Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

Botta, Cirino; Martino, Enrica Antonia; Conticello, Concetta; Mendicino, Francesco; Vigna, Ernesto; Romano, Alessandra; Palumbo, Giuseppe A.; Cerchione, Claudio; Martinelli, Giovanni; Morabito, Fortunato; Raimondo, Francesco Di; Gentile, Massimo

doi:10.3389/fonc.2021.643490

Cited by 14 publications

(31 citation statements)

References 19 publications

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“…The latter, indeed, also relies on significant epigenetic alterations of different "normal" cell populations within the bone marrow (BM) niche. Accordingly, the most active drugs for MM treatment or for reducing the risk of evolution from sMM to MM include agents with strong activity on the microenvironment, such as immunomodulatory drugs (IMiDs) or monoclonal antibodies [10,11]. In this context, much evidence supports the critical role played by stromal cells [12,13] and different cells of the IM (such as dendritic cells [14], myeloid-derived suppressor cells (MDSCs) [15,16], natural killer [17], and specific lymphocytes subclasses including the pro-inflammatory Th17 cells [18,19]) as well as BM-extrinsic drivers such as the microbiota [20] in driving MM evolution.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Botta

Mendicino

Martino

et al. 2021

Cancers

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Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Botta

Mendicino

Martino

et al. 2021

Cancers

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“…Nowadays, the pharmacological scenario of RRMM is constantly changing, crowded with new drugs, that is, novel PI (ixazomib and carfilzomib), IMiDs (pomalidomide), monoclonal antibodies (daratumumab, isatuximab, and elotuzumab), and other biological drugs 17 . Therefore, choosing the best treatment in this setting is very complicated in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 3‐year follow‐up of a multicenter, retrospective clinical experience with 319 cases outside of controlled clinical trials

Bruzzese

Derudas²,

Galli

et al. 2022

Hematological Oncology

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The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT‐2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3‐year follow‐up update of a previously published Italian real‐life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow‐up of 36 months (range 6–55), 236 patients experienced disease progression or died. Median progression‐free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow‐up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.

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“…For the latter, in fact, the results in terms of PFS are consistent with the findings from randomized clinical trials (lenalidomide-refractory patients treated with Kd at the second or third relapse had a median PFS of 8.8 months 22 ) and from real world, 23 in a population considered to be at high risk (for which, even when treated with different regimens, the reported median PFS is about 9 months) and which still represents an unmet medical need to date. 24 We also consider the studied scheme to be valid considering the risk profile. When compared to the registration study, dose reduction for adverse events occurred at a slightly different rate (23% vs. 30%); in no case we reported neuropathy, which was the most expected adverse event for first-generation PI.…”

Section: Discussionmentioning

confidence: 99%

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro‐prospective observational study

Giudice

Gozzetti

Antonioli

et al. 2022

European J of Haematology

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Objective We investigate safety and efficacy in common clinical practice of the combination of carfilzomib and dexamethasone (Kd56) approved for the ENDEAVOR trial for the treatment of relapsed or refractory multiple myeloma. Methods We retro‐prospective analyzed 75 patients in three centers in Tuscany, 48 of whom had a clinically relevant comorbidity and 50 of whom were older than 65 years, treated with a median use in the fourth line of therapy. We assessed the efficacy based on the International Myeloma Working Group criteria. Results The overall response rate was 60%. Median PFS was 10 months in the general cohort; in patients treated for more than 1 cycle of therapy PFS was 12 months. Quality of response to Kd56 treatment was found to positively impact PFS. Refractory status to previous line of therapy or to lenalidomide or an history of exposure to pomalidomide, seemed to have no impact on survival. We also showed a low adverse events rate, with no neuropathy events, and a relatively small number of cardiovascular events above grade 3 (10%). Conclusion Kd56 is an effective and well tolerated regimen in highly pretreated and elderly patients with a good safety profile.

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Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

Cited by 14 publications

References 19 publications

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 3‐year follow‐up of a multicenter, retrospective clinical experience with 319 cases outside of controlled clinical trials

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro‐prospective observational study

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