Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study.

Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma.

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

Trends in the use of therapeutic plasma exchange in multiple myeloma.

INTRODUCTION: Therapeutic plasma exchange (TPE) is traditionally performed for hyperviscosity, neuropathy and to mitigate renal injury in the setting of high clonal free light chain burden in patients with multiple myeloma (MM) with unknown clinical benefit. MATERIALS AND METHODS: Retrospective study of adults ≥18 years with MM who received TPE in the in-patient setting in the United States from 1993 to 2015. We examined the temporal trends of TPE utilization in MM hospitalizations, hospital charges, in-hospital mortality, and length of hospitalization and the predictors of in-hospital mortality and length of hospitalizations. RESULTS: The number of MM-hospitalizations for TPE in adults increased significantly from 1993 to 2015 (1% in 1993-1999 to 2.1% in 2008-2015 of all MM discharges, P for trend <.0001). About 70% of TPE recipients had acute kidney injury (AKI). The median hospital charges increased 5-fold during the time period ($ 24 407 to $ 113 496; P for trend <.0001). In-hospital mortality decreased (17.5% (SE 2.66) in 1993-1997 to 8.7% (1.39) in 2007 to 2013) P for trend <.005) while the length of stay remained unchanged (11.2 days vs 11.9 days, P for trend 0.17). On adjusted analysis, significant predictors of in-hospital mortality among MM TPE recipients include, Charlson Comorbidity Index (CCI) (3 vs 2 adjusted odds ratio, aOR 2.16, 95% CI 1.26-3.71; P = .005), year (continuous) (aOR 0.93, 95% CI 0.90-0.96; P < .001) and race (other vs white; aOR 0.44, 95% CI 0.25-0.78; P = 0.004). CONCLUSIONS: There has been a substantial increase in the use and associated cost of TPE in hospitalized MM patients.

NEW-ONSET CARDIAC AMYLOIDOSIS WHILE IN REMISSION FROM SYSTEMIC AL AMYLOIDOSIS.

In light chain amyloidosis, a reduction in dFLC to below 40 mg/l is a prerequisite for organ recovery as nearly half of the patients who achieve very good partial haematological responses have improvement in the function of the involved organ. We describe a patient who developed new-onset cardiac amyloidosis despite a post-treatment reduction in dFLC to <10 mg/l. LEARNING POINTS: Patients with light chain (AL) amyloidosis may develop new cardiac involvement despite achieving haematological remission.In patients with AL amyloidosis, a very good partial haematological response (dFLC <10 mg/l) does not obviate the need for regular cardiac monitoring.

Impact of Elotuzumab Plus Pomalidomide/Dexamethasone on Health-related Quality of Life for Patients With Relapsed/Refractory Multiple Myeloma: Final Data From the Phase 2 ELOQUENT-3 Trial.

Triplet regimens containing immunomodulatory drugs and proteasome inhibitors (PIs) have improved outcomes and extended survival for patients with relapsed/refractory multiple myeloma (RRMM). We evaluated updated health-related quality of life (HRQoL) findings from the phase 2 ELOQUENT-3 clinical trial (NCT02654132) after 4 years of treatment with elotuzumab plus pomalidomide and dexamethasone (EPd) and assessed the impact of the addition of elotuzumab on patients' HRQoL. HRQoL was assessed as an exploratory endpoint using the MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM), which evaluates symptom severity, symptom interference, and HRQoL, and the 3-level EQ-5D, a patient-reported measure of health utility and general health. Statistical analyses included descriptive responder, longitudinal mixed-model, and time-to-first-deterioration (TTD) analyses using prespecified minimally important differences and responder definitions. Of 117 randomized patients, 106 (EPd, n = 55; pomalidomide and dexamethasone [Pd], n = 51) were eligible for inclusion in HRQoL analyses. Completion rates at almost all on-treatment visits were ≥80%. The proportion of patients treated with EPd who improved or maintained stable HRQoL until cycle 13 ranged from 82% to 96% for MDASI-MM total symptom score and 64% to 85% for MDASI-MM symptom interference. Across measurements, there were no clinically meaningful differences in changes from baseline between treatment arms, and TTD was not significantly different for EPd versus Pd. In conclusion, HRQoL was not impacted by the addition of elotuzumab to Pd and did not significantly deteriorate in patients with RRMM previously treated with lenalidomide and a PI in ELOQUENT-3.

Melphalan flufenamide for relapsed/refractory multiple myeloma.

Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with relapsed/refractory MM (RRMM), especially those with triple-class-refractory disease or poor-prognostic features, have substantially unmet needs for new therapies with novel mechanisms of action. Melphalan flufenamide (melflufen) is the first alkylating peptide-drug conjugate that targets aminopeptidases to show efficacy and manageable safety, in combination with dexamethasone, in patients with RRMM who had received at least 4 prior lines of therapy, including at least 1 immunomodulatory drug, at least 1 proteasome inhibitor and at least 1 anti-CD38 monoclonal antibody, and received accelerated approval by the U.S. Food and Drug Administration (FDA) in early 2021 for use in this patient population. Initial analyses of the phase III OCEAN study data led to melflufen being voluntarily withdrawn from the U.S. market in late 2021, but subsequent analyses have prompted the manufacturer to rescind its voluntary withdrawal to allow further discussions with the U.S. FDA and the regulatory review with the European Medicines Agency (EMA) is also ongoing. Here, we provide a review of the novel mechanism of action and pharmacokinetics of melflufen, as well as key efficacy and safety from clinical studies that supported its initial approval, and discuss the nuances of the OCEAN study data. Melflufen demonstrates the potential of novel peptide-drug conjugates to positively impact the treatment landscape in RRMM.

Can Donor-Derived Cell-Free DNA Detect Graft-Versus-Host Disease in Solid Organ Transplantation: A Case Report.

Graft-versus-host disease (GVHD) is a rare complication after solid organ transplant. We present a case of GVHD after simultaneous pancreas kidney transplant. The patient was diagnosed with a cutaneous biopsy after developing the classic symptoms of maculopapular rash, diarrhea, and pancytopenia. However, this patient had unexplained elevations in donor-derived cell-free DNA (dd-cfDNA) for months before the onset of GVHD symptoms. We hypothesize that GVHD may be associated with elevated dd-cfDNA as a result of massive donor lymphocyte proliferation and turnover. Further investigation is warranted because earlier diagnosis and treatment could improve outcomes in an otherwise lethal disease.

Exercise, cancer and cardiovascular disease: what should clinicians advise?

Cardiovascular disease is one of the leading causes of morbidity and mortality in persons with cancer. The elevated risk is thought to derive from the combination of cardiovascular risk factors and direct cardiotoxicity from cancer therapies. Exercise may be a potential strategy to counteract these toxicities and maintain cardiovascular reserve. In this article, we review the evidence for the potential cardioprotective effects of exercise training in cancer patients before, during, and following treatment. We also propose a patient-tailored approach for the development of targeted prescriptions based on individual exercise capacity and cardiovascular reserve.

Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.

Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.

Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma.

PURPOSE: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.

The evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma.

Cytogenetic changes in multiple myeloma (MM) have emerged as one of the most important prognostic factors. Translocations of chromosomes 4 and 14 [t(4;14)], chromosomes 14 and 16 [t(14;16)] and deletion of chromosome 17p [del(17p)] have been incorporated in the Revised International Staging System as a measure of adverse disease biology. Ongoing research is unveiling a complex genomic landscape in MM, with new cytogenetic abnormalities important for prognosis identified and the significance of known cytogenetic changes revisited. In studies conducted before the novel agent era, t(11;14) was shown to carry standard risk for patients with MM. Findings from more recent retrospective reviews have shown that t(11;14) is associated with intermediate outcomes in patients treated with novel agents as compared with patients who have standard- or high-risk cytogenetic aberrations. MM cells with t(11;14) have a unique biology, with relatively higher expression of the antiapoptotic protein BCL2 and lower expression of MCL1, in contrast to MM cells without this translocation. Translocation t(11;14) has emerged as the first predictive marker in MM, indicating susceptibility to BCL2 inhibition. Future studies will be needed to explore if the combination of novel agents with BCL2 inhibitors can improve the prognosis of patients with t(11;14). In this article, current data on the evolving role of t(11;14) in the biology, prognosis, and treatment of MM are reviewed.

Melflufen for relapsed and refractory multiple myeloma.

INTRODUCTION: The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma. AREAS COVERED: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. EXPERT OPINION: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.

Renal Dysfunction and Recovery following Initial Treatment of Newly Diagnosed Multiple Myeloma.

INTRODUCTION: Renal insufficiency (RI) in Multiple Myeloma (MM) portends a higher tumor burden and worse prognosis. Reversal of RI in newly diagnosed MM (NDMM) improves patient outcomes, but it is unknown if there is a disparity in renal recovery in NDMM between African Americans (AA) and non-African Americans. METHODS: A retrospective chart review was conducted of 690 patients with NDMM at Rush University Medical Center from 2005 to 2016. 118 patients (59 AA and 59 non-AA) with NDMM and an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 at the time of diagnosis were identified and analyzed. The time to best renal response and best eGFR achieved during initial myeloma therapy were tabulated. RESULTS: Median eGFR at the time of diagnosis was similar between the AA and non-AA groups (47.89 versus 51.95, p=0.56). Median absolute change in eGFR after initial therapy was significantly higher in the AA (+33.64) versus the non-AA group (+21.07, p=0.00183). This difference remained whether the baseline eGFR at diagnosis was <90 or <60 mL/min/1.73 m2. DISCUSSION: AA patients with NDMM treated in the era of novel agents have greater improvement in renal function in comparison to non-AA patients, regardless of myeloma response. The biological underpinnings for this disparity require further investigation.

Triplet therapies - the new standard of care for multiple myeloma: how to manage common toxicities.

Introduction: Multiple three drug combination regimens have been approved for the treatment of multiple myeloma in the last few years. Triplets have become the new standard of care for transplant eligible and ineligible patients with newly diagnosed as well as relapsed multiple myeloma. Novel agents have a unique profile of side effects. The management of toxicities is important to maintain quality of life and maximize treatment duration and benefit. Areas covered: This article reviews efficacy data, incidence of key adverse events and provide recommendations and expert opinion regarding how to manage common toxicities in triplet therapies. Relevant publications and abstracts were searched in PubMed, ASH, ASCO and EHA meetings. Guidelines from IMWG, NCCN, ESMO and ASCO, published trial protocols and prescribing information were used to formulate recommendations for the management of toxicities. Expert commentary: Side effects are a critical factor guiding the selection of optimal chemotherapy regimens for multiple myeloma. The majority of toxicities encountered with triplet therapies are reversible and can be readily managed with supportive care and dose modifications.

Light Chain Amyloidosis Presenting as Bilateral External Auditory Canal Obstructing Masses.

: A morbidly-obese 57-year-old diabetic and hypertensive man with chronic kidney disease, diastolic heart failure, and bilateral hearing loss was found to have soft tissue masses/densities in the lateral aspect of both auditory canals on local examination and on imaging. He underwent biopsies of both ear canal masses and histologic examination revealed amyloid deposits in the dermis. These deposits were confirmed as AL (amyloid light chain) kappa-type amyloid by laser mass spectrometry. A systemic work-up showed plasma cell dyscrasia with 9% kappa light chain restricted plasma cells in the bone marrow as well as amyloid deposits on a kidney biopsy.Involvement of the external auditory canals is a rare manifestation of systemic amyloidosis with only 13 cases reported so far, of which four cases had bilateral external auditory canal involvement, associated with multiple myeloma. Interpretation of small biopsies can be challenging especially with early, scant amyloid deposits, but a sufficient biopsy to type amyloid by immunohistochemistry or laser mass spectrometry is imperative for further management. Early diagnosis and treatment of systemic light chain amyloidosis translates to better patient outcomes, while delay in management could lead to dismal prognosis.