OR absolute increase of involved serum free light chain of >250mg/L

• intolerant: grade 2 or higher toxicity unresponsive to dose adjustment 4. Prior autologous stem cell transplant, unless ineligible for transplant by the discretion of the investigator.

  5. age ≥18 years 6. ECOG performance status <2 7. The following values within 7 days of commencing NMP (blood transfusions prior to study entry are permitted)

• Haemoglobin >80g/L

• Absolute neutrophil count >1.0 x 109/L

• Platelet count ≥ 25 x 109/L

• Creatinine clearance >30ml/min (by Cockcroft/Gault)

• Bilirubin ≤ 3x upper limit of normal (ULN)

• ALT ≤ 3 x ULN

• Left ventricular ejection fraction (LVEF) ≥45% (by gated cardiac blood pool scan or echocardiography) 9. Life expectancy > 3 months 10. Able to give written informed consent 11. In the opinion of the investigator, willing and able to comply with required study procedures 12. Able to take oral medications (no malabsorptive condition)

Exclusion Criteria:

1. Pregnant or breastfeeding female patients

2. Female of child bearing potential unwilling or unable to use two methods of contraception

3. Received chemotherapy, immunotherapy or biological therapy within two weeks of enrolment. Prednisolone up to 20mg per day permitted for non-myeloma indications.

4. Patients with a history of another malignancy within 2 years of the baseline visit, excluding treated non-melanotic skin cancer and in-situ carcinoma.

5. Patients with known CNS involvement unless previously treated and well controlled for a period of ≥3 months AND which do not require the use of steroids.

6. Uncontrolled intercurrent illness including, but not limited to:

   • Active or uncontrolled infection, including active HIV or viral (A, B or C) hepatitis. NOTE: Patients with controlled infection on antibiotic or antifungal therapy are eligible i.e. the patient should be afebrile for at least 72 hours and be haemodynamically stable.

   • Impaired cardiac function, including any of the following:

     • Myocardial infarction within previous 3 months prior to starting study
     • Symptomatic congestive heart failure (New York Heart Association Class III, IV)
     • Symptomatic coronary artery disease
     • Cardiac arrhythmia not controlled by medication
     • Clinically significant resting bradycardia (<50 beats per minute)
     • Long QT syndrome or a known family history of long QT syndrome or QTc > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
     • Inability to monitor the QT/QTc interval on ECG
     • Other clinically significant uncontrolled heart disease (e.g. unstable angina or uncontrolled hypertension)

   • Impaired hepatic or renal impairment (see inclusion criteria)

   • Uncontrolled diarrhoea, nausea or vomiting

7. concomitant exposure to another investigational agent