Optimizing current and emerging therapies in multiple myeloma: a guide for the hematologist

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of endorgan damage. MM is an incurable malignancy previously associated with poor survival rates. However, over the past two decades, the introduction of novel treatment options has resulted in a dramatic improvement in response rates and overall survival (OS). The combination of a proteasome inhibitor and an immunomodulator (IMiD) is the preferred induction treatment for newly diagnosed transplant-eligible MM patients. After induction, high-dose therapy with autologous stem cell transplant (ASCT) is still the standard of care for these patients. In patients who are transplant ineligible, dose adjusted IMiDs or proteasome inhibitor-based combinations are the preferred treatment option. With the recent approval of novel drugs like carfilzomib, ixazomib, pomalidomide, panobinostat, and monoclonal antibodies (elotuzumab and daratumumab), as well as improved understanding of risk stratification, management of comorbidities and treatment side effects, clinicians can optimize anti-MM therapy, particularly in relapse/refractory MM patients. In this review, we outline the current therapeutic approach to the management of MM.

Multiple Myeloma: New Perspectives

“…Panobinostat is a histone deacetylase inhibitor used in combination with bortezomib and dexamethasone in patients who had received at least 2 prior chemotherapy regimens, including bortezomib and an immunomodulatory agent such as lenalidomide or pomalidomide [36]. Carfilzomib is a proteasome inhibitor that is indicated either as a single agent for therapy of patients with relapsed or refractory MM who had received one or more lines of therapy or in combination with dexamethasone or with lenalidomide + dexamethasone for treatment of patients with relapsed or refractory MM who had received one to three lines of therapy [37]. Daratumumab is a monoclonal antibody that is directed against CD38 indicated for treatment of patients with MM who had received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to an immunomodulatory agent and a proteasome inhibitor.…”

A Young Patient with Refractory Multiple Myeloma and Dialysis-Dependent Renal Failure has been Cured by Non-Cryopreserved Autologous Stem Cell Transplantation Followed by Live-Related Kidney Transplantation

“…Multiple myeloma (MM) is the second most common hematologic malignancy [1,2]. It accounts for 1% of all cancers and 10% of malignant hematological disorders [3,4].…”

“…MM is a disease that affects plasma cells and can lead to various clinical manifestations and occasionally life-threatening complications [1,3]. The diagnostic criteria of MM include: (1) clonal bone marrow (BM) plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma, and (2) at least one of the following: evidence of end-organ damage such as hypercalcemia, anemia, lytic bone lesions and renal insufficiency; clonal BM plasma cells ≥ 60%; involved: uninvolved serum free light chain ratio ≥ 100 and > one focal lesion on magnetic resonance imaging [2,3]. Highrisk features at the diagnosis of MM include: (1) cytogenetic abnormalities that include: 17 p deletion, t(14,16) and t(14, 20), (2) international scoring system stage II or III, (3) presence of comorbid medical conditions that limit therapy, and (4) renal failure, high serum lactic dehydrogenase and plasma cell leukemia [3,5].…”

“…The diagnostic criteria of MM include: (1) clonal bone marrow (BM) plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma, and (2) at least one of the following: evidence of end-organ damage such as hypercalcemia, anemia, lytic bone lesions and renal insufficiency; clonal BM plasma cells ≥ 60%; involved: uninvolved serum free light chain ratio ≥ 100 and > one focal lesion on magnetic resonance imaging [2,3]. Highrisk features at the diagnosis of MM include: (1) cytogenetic abnormalities that include: 17 p deletion, t(14,16) and t(14, 20), (2) international scoring system stage II or III, (3) presence of comorbid medical conditions that limit therapy, and (4) renal failure, high serum lactic dehydrogenase and plasma cell leukemia [3,5]. In patients with MM having high-risk features, the incorporation of bortezomib into the multi-agent chemotherapeutic regimen VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) has proven to be effective not only in induction therapy prior to hematopoietic stem cell transplantation (HSCT), but also in consolidation and maintenance therapy post-autologous HSCT (auto-HSCT) [6,7].…”

“…In patients with high-risk features, carfilzomib, lenalidomide and dexamethasone (KRD) is an alternative to VRD regimen [3]. The recently approved novel therapeutic agents for use in the treatment of MM include: (1) newer proteasome inhibitors such as carfilzomib and ixazomib, (2) histone acetylase inhibitors such as panobinostat and vorinostat, (3) new immunomodulatory drugs such as pomalidomide, (4) monoclonal antibodies such as daratumomab and elutuzumab, (5) Bruton tyrosine kinase inhibitors such as ibrutinib, (6) alkylating agents such as bendamustine, (7) interleukin-6 inhibitors such as situximab and (8) phosphoinositide 3-kinase inhibitors [1,2,9]. Substantial evidence indicates that bortezomib, high-dose dexamethasone ± a third drug such as cyclophosphamide, thalidomide or doxorubicin is an appropriate option to be used in induction therapy for patients with MM having any degree of renal impairment [12].…”