Study of SyB L-0501 to Treat Relapsed/Refractory Multiple Myeloma

A Multicenter, Open-Label Phase II Study of SyB L-0501 in Patients With Relapsed/Refractory Multiple Myeloma

The purpose of this study is to determine the antitumor efficacy and safety of bendamustine (SyB L-0501: 90 mg/m^2/day) for a maximum of 6 cycles (1 cycle: intravenous administration for 2 consecutive days and 26-day observation period) in patients with relapsed/refractory multiple myeloma.

Inclusion Criteria:

1. Patients who are diagnosed with multiple myeloma on the basis of the response criteria of the International Myeloma Working Group (IMWG) and confirmed to meet one or more of the following criteria:

   (definition of progression according to the IMWG response criteria)

   • 25% or more increase compared to baseline for the following values

     • Serum M-protein level (however, the absolute value is 0.5 g/dL or higher)
     • Urine M-protein level (however, absolute value is 200 mg/24 hours or higher)
     • For lesions without measurable serum or urine M-protein values. involved/uninvolved free light chain (FLC) ratio (however, absolute value is 10 mg/dL or higher)

   • Clear appearance of new bone lesions or soft tissue plasmacytoma or apparent growth in size of current bone lesions or soft tissue plasmacytoma

   • Appearance of hypercalcemia (corrected calcium level ≥ 11.5 mg/dL and if determined to be caused solely by myelomas)

2. Patients with measurable lesions (meets at least one of the following two criteria

   • Serum M-protein [Immunoglobulin G (IgG)≥ 1.0 g/dL, Immunoglobulin A (IgA) ≥ 0.5 g/dL, Immunoglobulin D (IgD) ≥ 0.1 g/dL)
   • Urine M-protein ≥ 200 mg/24 hours

3. Patients who meet either one of the following items for all prior chemotherapy using proteasome inhibitors, Immunomodulatory Drugs (IMiDs) (thalidomide or lenalidomide) or alkylating agents.

   • No response*
   • Relapse/recurrence after response*
   • Intolerance
   • Not applicable (reason can be confirmed in the source document) because of predicted aggravation of complications (neurotoxicity, etc.) * Patients whose disease has progressed based on the IMWG response criteria after receiving the most recent therapy

4. Patients who have undergone a washout period of more than 3 weeks after the end of the previous therapy and determined not to be under the effect of previous treatment (antitumor effectiveness).

5. Patients who are expected to survive for at least 3 months

6. Patients aged from 20 to 79 years at the time of interim registration

7. Performance Status (P.S.) of 0 to 125. However, P.S. 2 due to pain from lytic bone lesions is acceptable

8. Patients with adequately maintained organ functions (e.g., bone marrow, heart, lung, liver, and kidney functions)

   • Neutrophil count:≥ 1,500 /mm^3
   • Platelet count:≥ 75,000 /mm^3
   • Albumin:≥ 2.5 g /dL
   • Aspartate aminotransferase (AST) Glutamic oxaloacetic transaminase (GOT): < than 3.0 times the upper limit of normal range for the site
   • Alanine aminotransferase (ALT) Glutamic pyruvic transaminase (GPT): < than 3.0 times the upper limit of normal range for the site
   • Total bilirubin: < than 1.5 times the upper limit of normal range for the site
   • Serum creatinine: < than 3.0 times the upper limit of normal range for the site
   • Partial pressure of O2 (PaO2) ≥ 65 mmHg
   • No abnormalities which require treatment are detected on ECG
   • Left ventricular ejection fraction (LVEF)(echocardiography): ≥ 55%

9. Patients who have provided written consent for participation in this study

Exclusion Criteria:

1. Patients with apparent infections (including viral infections)

2. Patients with serious complications (hepatic or renal dysfunction, etc.)

3. Patients with complications or medical history of serious cardiac disease (e.g., myocardial infarction, ischemic heart disease) within 2 years of the date of interim registration or patients with arrhythmias that require treatment

4. Patients with serious gastrointestinal symptoms (e.g., severe nausea, vomiting, or diarrhea)

5. Patients positive for Hepatitis B surface (HBs) antigen, Hepatitis C virus (HCV) antibody, or HIV antibody

6. Patients with serious bleeding tendencies (e.g., disseminated intravascular coagulation: DIC)

7. Patients with, or confirmed in the past to have had, interstitial pneumonia, pulmonary fibrosis, or pulmonary emphysema which requires treatment.

8. Patients with a complication of apparent cardiac amyloidosis

9. Patients with infiltration to the central nervous system (CNS) or patients with clinical symptoms of suspected infiltration to the CNS,

10. Patients with active multiple primary cancer

11. Patients with, or confirmed in the past to have had, autoimmune hemolytic anemia

12. Patients who have received this investigational product in the past

13. Patients who have received allogeneic stem cell transplants in the past. (patients who have received autologous stem cell transplantation are acceptable)

14. Patients who received cytokine preparations such as erythropoietin or granulocyte colony stimulating factor (G-CSF) or blood transfusions within 1 week prior to the examination conducted before interim registration for this study

15. Patients who received other investigational products or unapproved medications within 3 months before interim registration for this study

16. Patients with prior allergies to medications that are similar to this investigational product (e.g., alkylating agents, or purine-nucleoside derivatives) or mannitol

17. Patients with drug addiction, narcotics addiction, and/or alcohol dependency

18. Patients who are pregnant, who may possibly be pregnant, or lactating

19. Patients who do not agree to practice contraception for the following periods:

    Male: During investigational product administration and until 6 months after final administration Female: During investigational product administration and until 4 months after final administration

20. Patients otherwise judged by the investigator or sub-investigator to be unsuitable for inclusion in this study