Therapeutic strategies for multiple myeloma have dramatically changed in the last two decades, especially after the introduction of proteasome inhibitors. The first-in-class proteasome inhibitor, bortezomib, was approved by the US Food and Drug Administration in 2003. Since then, it has been a backbone therapy for not only relapsed or refractory myeloma patients but also newly diagnosed multiple myeloma patients. Second-generation proteasome inhibitors, such as carfilzomib and ixazomib, have been approved, and three proteasome inhibitors were incorporated into several regimens with other cytotoxic agents, such as alkylating agents, immunomodulatory drugs and monoclonal antibodies. Because each proteasome inhibitor shows different properties with respect to adverse events, understanding and managing each adverse event of proteasome inhibitors are necessary for the continuation of therapy with minimal interruption of treatment. This review summarizes the recent advances in proteasome inhibitors used in the treatment of multiple myeloma.

/pdf/proteasome-inhibitors-for-multiple-myeloma-4x30kdi71y.pdf

Proteasome inhibitors for multiple myeloma

There have been many advances over the past decade that have dramatically changed the way we evaluate and treat patients with multiple myeloma (MM). These advances have more than doubled the average survival for patients with MM and have been crucial to an improved quality of life. We highlight recent changes to response assessment definitions, provide a review of minimal residual disease (MRD) testing, and describe how MRD testing may drive future goals of therapy. The evolving data from trials assessing novel combinations for frontline therapy and for the treatment of relapsed disease are reviewed. We present preliminary data from the 2 most promising novel agents, both of which may soon be approved by the US Food and Drug Administration for patients with relapsed MM. Finally, we examine the exciting early data from phase 1 clinical trials investigating novel immunotherapeutics in refractory myeloma, including antibody-drug conjugates, dual-targeted T-cell-engaging antibodies, and chimeric antigen receptor T cells.

Multiple Myeloma: Current Advances and Future Directions.

Purpose:
Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib9s dose with maintained efficacy and improved safety profile.
Experimental Design:
IFM2012-03 is a phase 1 multicenter study of KMP weekly in newly diagnosed elderly multiple myeloma (eNDMM), aimed to determine the maximum tolerated dose (MTD) of carfilzomib. Carfilzomib was given IV at 36, 45, 56 and 70mg/m2/day on days 1,8,15,22 with melphalan and prednisone, for nine 35-days induction cycles, followed by carfilzomib maintenance for 1 year. Three dose limiting toxicities (DLT) determined MTD at the lower dose.
Results: 
30 eNDMM were treated, 6 per cohort at 36, 45, 56mg/m2 and 12 at 70mg/m². There was one DLT at 36mg/m2 (lymphopenia), one at 45mg/m2 (lysis syndrome), two at 56mg/m2 (cardiac insufficiency and febrile neutropenia) and two at 70mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable, however, specific attention must be paid to the risk of cardiovascular events especially for elderly patients. The overall response rate was 93.3% with 46.6% complete response.
Conclusions:
The MTD dose of carfilzomib was 70mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed on a larger scale study.

/pdf/carfilzomib-weekly-plus-melphalan-and-prednisone-in-newly-2evdph7pk6.pdf

Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial.

Introduction: Despite major advances in the therapeutic management of multiple myeloma (MM), it remains an incurable disease. Several combinations of monoclonal antibodies with novel agents are being investigated with promising results in order to prolong progression-free and overall survival.Areas covered: This paper aims to critically present available data from clinical trials investigating the combination of elotuzumab with pomalidomide and dexamethasone in refractory/relapsed MM patients and determine its current role in clinical practice.Expert opinion: Pomalidomide-based combinations with monoclonal antibodies have been shown to be effective in patients with MM who are refractory to or have relapsed following treatment with lenalidomide and/or a proteasome inhibitor (PI). These regimens seem to be more effective than the standard combination of pomalidomide with dexamethasone alone. Taking into consideration that the vast majority of MM patients will receive upfront treatment including a PI and lenalidomide in the near future, pomalidomide-based triplets, such as elotuzumab-pomalidomide-dexamethasone, will become the standard of care in the second line of therapy.

Elotuzumab in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.

The multiple myeloma (MM) non transplant eligible (NTE) population is growing in line with the aging of the population in Western countries. Historically, this population has been known for having a greater risk of treatment related toxicity, and therefore drug development was slow and rather oriented towards the improvement of safety profile than the optimization of disease control. However, NTE MM patients, at least for the fit/non frail patients in recent years, seemed to have benefited more from a less palliative care to improve the depth of response and then prolong survival. NTE MM being a quite heterogeneous population, there are still a number of groups of patients that are in need of more efficient therapy, avoiding unnecessary toxicity, particularly for the frail patients. The use of triplet regimen with a melphalan-prednisone (MP) backbone has long been the standard of care for NTE MM, often dedicated to non-frail patients. New standards of care, triplet, and even quadruplet combinations, are emerging on the basis of the MP backbone but also on the more recently approved lenalidomide-dexamethasone (Rd) backbone. These developments were largely possible in line with the development of antibody-based immunotherapies (IT) in MM. The objective to improve outcomes with an acceptable safety profile will see other key therapeutic developments such as the dropping of dexamethasone early in the disease course or various attempts to allow permanent treatment discontinuation with a prolonged disease control. In that context, it is possible that immunomonitoring, minimal residual disease (MRD), and genomic risk-adaptation will become key elements of the treatment decisions on triplet-based regimens.

https://www.mdpi.com/2077-0383/9/11/3554/pdf

Three Drug Combinations in the Treatment of Fit Elderly Multiple Myeloma Patients.

tion at 12 months was 10% (90% CI 2-17) with deferasirox DT, and 19% (90% CI 12-25) with deferasirox FCT. It is important to note that mean actual deferasirox dose remained stable throughout the 6-month study with both DT (27.1-28.2 mg/kg/day) and FCT (20.1-21.6 mg/kg/day). According to the predicted results from the proposed model, and with a similar exposure to deferasirox, patients treated with FCT would have had a greater reduction in serum ferritin at 12 months than patients treated with DT. Although it cannot be excluded that other factors might have influenced the trajectories of this model, such as the higher baseline serum ferritin values in the FCT group, this greater serum ferritin reduction with deferasirox FCT could be attributed to better treatment adherence. Previous analyses have indicated that improved patient-reported outcomes, especially increased adherence, are significant mediators of the association between treatment with deferasirox DT vs FCT, and the reduction from baseline in serum ferritin achieved over 6 months of treatment. Further exploration of long-term efficacy outcomes and their associated factors is needed to confirm improved efficacy with deferasirox FCT.

Carfilzomib weekly 20/56 mg/m2 , lenalidomide and dexamethasone for early relapsed refractory multiple myeloma.

Carfilzomib Weekly 20/56mg/m², Lenalidomide and Dexamethasone for Early Relapsed Refractory Multiple Myeloma

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Carfilzomib weekly 20/56 mg/m2 , lenalidomide and dexamethasone for early relapsed refractory multiple myeloma.

Carfilzomib Weekly 20/56mg/m², Lenalidomide and Dexamethasone for Early Relapsed Refractory Multiple Myeloma