Quadruple Therapy for Multiple Myeloma
Recruiting in Palo Alto (17 mi)
Age: 65+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Jacob Laubach, MD
Must not be taking: Corticosteroids, Investigational agents
Disqualifiers: Other malignancy, CNS involvement, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This research is testing whether the investigational drug isatuximab is safe and effective when used in combination with standard agents for the treatment of newly diagnosed multiple myeloma.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or have certain medical conditions, it might affect your eligibility. It's best to discuss your current medications with the trial team.
What evidence supports the effectiveness of the drug combination used in the Quadruple Therapy for Multiple Myeloma?
Research shows that bortezomib and dexamethasone are effective in treating relapsed or refractory multiple myeloma, with 55% of patients achieving at least a partial response. Additionally, bortezomib and lenalidomide are well-established therapies for multiple myeloma, with studies indicating they are equally effective in terms of response and survival rates.
12345Is the quadruple therapy for multiple myeloma safe for humans?
The combination of bortezomib, lenalidomide, and dexamethasone has been studied and approved for multiple myeloma, showing it is generally safe for humans. Common side effects include neutropenia (low white blood cell count) and thrombocytopenia (low platelet count), but serious side effects like peripheral neuropathy (nerve damage) and deep vein thrombosis (blood clots) were not common. The treatment was well tolerated in studies, even in patients who had been previously treated with similar drugs.
678910What makes the quadruple drug therapy for multiple myeloma unique?
The quadruple drug therapy for multiple myeloma is unique because it combines four drugs—Bortezomib, Dexamethasone, Isatuximab, and Lenalidomide—to target the cancer in different ways, potentially improving effectiveness. Bortezomib is a proteasome inhibitor that can be administered subcutaneously to reduce side effects, while Lenalidomide and Isatuximab work through different mechanisms to prevent cancer cell growth, making this combination a comprehensive approach to treatment.
136711Eligibility Criteria
This trial is for people up to 75 years old with newly diagnosed multiple myeloma who need treatment and are eligible for stem cell transplant. They must have measurable disease, acceptable blood counts, organ function within certain limits, and agree to follow specific safety programs. Pregnant or breastfeeding women, those unwilling to use contraception, or anyone treated for another cancer in the last 3 years cannot join.Inclusion Criteria
Your blood platelet count is at least 75,000 cells/dL if less than half of your bone marrow cells are plasma cells, or at least 30,000 cells/dL if half or more of your bone marrow cells are plasma cells, without needing a blood transfusion in the 3 days before the screening test.
You have a high level of M protein in your blood.
I have been diagnosed with multiple myeloma and need treatment now.
+15 more
Exclusion Criteria
I cannot tolerate blood clot prevention treatments.
Receiving any other investigational agents
Any medical or psychiatric illness that in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study
+15 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
4 weeks
1 visit (in-person)
Induction
Participants receive two 42-day cycles of the 4-drug regimen: Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone
12 weeks
Multiple visits (in-person)
Stem Cell Mobilization
Stem cell mobilization at the discretion of the Principal Investigator
Maintenance
Participants continue treatment until disease progression
Follow-up
Participants are monitored for safety and effectiveness after treatment
42 months
Participant Groups
The study tests if isatuximab combined with standard drugs (lenalidomide, bortezomib injection, dexamethasone) is safe and effective for treating new cases of multiple myeloma. Participants will receive this combination therapy before potentially undergoing a stem cell transplant.
1Treatment groups
Experimental Treatment
Group I: Isa-RVDExperimental Treatment4 Interventions
The main study consists of 4 phases a) 28-day screening phase; b) an induction phase inclusive of two 42-day induction treatment cycles: Isatuximab (IV), Bortezomib (SQ). Lenalidomide (PO), Dexamethasone; c) Followed by stem cell mobilization (at the discretion of the Principal Investigator \[PI\]);d) Participants will proceed with either autologous stem cell transplant or two additional induction cycles.
- Induction will be followed by a maintenance phase that continues until disease progression.
Bortezomib Injection is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Velcade for:
- Multiple myeloma
- Mantle cell lymphoma
🇺🇸 Approved in United States as Velcade for:
- Multiple myeloma
- Mantle cell lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Dana Farber Cancer InstituteBoston, MA
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Who Is Running the Clinical Trial?
Jacob Laubach, MDLead Sponsor
Jacob LaubachLead Sponsor
SanofiIndustry Sponsor
References
Bortezomib for the treatment of multiple myeloma. [2015]Bortezomib is the first proteasome inhibitor drug tested in human patients. Bortezomib demonstrates a particular clinical utility in the treatment of multiple myeloma (MM), where it is the only one of the new drugs administered as mono-therapy that prolongs survival. The significant problem for the consistent pursuit of bortezomib was neurotoxicity, which has been significantly reduced by registering subcutaneous administration or being administered once per week. Bortezomib is currently approved for the treatment of patients with progressive MM in mono-therapy and in combination with prednisone and melphalan in cases of untreated patients who are not candidates for autologous hematopoietic stem cell transplantation (AHSCT) and in combination with dexamethasone or dexamethasone and thalidomide in untreated MM patients, who are candidates for treatment AHSCT. Clinical research is focused on the combination of bortezomib with other new drugs with the hope of further optimizing the treatment of patients with multiple myeloma.
Clinical update: novel targets in multiple myeloma. [2019]Novel therapies that can target the multiple myeloma (MM) cell, the MM cell-patient bone marrow interaction, and the bone marrow milieu can overcome resistance to conventional therapy in preclinical models and clinical trials. Both proteasome inhibitor bortezomib and immunomodulatory drug Revimid (Celgene Corporation, Warren, NJ) have gone from laboratory bench to bedside in 3 to 4 years, and achieve responses even in patients with relapsed refractory MM. They are now undergoing clinical evaluation, alone and combined with conventional and novel therapies, for treatment of patients earlier in their disease course, and offer great promise to improve patient outcome in MM.
Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. [2015]Bortezomib (bort)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-dex. The median number of bort-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-dex a single line of prior therapy. Bort-dex was an effective salvage treatment for MM patients, particularly for those in first relapse.
Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse. [2020]Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies. In this open-label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25·5) with RCD, and the two-year overall survival (OS) was 75% (95% CI: 66-86%) and 74% (95% CI: 64-85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib- and lenalidomide-naïve patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.
Bortezomib combination therapy in multiple myeloma. [2021]Bortezomib was approved for the treatment of multiple myeloma (MM) in 2003. Since then several bortezomib-based combination therapies have emerged. Although some combinations have been preceded by preclinical investigations, most have followed the inevitable process in which active (or potentially active) drugs are combined with each other to create new treatment regimens. Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide, and/or lenalidomide have resulted in high response rates. Despite the higher and often deeper response rates and prolongation of progression-free survival with bortezomib-based multiagent regimens, an overall survival (OS) advantage has not been demonstrated with most combinations compared to the sequential approach of using anti-myeloma agents, particularly in patients less than 65 years of age with newly diagnosed myeloma. The unique properties of some of these regimens can be taken into account when choosing a particular regimen based on the clinical scenario. For example, the combination of bortezomib, thalidomide, and dexamethasone (VTD) has particular value in renal failure since none of the drugs need dose modification. Similarly, the combination chemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) is of particular value in patients presenting with aggressive disease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials are testing combinations of bortezomib with several other classes of agents, including monoclonal antibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase.
The paradoxical pharmacological mechanisms of lenalidomide and bortezomib in the treatment of multiple myeloma. [2022]The combination of bortezomib (Velcade, PS-341) and lenalidomide (Revlimid) for the treatment of multiple myeloma was proved by USA Food and Drug Administration in 2006. Lenalidomide prevents the proliferation of multiple myeloma cells through binding to cereblon and promoting the ubiquitinational degradation of IKZF1 (Ikaros)/IKZF3 (Aiolos). However, the proteasome inhibitor bortezomib would inhibit the ubiquitinational degradation of IKZF1/IKZF3. How bortezomib could not block the antiproliferative effect of lenalidomide on multiple myeloma cells, which is the paradoxical pharmacological mechanisms in multiple myeloma. In this review, we summarized recent advances in molecular mechanisms underlying the combination of bortezomib and lenalidomide for the treatment multiple myeloma, discussed the paradoxical pharmacological mechanisms of lenalidomide and bortezomib in the treatment of multiple myeloma.
Subcutaneous administration of bortezomib: strategies to reduce injection site reactions. [2021]Bortezomib (Velcade) is approved by the FDA for IV or SC injection in select patients with multiple myeloma or mantle cell lymphoma. The SC route functions as an alternative to IV administration for patients with poor IV access. Learn about effective strategies used to reduce injection site reactions that can occur with SC delivery.
Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial. [2020]Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.
Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. [2018]This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.
United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. [2015]On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomib's efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomib's regulatory development are summarized here.
Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. [2023]The goal of induction therapy for multiple myeloma (MM) is to achieve adequate disease control. Current guidelines favor triplet (bortezomib-lenalidomide-dexamethasone; VRd) or quadruplet regimens (daratumumab, bortezomib-thalidomide-dexamethasone; D-VTd). In the absence of a direct comparison between two treatment regimens, we conducted this study to compare the outcomes and safety of VRd and D-VTd.