Monoclonal Antibodies: Leading Actors in the Relapsed/Refractory Multiple Myeloma Treatment.
27 Nov 2020-Pharmaceuticals, policy and law (Multidisciplinary Digital Publishing Institute)-Vol. 13, Iss: 12, pp 426
TL;DR: The results of major clinical studies that have been conducted with elotuzumab, daratumumab and isatuximab in RRMM are described and the emerging MoAbs-based combinations in the RRMM landscape are summarized.
Abstract: Multiple myeloma is a complex hematologic malignancy, and despite a survival improvement related to the growing number of available therapeutic options since 2000s, it remains an incurable disease with most patients experiencing relapse. However, therapeutic options for this disease are constantly evolving and immunotherapy is becoming the mainstay of the therapeutic armamentarium of Multiple Myeloma (MM), starting with monoclonal antibodies (MoAbs) as elotuzumab, daratumumab and isatuximab. Elotuzumab, the first in class targeting SLAMF7, in combination with lenalidomide and dexamethasone and daratumumab, directed against CD38, in combination with Rd and with bortezomib and dexamethasone (Vd), have been approved for the treatment of relapsed/refractory MM (RRMM) after they demonstrated excellent efficacy. More recently, another anti-CD38 MoAb named isatuximab was approved by FDA in combination with pomalidomide-dexamethasone (Pd) in the same setting. Many phase II and III trials with regimens containing these MoAbs are ongoing, and when available, preliminary data are very encouraging. In this review we will describe the results of major clinical studies that have been conducted with elotuzumab, daratumumab and isatuximab in RRMM, focusing on phase III trials. Moreover, we will summarized the emerging MoAbs-based combinations in the RRMM landscape.
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TL;DR: In this article, the anti-BCMA CAR T-cell therapy was used for the treatment of relapsed/refractory multiple myeloma (R/R) patients.
Abstract: Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise.
11 citations
TL;DR: In patients affected by multiple myeloma, vitamin D deficiency is commonly correlated with an advanced stage of the disease, greater risk of progression, the development of pathological fractures, and a worse prognosis.
Abstract: Vitamin D is a steroid hormone that is essential for bone mineral metabolism and it has several other effects in the body, including anti-cancer actions. Vitamin D causes a reduction in cell growth by interrupting the cell cycle. Moreover, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, exerts various effects via its interaction with the vitamin D receptor on the innate and adaptive immune system, which could be relevant in the onset of tumors. Multiple myeloma is a treatable but incurable malignancy characterized by the growth of clonal plasma cells in protective niches in the bone marrow. In patients affected by multiple myeloma, vitamin D deficiency is commonly correlated with an advanced stage of the disease, greater risk of progression, the development of pathological fractures, and a worse prognosis. Changes in the vitamin D receptor often contribute to the occurrence and progress of deficiencies, which can be overcome by supplementation with vitamin D or analogues. However, in spite of the findings available in the literature, there is no clear standard of care and clinical practice varies. Further research is needed to better understand how vitamin D influences outcomes in patients with monoclonal gammopathies.
3 citations
TL;DR: In this paper, the authors reported the case of massive intracerebral hemorrhage form intracranial plasmacytoma that arose from the dura mater without bone involvement.
Abstract: Background: Intracranial and central nervous system’s involvement with multiple myeloma (MM) is a clinically rare manifestation. Furthermore, the development of intracranial plasmacytoma without bone involvement is much rarer. Herein, we report the case of massive intracerebral hemorrhage form intracranial plasmacytoma that arose from the dura mater without bone involvement. Case Description: A 71-year-old woman, who had been diagnosed as MM and treated 2 years prior, developed sudden lethal intracerebral hemorrhage from the intracranial plasmacytoma. Massive hemorrhage was observed after a rapid tumor growth in the middle fossa. Immediate hematoma evacuation and tumor resection allowed the patient to avoid severe neurological deficits and lethal conditions. Conclusion: A close follow-up by neuroimaging studies is essential in cases of intracranial plasmacytoma in MM patients and early intervention with surgical resection or radiotherapy should be considered.
1 citations
TL;DR: In cases of grade 1–2 toxicity, symptomatic management is recommended, but in more severe symptoms temporary or permanent discontinuation of therapy and use of glucocorticosteroids are recommended.
Abstract: Monoclonal antibodies given as monotherapy or combination therapy have emerged as effective treatment options for hematologic malignancies. By prolonging survival, mAbs reduced mortality and improved the clinical prognosis for patients with these diseases. However, despite the effective anticancer activity of mAbs, they induce adverse events. The most common side effects are infusion related reactions (IRR), associated with cytokine release within the first few hours after administra tion. IRR are usually mild to moderate and manifest in rash, fever, nausea, vomiting, dizziness, headache, hypotension or tachycardia. Other, common toxicities are cytopenias, increasing the risk of infections and bleeding. Most preventive strategies involve the use of glucocorticosteroids, acetaminophen, antihistamines, screening for antibodies against microorganisms and prophylaxis for infections. Cytokine release syndrome, cardiac, pulmonary, neurologic adverse effects occur less frequently. In cases of grade 1–2 toxicity, symptomatic management is recommended, but in more severe symptoms temporary or permanent discontinuation of therapy and use of glucocorticosteroids are recommended. In an effort to limit the incidence and severity of adverse events clinicians should know how to early recognize, precisely assess and timely manage.
TL;DR: In this article, the authors investigated the impact of increased utilization of daratumumab on the cost of care for multiple myeloma patients, and found that patients received an average of 14% more daratumab doses than the FDA-approved label indicates, increasing the 1-year daramab costs by an estimated US$31,353.
Abstract: Background: The introduction of daratumumab into the treatment of multiple myeloma has improved outcomes in patients; however, community oncologists often dose more frequently than the US FDA-approved label. Materials and methods: Integra analyzed its database to elucidate daratumumab treatment patterns and the impact of increased utilization on the cost of care for multiple myeloma. Results: Following week 24, 671 (65%) of 1037 patients remained on daratumumab-containing regimens, with 330 patients continuing more frequent treatments than the expected once-every-4-weeks dosing described in the standard dosing schedule. Patients received an average of 14% more daratumumab doses than the FDA-approved label indicates, increasing the 1-year daratumumab costs by an estimated US$31,353. Conclusion: Daratumumab is utilized more frequently than the FDA-recommended dosing, leading to higher multiple myeloma treatment costs.
References
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TL;DR: Improved outcome of patients with myeloma in recent years is demonstrated, both in the relapsed setting as well as at diagnosis, both from time of diagnosis and the time of relapse.
2,077 citations
TL;DR: The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP and underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.
1,146 citations
University of Turin1, Mayo Clinic2, University of Tübingen3, Emory University4, Semmelweis University5, Ankara University6, Charles University in Prague7, University of Mainz8, Cornell University9, Johnson & Johnson Pharmaceutical Research and Development10, Janssen Pharmaceutica11, Monash University12, Erasmus University Rotterdam13
TL;DR: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than borteonib and DexamethAsone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia.
Abstract: BackgroundDaratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. MethodsIn this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. ResultsA prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period ...
1,135 citations
Additional excerpts
...Daratumumab was assessed in combination with bortezomib and dexamethasone (DVd) in the phase III CASTOR trial [28] in which Vd (bortezomib 1....
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National and Kapodistrian University of Athens1, Karolinska University Hospital2, University of Navarra3, University of Calgary4, University College London5, University of Texas at Austin6, Poznan University of Medical Sciences7, New Generation University College8, Hadassah Medical Center9, Harvard University10, University Hospital Heidelberg11, German Cancer Research Center12, Princess Margaret Cancer Centre13, Genmab14, Janssen Pharmaceutica15
TL;DR: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma.
Abstract: BackgroundDaratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1–2 study involving patients with relapsed or refractory multiple myeloma. MethodsIn this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. ResultsAt a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan–Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in t...
1,100 citations
"Monoclonal Antibodies: Leading Acto..." refers background in this paper
...As seen in POLLUX trial most IRRs occurred during the first infusion and were grade 1 or 2....
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...The phase III POLLUX trial [39], with primary endpoint PFS, compared DRd versus Rd alone in 569 patients with RRMM who had previously received ≥1 prior line of therapy....
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...POLLUX [27] DRd versus Rd 52 versus 37 12....
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...One hundred and three patients with a median of 4 (range 1–13) prior therapies, 71% of whom refractory to PIs and IMiDs and 25% at high-risk cytogenetics received daratumumab (at the same dose and schedule of POLLUX trial), pomalidomide (4 mg on days 1–21) and dexamethasone (40 mg weekly)....
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Emory University1, National and Kapodistrian University of Athens2, Princess Margaret Cancer Centre3, Medical University of Lublin4, Charles University in Prague5, University of Navarra6, Rabin Medical Center7, Ankara University8, Monash University9, Queen Mary University of London10, University of Texas MD Anderson Cancer Center11, Kyoto Prefectural University of Medicine12, Dresden University of Technology13, Bristol-Myers Squibb14, Harvard University15
TL;DR: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.
Abstract: BackgroundElotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b–2 study in patients with relapsed or refractory multiple myeloma. MethodsIn this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. ResultsOverall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progressi...
1,083 citations
"Monoclonal Antibodies: Leading Acto..." refers result in this paper
...The results of this retrospective analysis were consistent with ELOQUENT-2 trial since ORR was 77% and median PFS 17.6 months....
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...Based on these results, the phase 3 trials ELOQUENT-2 [21], compared Elo-Rd versus Rd in 646 RRMM patients with a median age of 66 years and a median of 2 lines of prior therapies (range 1–4)....
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...Although, the overall survival data are still immature for mostly phase III studies, in the ELOQUENT-2 trial elotuzumab, in combination with lenalidomide and dexamethasone, demonstrated significant improvement in overall survival after a median follow-up of almost six years....
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...After a median follow-up of 70.6 months [23], final analysis the study showed a significant OS benefit in patients receiving Elo-Rd versus Rd since median OS was 48.3 versus 39.6 months in the Rd arm (hazard ratio, HR = 0.82; p = 0.04) so ELOQUENT-2 represents the first trial to demonstrate a significant OS advantage with an antibody-based triplet regimen in RRMM. Remarkably, OS benefit was maintained across relevant subgroups of patients as well as ≥75 years old (median 48.5 months versus 27.4 months; HR = 0.69), those with 2–3 prior lines of therapy (median 51 months versus 33.6 months; HR = 0.71) and patients with high-risk cytogenetics (median 29.8 months versus 24.8 months; HR = 0.69) [23]....
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