Overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR) according to the International Myeloma Working Group (IMWG) criteria

Duration of response (DR) was analyzed for all patients in whom a response had been observed and was calculated from the date of the first documentation of response to the date of PD or further therapy or death

Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.

Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.

Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first

Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first

Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance

Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance

Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles

Total of all reporting groups

ECOG PS, Eastern Cooperative Oncology Group performance status PS 0 Fully active able to carry on all pre-disease performance without restriction PS 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature PS 2 Ambulatory and capable of all selfcare but unable to carry out any work activities up and about more than 50% of waking hours PS 3 Capable of only limited selfcare confined to bed or chair more than 50% of waking hours PS 4 Completely disabled cannot carry on any selfcare; totally confined to bed or chair PS 5 Dead

Stage I: small number of myeloma cells. All are present:

• Hemoglobin >100 g/L
• Blood calcium <2.8 mmol/L
• No areas of bone damage or a solitary plasmacytoma of the bone
• Immunoglobulin G (IgG) <50 g/L
• Immunoglobulin A (IgA) <30 g/L
• Urine M-protein <4 g

Stage II: Moderate number of myeloma cells. The features are between stage 1 and 3

Stage III: Large number of myeloma cells. One/more are present:

• Hemoglobin <85 g/L
• Blood calcium >2.8 mmol/L
• Several areas of bone damage
• IgG >70 g/L
• IgA >50 g/L
• Urine M-protein >12 g

Stage I: small number of myeloma cells. All are present:

• Hemoglobin more than 100 g/L
• Blood calcium less than 2.8 mmol/L
• No areas of bone damage or a solitary plasmacytoma of the bone
• IgG less than 50 g/L
• IgA less than 30 g/L
• Urine M-protein less than 4 g

Stage II: Moderate number of myeloma cells. The features are between stage 1 and 3

Stage III: Large number of myeloma cells. One/more are present:

• Hemoglobin less than 85 g/L
• Blood calcium more than 2.8 mmol/L
• Several areas of bone damage
• IgG more than 70 g/L
• IgA more than 50 g/L
• Urine M-protein more than 12 g

The stages of multiple myeloma are further divided according to creatinine level in the blood, which shows how well the kidneys are working.

Substage A: Kidney function is normal. Creatinine level is less than 180 µmol/L.

Substage B: Kidney function is abnormal. Creatinine level is 180 µmol/L or more.

The International Staging System uses the results of 2 blood tests: albumin and beta-2-microglobulin level.

Stage 1: Beta-2-microglobulin level less than 3.5 mg/L and albumin level more equal than 35 g/L.

Stage 2: Beta-2-microglobulin level less than 3.5 mg/L and Albumin level less than 35 g/L or beta-2-microglobulin level is more than 3.5 mg/L but less than 5.5 mg/L and any albumin level.

Stage 3: Beta-2-microglobulin is 5.5 mg/L or more and any albumin level.

CR, complete response; PD, progressive disease; PR, partial response; RD, recommended dose; SD, stable disease; UK, unknown; VGPR, very good partial response.

To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle.

Participants who received at least 1 dose study treatment

To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle.

Participants who received at least 1 dose study treatment

DLTs were defined as:

Hematological Toxicity

• Grade 3/4 neutropenia associated with fever or lasting>7 days related to the study treatment

• Grade 3/4 thrombocytopenia accompanied by grade 3/4 hemorrhage

• Extensive bone marrow (BM) infiltration, DLT was defined as grade 4 thrombocytopenia with grade 3/4 hemorrhage or grade 4 neutropenia lasting >7 days or with fever Non-hematological Toxicity

• Grade 3/4 nausea and vomiting refractory to antiemetic therapy

• Grade≥3 muscular Adverse events (AE) (myalgia, muscular weakness, muscle cramps, myopathy)

• Grade≥3 alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) lasting more than 1 week

• Grade≥3 bilirubin increase

• Grade≥3 creatine phosphokinase (CPK) increase

• Cardiac toxicity

  • Symptomatic or treatment-requiring grade ≥1 cardiac arrhythmia related to plitidepsin
  • Grade≥1 left ventricular systolic dysfunction related to plitidepsin

• Neuropathic pain and peripheral sensory neuropathy related to BTZ

Stringent complete response (sCR) normal Free Light Chains (FLC) ratio. No clonal cells Complete response (CR) no serum/urine M-protein, no evidence of soft tissue plasmacytoma. <5% clonal plasma cells Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or >90% reduction in serum M-protein and urine M-protein <100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to <200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium >11.5 mg/dL

Overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR) according to the International Myeloma Working Group (IMWG) criteria

Duration of response (DR) was analyzed for all patients in whom a response had been observed and was calculated from the date of the first documentation of response to the date of PD or further therapy or death

Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.

Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.

Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first

Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first

Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance

Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance

Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles

Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles