scholarly journals Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone As Salvage Therapy in Relapsed/Refractory Multiple Myeloma: Results of a Safety Run-in Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3117-3117 ◽  
Author(s):  
Caitlin L. Costello ◽  
Michelle Padilla ◽  
Edward D. Ball ◽  
Carolyn Mulroney
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Residual Disease ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Grade 3 ◽  
Observation Period

Background: Triplet combination strategies have widely been accepted as the standard of care for the management of multiple myeloma due to improved outcomes as compared to doublets. The combination of daratumumab, pomalidomide and dexamethasone (DPd) has previously demonstrated deep and durable responses, including high rates of MRD negativity, in a heavily pretreated patient population. Quadruplet regimens offer an opportunity to further improve upon these results. We report preliminary findings from an ongoing phase 2 multicenter trial of the addition of ixazomib to the combination of DPd in patients with relapsed/refractory multiple myeloma. The primary objective is to determine overall response rate and the safety and tolerability of this novel regimen. Key secondary endpoints include PFS, OS and MRD negativity rates. Methods: Eligible patients may have received ≥1 and ≤3 prior lines of therapy, have had no prior exposure to daratumumab or ixazomib, and may have not progressed on prior pomalidomide. Patients receive daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg PO days 1-21/28, ixazomib 4mg PO days 1,8,15 every 28 days, and dexamethasone 40mg PO weekly. Patients continue on therapy until disease progression, intolerability or preference. Dose-limiting toxicities (DLT) were defined as grade 3-4 hematologic adverse events (AE) or any AE that required a dose modification of pomalidomide or ixazomib at the lowest dose levels on a dose de-escalation plan. An interim safety review was performed after the first 6 patients were enrolled and completed the DLT observation period, which is the first cycle (28 days) since the start of a new dose level of pomalidomide and/or ixazomib. Results: At the time of this analysis, six patients have been enrolled and treated, and completed the DLT observation period. Patients had a median age of 62 (range 52-65) and median number of 2 prior lines of therapy (range 1-2). All patients were refractory to lenalidomide and pomalidomide-naïve. Common adverse events (AEs) included neutropenia, thrombocytopenia, GI upset, and upper respiratory infection. Grade 3-4 AEs were predominantly hematologic including neutropenia and thrombocytopenia, but also included grade 3 hypertension in 1 patient, and grade 3 hypophosphatemia, grade 4 hypokalemia, and grade 3 small bowel infection in 1 patient. No IRR > grade 2 occurred with daratumumab administration. No DLTs occurred in the first six patients in the safety run-in. The overall response rate of the cohort is 100% with 3 patients achieving a stringent complete response (CR), and 3 patients achieving a very good partial response (VGPR) after a median of 7 cycles of treatment. One patient discontinued therapy due to influenza A, the other five remain on therapy. Minimal residual disease assessments are being performed by EuroFlow for patients in VGPR or better due to concern for daratumumab interference. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Conclusion: The quadruplet regimen DIPd in patients with relapsed/refractory myeloma is a well-tolerated combination and has shown early safety in an initial safety run-in analysis. Enrollment continues in an expansion cohort to assess efficacy at multiple sites with the University of California Hematologic Malignancies Consortium. Figure Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

scholarly journals Efficacy of Lenalidomide plus Low-Dose Dexamethasone in Thai Patients with Relapsed and/or Refractory Multiple Myeloma

2021 ◽  
Vol 73 (5) ◽  
Author(s):  
Chutima Kunacheewa ◽  
Noppadol Siritanaratkul
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Serious Adverse Events ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Depth Of Response

Objective: Lenalidomide is an immunomodulatory agent with proven efficacy in the treatment of multiple myeloma. In large global clinical studies, lenalidomide plus dexamethasone has demonstrated significant improvements in the overall response rate and overall survival in patients with relapsed and/or refractory multiple myeloma, compared with a placebo and dexamethasone. This is the first study to report lenalidomide plus low-dose dexamethasone administered in Thai patients. Methods: The aim of this phase II, single-center, single-arm study was to evaluate the efficacy and safety of lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. The primary endpoint was the overall response rate at the fourth treatment cycle. Secondary endpoints included depth of response, time to response, and adverse events. Results: In total, 15 patients with a median age of 61 years old (range 23–74 years old) who had received at least one prior anti-myeloma therapy were enrolled in the study and administered 4-week cycles of lenalidomide 25 mg/day (days 1–21) and dexamethasone 40 mg/week. Patients continued in the study until the occurrence of disease progression or serious adverse events. The overall response rate was 86% and 73.3% at the fourth and from all treatment cycles, respectively (median number of treatment cycles, 10.25), and the median dose for patients aged >60 years old was 15 mg/day. The overall response rate at the fourth cycle in patients who had received prior novel agents (bortezomib and/or thalidomide) was 81.82% compared with 100% in those who had received prior conventional therapy (p = 0.15). The most common adverse events reported were anemia and neutropenia, which were both manageable. Conclusion: Lenalidomide and low-dose dexamethasone was highly effective in Thai patients with relapsed and/or refractory multiple myeloma, with a manageable adverse event profile. These findings suggest that lenalidomide 15 mg/day is a safe and effective dose for Thai patients aged ≥60 years old.

scholarly journals Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

2021 ◽  
pp. JCO.21.00443
Author(s):  
Nizar J. Bahlis ◽  
Rachid Baz ◽  
Simon J. Harrison ◽  
Hang Quach ◽  
Shir-Jing Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Phase I Study ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Grade 3

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Bendamustine Combined with Bortezomib Has Efficacy in Patients with Relapsed or Refractory Multiple Myeloma: A Phase 1/2 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1857-1857 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Alberto Bessudo ◽  
Ralph V. Boccia ◽  
Stephen J. Noga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
The United States ◽  
Overall Response ◽  
Previous Level ◽  
Grade 3

Abstract Abstract 1857 Background: Multiple myeloma (MM), the second most common hematologic cancer in the United States, has a 5-year survival rate of 38%. Bendamustine is a unique alkylating agent with multiple actions leading to cancer cell death in several tumor types. In patients with MM, bendamustine, alone and in combination with prednisone, has been shown to be efficacious, with durable responses. Bortezomib is a proteasome inhibitor approved as monotherapy for MM. It has been found to sensitize highly chemoresistant MM cell lines to alkylating agents such as melphalan. Subsequent clinical trials have reported anti-MM activity and acceptable safety for bortezomib plus melphalan for relapsed or refractory MM and for bortezomib, ascorbic acid, and melphalan (BAM) for patients with newly diagnosed MM. The present phase 1/2 study assessed the safety, tolerability, and efficacy of bortezomib plus bendamustine for patients with relapsed or refractory MM. Methods: All patients were ≥18 years old and had biopsy-confirmed MM, measurable by a serum monoclonal immunoglobulin spike ≥1 gm/dL and/or a urine monoclonal spike ≥200 mg/24 hours. Also, all patients received ≥1 prior MM treatment, not including bendamustine, and showed signs or symptoms of progressive disease, either relapsed (progression following stabilization or response) or refractory (progression during or within 6 months after an antimyeloma regimen). Patients were enrolled in successive groups of 3 to 5. The groups received open-label bendamustine administered as a 1-hour intravenous (IV) infusion of 50, 70, or 90 mg/m2 on days 1 and 4 of each 28-day treatment cycle. Each infusion was preceded by bortezomib administered as a 3- to 5-second IV push of 1.0 mg/m2. Bortezomib was also given on days 8 and 11. Enrollment at each dose level was permitted only if the first 3 patients at the previous level received 1 cycle without unacceptable dose-limiting toxicity (DLT). If not, an additional 3 patients would be treated at the previous level (for a maximum 6 at each level). The maximum tolerated dose was defined as the highest dose at which <33% of recipients had unacceptable DLT. Additional patients were then enrolled and were treated to maximum response plus 2 cycles, for a total of up to 8 cycles without progressive disease. Overall response rate (complete, very good partial, partial, and minimal response rates), duration of response, time to progression, and adverse events (AEs) were assessed by International Myeloma Working Group criteria. Results: Because no DLT was observed in phase 1, the bendamustine dosage selected for phase 2 was 90 mg/m2 (plus bortezomib at 1.0 mg/m2). A total of 40 patients (median age, 67.0 years; range, 43–89) were enrolled and had received a median of 6 (range, 2–20) prior therapies, including bortezomib (75%) and alkylators (70%). Following enrollment, 5 patients received a mean (SD) of 3.0 (1.7) cycles of 50 mg/m2 of bendamustine, 4 received 4.0 (2.9) cycles of 70 mg/m2, and 31 received 4.7 (2.8) cycles of 90 mg/m2. Among the 39 patients with efficacy data, the overall response rate was 48.7% (n=19); 53.3% in the subgroup of patients receiving 90 mg/m2 (n=16). Of the 19 responses, 1 was complete (in the 90 mg/m2 group), 2 were very good partial (both in the 90 mg/m2 group), 8 were partial, and 8 were minimal. Another 16 patients (41.0% of 39) had stable disease, and the remaining 4 (10.3%) individuals showed progressive disease. Among all 40 patients, 28 (70.0%) had grade 3 or 4 AEs: 3 of 5 patients (60.0%) receiving 50 mg/m2, 3 of 4 (75.0%) receiving 70 mg/m2, and 22 of 31 (71.0%) receiving 90 mg/m2. There were 3 deaths (unknown/old age, disease progression, and septic shock). Grade 3 or 4 AEs in ≥10% of patients were neutropenia (37.5%), thrombocytopenia (25.0%), anemia (12.5%), and leukopenia (10.0%). Conclusions: In pretreated patients with relapsed or refractory MM, 28-day cycles of bendamustine 90 mg/m2 on days 1 and 4 plus bortezomib 1.0 mg/m2 on days 1, 4, 8, and 11 were well tolerated and showed promising efficacy. This research was sponsored by and conducted by Cephalon, Inc., Frazer, PA. Disclosures: Berenson: Millennium: Consultancy, Honoraria, Research Funding; Cephalon, Inc.: Research Funding. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Boccia:Millennium: Speakers Bureau. Noga:Cephalon, Inc.: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene Corporation: Honoraria; Millennium: Honoraria; Takeda: Honoraria. Gravenor:Cephalon, Inc.: Research Funding. Siegel:CVS/Caremark: Consultancy; Cephalon, Inc.: Research Funding. Kewalramani:Cephalon, Inc.: Research Funding. Swift:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mayo:Cephalon, Inc.: Employment.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

A Phase I/II Trial of Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3542-3542 ◽  
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Chemotherapeutic Agents ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (MR+PR+CR) of 46% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were classified by EBMT criteria. Results: To date 39 patients have been enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. 36 have now completed at least 1 cycle and are therefore evaluable for response. The overall response rate (CR+PR+MR) across all treatment levels was 75% rising to 81% (CR 11%; nCR 3%; VGPR 8%; PR 39%; MR 19%) with the addition of dexamethasone in 13 cases for suboptimal response. Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression is 10.1 months and the median overall survival has not yet been reached at a median follow-up of 7.4 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 13 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma where a response rate of 81% is seen with 14% achieving nCR/CR. The toxicity profile associated is predictable, manageable and predominantly haematological. Recruitment is ongoing to a total of 53 patients.

Bortezomib, Low Dose Intravenous Melphalan and Dexamethasone for Patients with Relapsed Multiple Myeloma: Final Results of a Phase I/II Clinical Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2713-2713
Author(s):  
Rakesh Popat ◽  
Catherine Williams ◽  
Mark Cook ◽  
Charles Craddock ◽  
Supratik Basu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase I ◽  
Median Time ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Time To Progression ◽  
Overall Response ◽  
Grade 3

Abstract Background: Bortezomib is an effective treatment for patients with relapsed multiple myeloma with an overall response rate (≥PR) of 43% and time to progression of 6.2 months (APEX study). We and others have previously demonstrated potent in-vitro synergy with chemotherapeutic agents such as melphalan and it is likely that this will translate into improved responses in the clinical setting. Methods: This was a multi-centre, non-randomised Phase I/II clinical trial for patients with relapsed multiple myeloma. Bortezomib 1.3mg/m2 was given on Days 1,4,8 and 11 of a 28 day cycle, and intravenous melphalan on Day 2 for a maximum of 8 cycles. In the Phase I component melphalan was given at 2.5, 5,7.5 and 10mg/m2 in a dose escalation scheme and the maximum tolerated dose (MTD) of 7.5mg/m2 was taken forward to an expanded Phase II component. Dexamethasone 20mg on the day of and the day after each dose of bortezomib was permitted for progressive or stable disease after 2 or 4 cycles respectively. Responses were defined by EBMT criteria. Results: 53 patients were enrolled (median age 61years [range 40–77]) with a median of 3 lines of prior therapy [range 1–5] of which 26 (67%) have had one previous autologous stem cell procedure and 4 (10%) have had two. 23 (59%) have had prior exposure to thalidomide and 4 (10%) to bortezomib. The overall response rate (≥PR) across all treatment levels (n=52) was 65% rising to 69% (CR 19%; nCR 4%; VGPR 6%; PR 40%; MR 15%) with the addition of dexamethasone in 27 cases for suboptimal response. Of the 32 patients treated at the MTD the overall response rate (≥PR) was 78% (CR 28%; nCR 6%; VGPR 6%; PR 38%; MR 9%). Rapid responses were seen with the median time to response being 1 month [range 1–6]. The median time to progression was 10 months and the median overall survival has not yet been reached at a median follow-up of 17 months. Of the patients that have had disease progression 7 (35%) had responses of longer duration than their previous therapy. The MTD was defined by unacceptable delays in administering treatment due to myelosuppresion. The toxicities have been acceptable with 13 SAEs reported of which 8 were hospitalisation due to infection. The most common grade 3–4 adverse events were: thrombocytopenia (53%), infections (25%), neutropenia (17%) and neuropathy (17%). Three grade 3 cardiac events were seen (myocardial infarction, atrial fibrillation and cardiac failure) and GCSF was administered to 13 patients as treatment and prophylaxis of grade 4 neutropenia. 19 patients were withdrawn from the study due to toxicity of which 7 were for neuropathy and 3 for delayed haematological recovery. Of note, 11 patients (28%) had pre-existing grade 1 neuropathy prior to starting therapy. Summary: The combination of bortezomib, low dose intravenous melphalan and dexamethasone appears to be highly effective in patients with relapsed multiple myeloma with a response rate (≥PR) at the MTD of 78% including 34% nCR/CR. The toxicity profile is predominantly haematological.

Bortezomib in Combination with Dexamethasone and Subsequent Thalidomide for Newly-Diagnosed Multiple Myeloma in Chinese Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4827-4827
Author(s):  
Zhen Cai ◽  
Weiyan Zheng ◽  
Guoqing Wei ◽  
Xiujin Ye ◽  
Jingsong He ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Staging System ◽  
Primary Treatment ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Overall Response ◽  
International Staging System ◽  
Grade 3

Abstract Background: Bortezomib-dexamethasone-thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology12(3):235–239, 2007), but this regimen has not been reported in Chinese patients. We now report our experience with this combination. Objectives: To investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM. Patients and Method: Between June 2006 and August 2007, 11 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m2 IV on days 1, 4, 8 and 11, dexamethasone at 20 mg/m2 IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Seven of 11 patients were male and 4 were female. Median age was 57 years (range 47–86). Seven of 11 patients were stage 2 according to the International Staging System, 4 out of 11 patients were stage 3. Eleven patients received a median of 2 cycles of therapy (range 1–6). The Blade criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3. Results: Nine out of 11 patients (82%) achieved PR and 2 (18%) achieved CR; therefore the overall response rate was 100%. With a median follow-up duration of 5 months (1– 14 months), no patients died. Grade 3–4 toxicities included fatigue (3/11), thrombocytopenia (3/11), diarrhea (3/11) and orthostatic hypotension (2/11). Grade 2 neuropathy occurred in 3 out of 11 patients, herpes zoster occurred in 3 out of 11 patients. Routine anticoagulation or anti-thrombosis was not used. There was no DVT/PE in 11 patients. Conclusion: Our preliminary experience indicated that bortezomib-dexamethasone-thalidomide is highly effective in newly-diagnosed MM. Grade 3 and 4 toxicities were rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in this report with Chinese MM patients are being cautiously observed.

Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 303-303 ◽  
Author(s):  
Rachid Baz ◽  
Thomas G. Martin ◽  
Melissa Alsina ◽  
Kenneth H. Shain ◽  
Hearn J. Cho ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advisory Committees ◽  
Overall Response ◽  
Best Response ◽  
Randomized Phase Ii ◽  
Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

scholarly journals MP0250 Combined with Bortezomib and Dexamethasone in Multiple Myeloma Patients Previoulsy Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1980-1980
Author(s):  
Stefan Knop ◽  
Hartmut Goldschmidt ◽  
Marc S Raab ◽  
Monika Szarejko ◽  
Artur Jurczyszyn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Half Life ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Drugs ◽  
Multiple Cycles ◽  
Grade 3 ◽  
To Receive

Abstract Background MP0250 is a first-in-class selective tri-specific multi-DARPin® drug candidate neutralizing VEGF-Α and HGF as well as binding to human serum albumin to increase its plasma half-life. Preclinical studies have shown that MP0250 enhances sensitivity of Multiple Myeloma (MM) cells to bortezomib, inhibits tumor growth and reduces bone destruction. In this clinical phase 2 trial (NCT03136653), we are investigating the safety, tolerability and efficacy of the combination of MP0250 plus bortezomib and dexamethasone (dex) in patients (pts) with relapsed/refractory (RR) MM previously exposed to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Aims To study the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM. Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. A dose-escalation phase (part 1) consisting of two cohorts will define a safe dose of the combination of MP0250 plus bortezomib + dex followed by a dose-expansion phase (part 2). Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone (dex) 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Up to 40 patients will be enrolled. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, pharmacokinetics and potential biomarkers that include MM specific markers and cytokines monitoring bone homeostasis. The safety analysis set (SAF) is defined as patients who have received at least 1 dose of the combination of MP0250 plus bortezomib + dex. Results Data cut off was 21 July 2018. 8 pts have been treated in cohort 1 and 3 pts in cohort 2. Median time from initial diagnosis to first dose was 4.8 years (range, 1-10). Median number of prior therapies was 3 (range, 2-5). All 11 pts had prior exposure to IMiDs and PIs and 4 pts were considered PI refractory. Four patients received PI immediately prior to receive MP250 in combination. The most frequent drug-related grade ≥ 3 AEs: hypertension in 3 pts, thrombocytopenia in 6 pts, proteinuria in 2 pts and transient liver enzyme elevation in 1 patient. One dose-limiting toxicity has been reported in cohort 1 (grade 3 hypertension) and two in cohort 2 (grade 3 epistaxis, grade 3 proteinuria). There were no infusion-related reactions. Best response achieved in the 8 efficacy evaluable pts in cohort 1 was VGPR in 1 and PR in 4 for an overall response rate (ORR, ≥PR) of 62.5%. In cohort 2, 1 patient achieved Minimal Response (MR), 1 patient stable disease and 1 progressive disease. Three of four patients who were coming immediately from a PI based regimen achieved a response. Pharmacokinetics data in cohort 1 show sustained exposure over multiple cycles with a mean half-life of 11 days, and no indication of ADA mediated drug clearance was observed. Data from cohort 1 patients show accumulation of MP0250-HGF complexes over multiple cycles confirming the stable binding of MP0250 to HGF suggesting that all circulating HGF is neutralized. Summary Data from cohort 1 (8 mg/Kg q3w) suggest that MP0250 can be safely combined with bortezomib and dex in patients with relapsed and refractory MM. Durable responses were seen in patients who came from PI based pretreatment suggesting that MP0250 might be capable to reverse PI resistance. Disclosures Knop: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldschmidt:Sanofi: Consultancy, Research Funding; ArtTempi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Castellano Acosta:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Cortijo:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

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