Overcoming drug resistance by targeting protein homeostasis in multiple myeloma

Multiple myeloma (MM) is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains. Although incurable, a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades, significantly improving patient outcomes. Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are among the most effective anti-MM drugs, targeting not only the cancerous cells, but also the bone marrow microenvironment. However, de novo resistance has been reported, and acquired resistance is inevitable for most patients over time, leading to relapsed/refractory disease and poor outcomes. Sustained protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis, offering us the opportunity to target this intrinsic vulnerability for therapeutic purposes. This review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM

Laboratory-Based Rationale for Targeting the Protein Homeostasis Network in AL Amyloidosis

AL amyloidosis is an incurable plasma cell dyscrasia with limited therapeutic options. The pathogenetic mechanism in AL amyloidosis is the deposition of insoluble fibrillary aggregates of misfolded immunoglobulin (Ig) free light chains (FLC) and chaperone proteins in target organs. Therefore, AL amyloidosis is the prototypic, protein-toxicity hematologic disorder. Based on laboratory evidence of increased, constitutive proteotoxic stress, PCs are intrinsically vulnerable to agents that target proteins whose function is to guarantee that nascent polypeptides either reach a functional conformation or are disposed of (proteostasis network). The clinical efficacy of proteasome inhibitors (PIs), such as bortezomib, in the treatment of plasma cell (PC) disorders has provided proof of concept that disrupting protein homeostasis is an effective and generally safe therapeutic approach. Therefore, the intrinsic biology of PC offers us the opportunity to rationally develop therapies that target this distinct proteostasis vulnerability of PC dyscrasias. In this manuscript, we will review the laboratory rationale for the effectiveness of FDA-approved and investigational agents targeting protein homeostasis in AL amyloidosis and related PC disorders

Laboratory-Based Rationale for Targeting the Protein Homeostasis Network in AL Amyloidosis

AL amyloidosis is an incurable plasma cell dyscrasia with limited therapeutic options. The pathogenetic mechanism in AL amyloidosis is the deposition of insoluble fibrillary aggregates of misfolded immunoglobulin (Ig) free light chains (FLC) and chaperone proteins in target organs. Therefore, AL amyloidosis is the prototypic, protein-toxicity hematologic disorder. Based on laboratory evidence of increased, constitutive proteotoxic stress, PCs are intrinsically vulnerable to agents that target proteins whose function is to guarantee that nascent polypeptides either reach a functional conformation or are disposed of (proteostasis network). The clinical efficacy of proteasome inhibitors (PIs), such as bortezomib, in the treatment of plasma cell (PC) disorders has provided proof of concept that disrupting protein homeostasis is an effective and generally safe therapeutic approach. Therefore, the intrinsic biology of PC offers us the opportunity to rationally develop therapies that target this distinct proteostasis vulnerability of PC dyscrasias. In this manuscript, we will review the laboratory rationale for the effectiveness of FDA-approved and investigational agents targeting protein homeostasis in AL amyloidosis and related PC disorders

CLO21-016: Incidence, Risk Factors, and Prognostic Implications of Peri-Transplant Orthostatic Hypotension in Patients With Multiple Myeloma

Background: Orthostatic hypotension (OH) is a well-recognized phenomenon occurring in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) that poses a morbidity and mortality threat due to increased risk of falls. Surprisingly, few studies have examined its incidence, risk and protective factors, and prognostic implications. Methods: This was a retrospective, single-center study of 226 consecutive newly diagnosed MM patients who were admitted for first ASCT between June 2012 to April 2014 at Dana Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA. Patients with AL amyloidosis were excluded. Orthostatic vital signs were checked on Monday, Wednesday and Friday. Median time to onset of OH, progression free survival (PFS), overall survival (OS), and time to discharge were estimated using the Kaplan-Meier method. Univariable and multivariable logistic regression were used to investigate factors associated with the development of OH. Results: Overall, 165/226 (73%) patients were diagnosed with OH during the course of their hospital admission for ASCT. Fifty-one patients were found to have OH on the day of first orthostatic vitals check, making it impossible to distinguish whether OH was pre-existent or developed during the transplant admission. Excluding these 51 patients, 114/175 (65%) patients developed OH during the peri-transplant period, at a median of 7 days post ASCT (range; 6–8). Of these patients, only eleven were found to have moderate to severe dehydration as defined by weight loss ≥ 5% body weight, suggesting OH could not be simply be explained by volume depletion. Multivariable analysis revealed three risk factors (white race, gabapentin, antihypertensives) and two protective factors (antihistamine, proton pump inhibitor) associated with the development of peri-transplant OH that were independent of significant fluid losses. Further, we found that OH did not significantly impact length of hospitalization, progression free and overall survival. Conclusions: New onset OH occurs frequently (65%) during the peri-transplant period in MM patients undergoing ASCT (median time of onset of 7 days post ASCT). White race, use of gabapentin and antihypertensives were identified as risks factors, while use of antihistamines and proton pump inhibitor were identified as protective factors

Risk factors for the development of orthostatic hypotension during autologous stem cell transplant in patients with multiple myeloma

Orthostatic hypotension (OH) is a well-recognized phenomenon occurring in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), and is associated with significant morbidity and mortality. A retrospective analysis of patients admitted for first ASCT between June 2012 and April 2014 found that 161/222 (73%) patients were diagnosed with OH during the course of ASCT, including 51 patients who were found to have OH on the day of first orthostatic vitals check. Excluding these 51 patients, 110/171 (64%) patients developed OH during the peri-transplant period, at a median of 7 days post ASCT (95% CI: 6.5-8.5). OH did not significantly impact length of hospitalization, progression free and overall survival. Multivariable analysis revealed four risk factors (i.e. ≥ 0.5% weight loss/day, white race, gabapentin, antihypertensives) and two protective factors (i.e. antihistamine, proton pump inhibitor) associated with the development of peri-transplant OH

Characterizing dry mass and volume changes in human multiple myeloma cells upon treatment with proteotoxic and genotoxic drugs.

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells. MM remains incurable, but overall survival of patients has progressively increased over the past two decades largely due to novel agents such as proteasome inhibitors (PI) and the immunomodulatory agents. While these therapies are highly effective, MM patients can be de novo resistant and acquired resistance with prolonged treatment is inevitable. There is growing interest in early, accurate identification of responsive versus non-responsive patients; however, limited sample availability and need for rapid assays are limiting factors. Here, we test dry mass and volume as label-free biomarkers to monitor early response of MM cells to treatment with bortezomib, doxorubicin, and ultraviolet light. For the dry mass measurement, we use two types of phase-sensitive optical microscopy techniques: digital holographic tomography and computationally enhanced quantitative phase microscopy. We show that human MM cell lines (RPMI8226, MM.1S, KMS20, and AMO1) increase dry mass upon bortezomib treatment. This dry mass increase after bortezomib treatment occurs as early as 1 h for sensitive cells and 4 h for all tested cells. We further confirm this observation using primary multiple myeloma cells derived from patients and show that a correlation exists between increase in dry mass and sensitivity to bortezomib, supporting the use of dry mass as a biomarker. The volume measurement using Coulter counter shows a more complex behavior; RPMI8226 cells increase the volume at an early stage of apoptosis, but MM.1S cells show the volume decrease typically observed with apoptotic cells. Altogether, this cell study presents complex kinetics of dry mass and volume at an early stage of apoptosis, which may serve as a basis for the detection and treatment of MM cells