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

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.

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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 ◽

10.1182/blood-2019-123506 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3117-3117 ◽

Cited By ~ 2

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.

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

Blood ◽

10.1182/blood.v106.11.2555.2555 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2555-2555 ◽

Cited By ~ 8

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.

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

Blood ◽

10.1182/blood.v108.11.3542.3542 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3542-3542 ◽

Cited By ~ 6

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.

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

Blood ◽

10.1182/blood.v110.11.2713.2713 ◽

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.

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A Case Series Of Continuous Low Dose Lenalidomide In Patients With Relapsed Or Refractory Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.5134.5134 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5134-5134 ◽

Cited By ~ 1

Author(s):

Ahmed Sawas ◽

Sean Clark-Garvey ◽

Ellen Neylon ◽

Ameet Narwal ◽

Kathleen Maignan ◽

...

Keyword(s):

Clinical Trials ◽

Stem Cell ◽

Dose Reduction ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Median Number ◽

Classical Hodgkin Lymphoma ◽

Time To Progression ◽

Overall Response

Abstract Background Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge with limited effective treatments after high dose therapy with autologous stem cell transplantation (ASCT). Lenalidomide (Revlimid®) is an approved anti-neoplastic therapy for multiple myeloma, mantle cell lymphoma and myelodysplastic syndrome with del(5q). It has emerged as an agent with a manageable toxicity profile and promising clinical activity in a number of B cell malignancies. Two clinical trials have evaluated lenalidomide in rel/ref patients with cHL at a dose of 25mg daily for 21 days of a 28 day cycle. One study reported an overall response rate of 14%, a median time to progression of 3.2 month, with a median number of prior therapies of 2. The second study reported an overall response rate of 19%, a cytostatic response rate (CR+PR+SD> 6 month) of 33%, with a median number of prior therapies of 4. The most common reported grade 3-4 side effects in these studies respectively were: neutropenia 28% and 47%, thrombocytopenia 28% and 27%, and anemia 21% and 27%. We report on our experience in this case series with continuous low dose (10-20mg) lenalidomide in rel/ref cHL patients. Methods Twelve rel/ref cHL patients (pts) who previously underwent (or were not candidates for) ASCT and/or clinical trials were administered a daily dose of lenalidomide. Pts received 10mg and were titrated up to 20mg, if tolerated, with continuous dosing for 30 day cycles. Treatment continued until disease progression or the development of unacceptable adverse event at the lowest administered dose (5mg) of lenalidomide. Results The median age at treatment was 33 (range 24-61) years with 5 females. Median number of prior therapies was 8 (range 3-16). Ten pts had received a prior stem cell transplant (9 ASCT, 1 allogenic, and 1 both ASCT and allogeneic). Of the 12 pts, we observed 3 PR (25%), and 9 SD (8 for more than 6 months) for an overall response rate of 25% and an overall cytostatic response rate (CR+PR+SD> 6 month) of 92%. Median number of cycles received was 6 (range 2-15); six patients remain on therapy. One patient with a PR after 2 cycles of therapy underwent allogeneic stem cell transplant. The median time to progression for the remaining 11 patients was 7.5 months (range 4-15 months). Three patients had progression of disease, all of whom were able to enroll on clinical trials. One patient discontinued therapy because of exacerbation of preexisting neuropathy and was able to transition to chemotherapy. A second patient discontinued therapy after experiencing significant fatigue. In general, the treatment was well tolerated, and the most common clinically significant adverse events were: neutropenia in 4 patients which was managed by GCSF support and dose reduction, exacerbation of neuropathy in 2 patients with one patient discontinuing therapy and dose reduction in the second, and diarrhea in one patient managed with dose reduction. Conclusions Despite a far more heavily treated patient population, continuous, low dose, single agent lenalidomide was both tolerable and effective in patients with rel/ref cHL. Continuous low dose lenalidomide is able to provide meaningful time to progression and bridge to further therapy. A clinical trial to evaluate the efficacy of continuous daily dosing of lenalidomide in rel/ref cHL is warranted. Disclosures: Off Label Use: Lenalidomide in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma. O'Connor:Celgene: Consultancy, Research Funding.

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Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

Blood ◽

10.1182/blood-2011-02-338665 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1231-1238 ◽

Cited By ~ 134

Author(s):

Gareth J. Morgan ◽

Faith E. Davies ◽

Walter M. Gregory ◽

Nigel H. Russell ◽

Sue E. Bell ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

Autologous Transplantation ◽

Progression Free Survival ◽

Initial Therapy ◽

Newly Diagnosed ◽

Free Survival ◽

Overall Response ◽

Depth Of Response

Abstract As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

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Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Blood ◽

10.1182/blood-2016-07-726729 ◽

2016 ◽

Vol 128 (14) ◽

pp. 1821-1828 ◽

Cited By ~ 66

Author(s):

Torben Plesner ◽

Hendrik-Tobias Arkenau ◽

Peter Gimsing ◽

Jakub Krejcik ◽

Charlotte Lemech ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Adverse Events ◽

Overall Response Rate ◽

Response Rate ◽

Phase 1 ◽

Overall Response ◽

Key Points ◽

The Individual ◽

Good Partial Response

Key Points Daratumumab plus lenalidomide/dexamethasone elicited an overall response rate of 81% (63% very good partial response or better). Adverse events were manageable and in accord with the individual toxicity profiles of daratumumab and lenalidomide/dexamethasone.

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An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma

Blood ◽

10.1182/blood-2012-03-414359 ◽

2012 ◽

Vol 119 (24) ◽

pp. 5661-5670 ◽

Cited By ~ 180

Author(s):

Ravi Vij ◽

Michael Wang ◽

Jonathan L. Kaufman ◽

Sagar Lonial ◽

Andrzej J. Jakubowiak ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

Phase 1 ◽

Single Agent ◽

Phase 2 ◽

Open Label ◽

Refractory Multiple Myeloma ◽

Overall Response ◽

To Receive

Abstract Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

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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)

Journal of Clinical Oncology ◽

10.1200/jco.21.00443 ◽

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).

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rHuPH20-facilitated subcutaneous administration of monoclonal antibodies in cancer therapy

Immunotherapy ◽

10.2217/imt-2020-0204 ◽

2021 ◽

Vol 13 (1) ◽

pp. 79-88

Author(s):

Wenliang Dong ◽

Min Chen ◽

Jiaxue Wang ◽

Lin Xia ◽

Qian Wang ◽

...

Keyword(s):

Monoclonal Antibody ◽

Adverse Events ◽

Overall Response Rate ◽

Response Rate ◽

Meta Analysis ◽

Subcutaneous Administration ◽

Serious Adverse Events ◽

Overall Response ◽

Antidrug Antibody ◽

Antibody Positivity

Aim: This meta-analysis aimed to evaluate the pharmacokinetics, efficacy, safety and immunogenicity of rHuPH20-facilitated subcutaneous (SC) administration of monoclonal antibody compared with intravenous (IV) administration for patients with cancer. Materials & methods: Outcomes included trough concentrations (Ctrough), overall response rate, adverse events, serious adverse events and antidrug antibody positivity rate. Subgroup analysis was also performed. Results: Five studies involving 1575 participants (788/787) were included. All studies met the non-inferiority criterion in Ctrough. No significant differences were observed in overall response rate (p = 0.12), adverse events (p = 0.05), and severe adverse events (p = 0.73) between SC and IV groups. The SC group also had lower immunogenicity than the IV group. Conclusion: rHuPH20-facilitated subcutaneous administration of monoclonal antibody is highly similar to IV administration in terms of pharmacokinetics, efficacy, and safety, but with lower immunogenicity.

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