Triplet produces ‘unprecedented’ ORR in PI-refractory MM

Photo courtesy of the CDC

Phase 2 results suggest a three-drug regimen may improve response rates in patients with proteasome inhibitor (PI)-refractory multiple myeloma (MM).

The combination—nelfinavir, bortezomib, and dexamethasone (NeVd)—produced an objective response rate (ORR) of 65% in this trial.

In comparison, past studies have shown response rates of 24% to 36% in the PI-refractory MM population.^1,2,3

“The unprecedented ORR of NeVd observed in this heavily pretreated, multi-refractory setting warrants further investigation to explore the potential of nelfinavir in combination with PIs . . . ,” Christoph Driessen, of Kantonsspital St. Gallen in Switzerland, and his colleagues wrote in a letter to Blood.

The researchers noted that NeVd previously demonstrated activity in a phase 1 trial of MM patients who were refractory to both bortezomib and lenalidomide.

For the phase 2 study (NCT02188537), Dr. Driessen and his colleagues tested NeVd in MM patients who were refractory to their most recent PI-containing regimen and were previously exposed to or intolerant of at least one immunomodulatory drug.

The 34 patients had a median age of 67 (range, 42-82). Sixty-two percent were male, 38% had poor-risk cytogenetics, and most had a performance status of 0 (59%) or 1 (32%).

All patients had received lenalidomide, 47% had prior pomalidomide, 76% had prior high-dose chemotherapy, and 76% had a prior transplant.

All patients were bortezomib-refractory, 79% were refractory to a PI and lenalidomide, 44% were refractory to a PI and pomalidomide, and 38% were refractory to a PI, lenalidomide, and pomalidomide.

In this study, the patients received:

• Nelfinavir at 2500 mg on days 1 to 14 twice daily
• Bortezomib at 1.3 mg/m² subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1 to 2, 4 to 5, 8 to 9, and 11 to 12.

The patients were treated for up to six 21-day cycles. They received a median of 4.5 cycles (range, 1-6).

Results

The ORR was 65%, with 17 partial responses (PRs) and five very good PRs. Three patients had a minimal response, and four had stable disease.

The ORR (PR or better) was:

• 77% in patients with poor-risk cytogenetics
• 67% in patients with fewer than five prior therapies
• 63% in patients with five or more prior therapies
• 70% in patients refractory to bortezomib and lenalidomide
• 60% in patients refractory to bortezomib and pomalidomide
• 62% in patients refractory to bortezomib, lenalidomide, and pomalidomide.

The researchers said the clinical benefit of NeVd may have been underestimated in this trial because patients were only able to receive six cycles of treatment on study due to a lack of external funding support.

“The time course of paraprotein levels also suggests that individual patients might potentially have experienced myeloma control if NeVd had been continued until progression,” the researchers wrote.

Five patients did receive more than six cycles of NeVd on a compassionate-use basis. In all, 27 patients received additional anti-myeloma treatment during follow-up.

The median progression-free survival was 12 weeks for the entire cohort and 16 weeks among patients who achieved a PR or better.

The median overall survival was 12 months, and 17 patients had died as of November 2016.

The researchers said the most common adverse events in this trial were anemia (97%), thrombocytopenia (82%), hypertension (53%), diarrhea (47%), fatigue (38%), and dyspnea (35%).

There were four deaths during treatment—three due to septicemia and one from heart failure. Three of the deaths were associated with underlying pneumonia.

“Although this mortality rate is consistent with the background mortality among patients with heavily pretreated, refractory myeloma, these findings suggest that prophylactic antibiotic therapy should be considered in those with low neutrophil counts and/or advanced age undergoing NeVd treatment,” the researchers wrote.

This work was supported by the Swiss Group for Clinical Cancer Research, the Swiss State Secretariat for Education, Research and Innovation, the Rising Tide Foundation for Clinical Cancer Research, and the Gateway for Cancer Research.

Most of the researchers declared no competing financial interests, but one reported personal fees from Celgene, Takeda, Amgen, Novartis, and Janssen-Cilag that were unrelated to this trial.

1. Lokhorst HM et al. N Engl J Med. 2015; 373(13):1207-1219.

2. Dimopoulos MA et al. Blood. 2016;128(4): 497-503.

3. Siegel DS et al. Blood. 2012;120(14):2817-2825.

Photo courtesy of the CDC

Phase 2 results suggest a three-drug regimen may improve response rates in patients with proteasome inhibitor (PI)-refractory multiple myeloma (MM).

The combination—nelfinavir, bortezomib, and dexamethasone (NeVd)—produced an objective response rate (ORR) of 65% in this trial.

In comparison, past studies have shown response rates of 24% to 36% in the PI-refractory MM population.^1,2,3

“The unprecedented ORR of NeVd observed in this heavily pretreated, multi-refractory setting warrants further investigation to explore the potential of nelfinavir in combination with PIs . . . ,” Christoph Driessen, of Kantonsspital St. Gallen in Switzerland, and his colleagues wrote in a letter to Blood.

The researchers noted that NeVd previously demonstrated activity in a phase 1 trial of MM patients who were refractory to both bortezomib and lenalidomide.

For the phase 2 study (NCT02188537), Dr. Driessen and his colleagues tested NeVd in MM patients who were refractory to their most recent PI-containing regimen and were previously exposed to or intolerant of at least one immunomodulatory drug.

The 34 patients had a median age of 67 (range, 42-82). Sixty-two percent were male, 38% had poor-risk cytogenetics, and most had a performance status of 0 (59%) or 1 (32%).

All patients had received lenalidomide, 47% had prior pomalidomide, 76% had prior high-dose chemotherapy, and 76% had a prior transplant.

All patients were bortezomib-refractory, 79% were refractory to a PI and lenalidomide, 44% were refractory to a PI and pomalidomide, and 38% were refractory to a PI, lenalidomide, and pomalidomide.

In this study, the patients received:

• Nelfinavir at 2500 mg on days 1 to 14 twice daily
• Bortezomib at 1.3 mg/m² subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1 to 2, 4 to 5, 8 to 9, and 11 to 12.

The patients were treated for up to six 21-day cycles. They received a median of 4.5 cycles (range, 1-6).

Results

The ORR was 65%, with 17 partial responses (PRs) and five very good PRs. Three patients had a minimal response, and four had stable disease.

The ORR (PR or better) was:

• 77% in patients with poor-risk cytogenetics
• 67% in patients with fewer than five prior therapies
• 63% in patients with five or more prior therapies
• 70% in patients refractory to bortezomib and lenalidomide
• 60% in patients refractory to bortezomib and pomalidomide
• 62% in patients refractory to bortezomib, lenalidomide, and pomalidomide.

The researchers said the clinical benefit of NeVd may have been underestimated in this trial because patients were only able to receive six cycles of treatment on study due to a lack of external funding support.

“The time course of paraprotein levels also suggests that individual patients might potentially have experienced myeloma control if NeVd had been continued until progression,” the researchers wrote.

Five patients did receive more than six cycles of NeVd on a compassionate-use basis. In all, 27 patients received additional anti-myeloma treatment during follow-up.

The median progression-free survival was 12 weeks for the entire cohort and 16 weeks among patients who achieved a PR or better.

The median overall survival was 12 months, and 17 patients had died as of November 2016.

The researchers said the most common adverse events in this trial were anemia (97%), thrombocytopenia (82%), hypertension (53%), diarrhea (47%), fatigue (38%), and dyspnea (35%).

There were four deaths during treatment—three due to septicemia and one from heart failure. Three of the deaths were associated with underlying pneumonia.

“Although this mortality rate is consistent with the background mortality among patients with heavily pretreated, refractory myeloma, these findings suggest that prophylactic antibiotic therapy should be considered in those with low neutrophil counts and/or advanced age undergoing NeVd treatment,” the researchers wrote.

This work was supported by the Swiss Group for Clinical Cancer Research, the Swiss State Secretariat for Education, Research and Innovation, the Rising Tide Foundation for Clinical Cancer Research, and the Gateway for Cancer Research.

Most of the researchers declared no competing financial interests, but one reported personal fees from Celgene, Takeda, Amgen, Novartis, and Janssen-Cilag that were unrelated to this trial.

1. Lokhorst HM et al. N Engl J Med. 2015; 373(13):1207-1219.

2. Dimopoulos MA et al. Blood. 2016;128(4): 497-503.

3. Siegel DS et al. Blood. 2012;120(14):2817-2825.

Photo courtesy of the CDC

Phase 2 results suggest a three-drug regimen may improve response rates in patients with proteasome inhibitor (PI)-refractory multiple myeloma (MM).

The combination—nelfinavir, bortezomib, and dexamethasone (NeVd)—produced an objective response rate (ORR) of 65% in this trial.

In comparison, past studies have shown response rates of 24% to 36% in the PI-refractory MM population.^1,2,3

“The unprecedented ORR of NeVd observed in this heavily pretreated, multi-refractory setting warrants further investigation to explore the potential of nelfinavir in combination with PIs . . . ,” Christoph Driessen, of Kantonsspital St. Gallen in Switzerland, and his colleagues wrote in a letter to Blood.

The researchers noted that NeVd previously demonstrated activity in a phase 1 trial of MM patients who were refractory to both bortezomib and lenalidomide.

For the phase 2 study (NCT02188537), Dr. Driessen and his colleagues tested NeVd in MM patients who were refractory to their most recent PI-containing regimen and were previously exposed to or intolerant of at least one immunomodulatory drug.

The 34 patients had a median age of 67 (range, 42-82). Sixty-two percent were male, 38% had poor-risk cytogenetics, and most had a performance status of 0 (59%) or 1 (32%).

All patients had received lenalidomide, 47% had prior pomalidomide, 76% had prior high-dose chemotherapy, and 76% had a prior transplant.

All patients were bortezomib-refractory, 79% were refractory to a PI and lenalidomide, 44% were refractory to a PI and pomalidomide, and 38% were refractory to a PI, lenalidomide, and pomalidomide.

In this study, the patients received:

• Nelfinavir at 2500 mg on days 1 to 14 twice daily
• Bortezomib at 1.3 mg/m² subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1 to 2, 4 to 5, 8 to 9, and 11 to 12.

The patients were treated for up to six 21-day cycles. They received a median of 4.5 cycles (range, 1-6).

Results

The ORR was 65%, with 17 partial responses (PRs) and five very good PRs. Three patients had a minimal response, and four had stable disease.

The ORR (PR or better) was:

• 77% in patients with poor-risk cytogenetics
• 67% in patients with fewer than five prior therapies
• 63% in patients with five or more prior therapies
• 70% in patients refractory to bortezomib and lenalidomide
• 60% in patients refractory to bortezomib and pomalidomide
• 62% in patients refractory to bortezomib, lenalidomide, and pomalidomide.

The researchers said the clinical benefit of NeVd may have been underestimated in this trial because patients were only able to receive six cycles of treatment on study due to a lack of external funding support.

“The time course of paraprotein levels also suggests that individual patients might potentially have experienced myeloma control if NeVd had been continued until progression,” the researchers wrote.

Five patients did receive more than six cycles of NeVd on a compassionate-use basis. In all, 27 patients received additional anti-myeloma treatment during follow-up.

The median progression-free survival was 12 weeks for the entire cohort and 16 weeks among patients who achieved a PR or better.

The median overall survival was 12 months, and 17 patients had died as of November 2016.

The researchers said the most common adverse events in this trial were anemia (97%), thrombocytopenia (82%), hypertension (53%), diarrhea (47%), fatigue (38%), and dyspnea (35%).

There were four deaths during treatment—three due to septicemia and one from heart failure. Three of the deaths were associated with underlying pneumonia.

“Although this mortality rate is consistent with the background mortality among patients with heavily pretreated, refractory myeloma, these findings suggest that prophylactic antibiotic therapy should be considered in those with low neutrophil counts and/or advanced age undergoing NeVd treatment,” the researchers wrote.

This work was supported by the Swiss Group for Clinical Cancer Research, the Swiss State Secretariat for Education, Research and Innovation, the Rising Tide Foundation for Clinical Cancer Research, and the Gateway for Cancer Research.

Most of the researchers declared no competing financial interests, but one reported personal fees from Celgene, Takeda, Amgen, Novartis, and Janssen-Cilag that were unrelated to this trial.

1. Lokhorst HM et al. N Engl J Med. 2015; 373(13):1207-1219.

2. Dimopoulos MA et al. Blood. 2016;128(4): 497-503.

3. Siegel DS et al. Blood. 2012;120(14):2817-2825.