New Cases Of Multiple Myeloma Research Articles

Myelomatous Ascitis, a Rare Presenting Symptom of Multiple Myeloma

Abstract Introduction/Objective In 2022, plasma cell neoplasms accounted for approximately 1.8% of all new cancers in the United States with an estimated 34,470 new cases of multiple myeloma. Diagnosis is often straight forward in ~80% of cases by performing serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and/or urine immunofixation (UIFE) with M-spike quantification. The diagnostic challange is in the remainder of asymptomatic myeloma cases (~20%) which are found incidentally. Specialized laboratory technicians are often the first step in identifying plasma cells in body fluids and/or peripheral blood smears. These incidental findings on routine labs, paired with the keen eye of a specialist, are one of the first steps in early detection of multiple myeloma. Methods/Case Report A 62 year-old male, originally from Cambodia, presented to an outside hospital emergency department with abdominal distention and pain. His past medical history was significant for dialysis-dependent end- stage renal disease and insulin-dependent diabetes mellitus type 2. Abdominal CT showed ascites with no other diagnostic findings. Cardiac, renal and hepatic etiologies of ascites were ruled out. Body fluid analysis of the ascites in the Clinical Pathology laboratory revealed numerous plasma cells. Cytologic examination, after consultation with Clinical Pathology, also revealed numerous plasma cells. Subsequent SPEP and SIFE disclosed an IgA lambda monoclonal protein. A diagnosis of multiple myeloma was confirmed by bone marrow biopsy with FISH studies. Results showed several high-risk abnormalities including translocations of 4::14, 14::16, and 14::20, denoting a “triple hit” multiple myeloma. Results (if a Case Study enter NA) NA Conclusion Plasmacytosis in ascites is an extremely rare initial presentation for multiple myeloma. With only a few cases reported in the literature, many technicians and pathologists might easily overlook plasma cells on routine cytology, especially with normal imaging and no previous diagnosis of myeloma. In this case, flagged peritoneal fluid by a skilled medical laboratory technician was key to making a diagnosis. Without any signs of a plasmacytoma or lytic bone lesions on imaging, a normal CBC with non-specific labs, and an unsuspecting surgical pathology report, multiple myeloma was not on the differential. Fast interdepartmental consultation, communication, and teamwork between surgical pathology and clinical pathology, lead to a rapid diagnosis and prompt treatment of this patient.

Demographic Disparities in Clinical Trial Enrollment of US Patients with Newly-Diagnosed Multiple Myeloma

Background: Racial, ethnic and gender disparities impact the real-world reproducibility of clinical trials leading to drug approvals for hematologic malignancies. Interestingly, a prior abstract (Boisclair et al., 2022) has shown an equitable enrollment between US demographic groups in frontline trials for newly-diagnosed non-Hodgkin lymphoma. Although disparities in multiple myeloma (MM) trial participation have been oftentimes demonstrated, prior studies (Kanapuru et al., 2022; Alqazaqi et al., 2022) predominantly involved patients with relapsed/refractory MM (RRMM). To further assess this gap, we conducted a cross-sectional analysis of US demographic representation in phase II or III trials for newly-diagnosed MM (NDMM). Methods: Clinicaltrials.gov was searched for completed NDMM trials with a recruitment period between 01/01/2007-12/31/2020. Studies limited to phase I data (n=10), enrolling <30 patients (n=35), including RRMM or other malignancies (n=18), and/or recruiting outside the US (n=93) were excluded. We subdivided patients according to gender, race, and ethnicity. For each subgroup, total new cases of MM from 2007-2020 were identified via the Surveillance, Epidemiology and End Results (SEER) Cancer Statistics Explorer Network, with subsequent calculation of a trial enrollment fraction (TEF; number of trial enrollees divided by incident US cases). Pearson's chi-square test was used to compare TEF between subgroups, yielding odds ratio (OR) and 95% confidence interval (95%CI) values, with P<0.05 deemed significant. Results: Among the 194 trials found on initial review, 25 met the established criteria for inclusion (Figure 1). All studies (n=3,559) described the participants' gender, while only 18 (72%; n=3,129) reported race and 9 (36%; n=2,319) reported ethnicity. Overall, women showed a significantly lower TEF compared to men (OR, 0.88; 95%CI, 0.82-0.94; P<0.001). When compared to White Americans, TEF was significantly lower for African Americans (OR, 0.71; 95%CI, 0.64-0.78; P<0.001) and Asian Americans/Pacific Islanders (AAPIs; OR, 0.64; 95%CI, 0.22-0.41; P<0.001). In studies reporting ethnicity, TEF was significantly lower for Hispanics compared to non-Hispanics (OR, 0.18; 95%CI, 0.14-0.24; P<0.001). Conclusion: Our cross-sectional analysis reveals an underrepresentation of women, African Americans, AAPIs, and Hispanics in NDMM trials conducted around the US. These findings are complementary to the enrollment disparities previously shown in RRMM trials. Through the implementation of a comprehensive diversity plan, MM trials must include a more inclusive representation of the US population affected by this blood cancer. Such an approach will not only enhance the external validity of these trials but also mitigate the impact of ascertainment bias and promote healthcare equity.

#3709 KIDNEY IMPAIRMENT AT DIAGNOSIS IN MULTIPLE MYELOMA: THE NEPHROLOGIST PERSPECTIVE

Abstract Background and Aims Kidney impairment (KI) at multiple myeloma (MM) diagnosis ranges between 20 and 50% and is associated with high mortality. Therefore, an important percentage of the newly diagnosed cases of MM come from nephrologists. We aimed to evaluate the new cases of MM with KI diagnosed in our nephrology tertiary care center for presentation features, initial treatment, and survival. Method We performed a unicentric retrospective study on 89 consecutive patients newly diagnosed with MM (median age 66 years, 38% male) between 2015-2020. Patients were followed until death or end of study (September 2022), whichever came first. Results The most common MM type was free light chain (FLC) only (55%) followed by IgG (30%), IgA (14%) and IgM (1%). Kappa FLC was more frequent than lambda FLC (53 vs 47%); the median FLC level was 1760 (IQR 450, 7373) mg/L, and the median marrow plasmocytosis was 30 (IQR 15, 60) %. Among the 89 patients, 81% presented with acute kidney injury, 12% with chronic kidney disease, 5% with isolated proteinuia and 2% with nephrotic syndrome. Baseline median serum creatinine and eGFR were 5 mg/dL and 9 mL/min, respectively. Median proteinuria was 3.3 (IQR 1.3, 6) g/g with median albuminuria of 0.27 (IQR 0.11, 0.66) g/g. More than one third (34%) of the studied patients needed hemodialysis (HD) at diagnosis, and 50% progressed to renal replacement therapy by the end of the follow up period (CKD5D). The most frequent clinical features at presentation were asthenia (75%), followed by bone pain (51%), orthostatic hypotension (14%), peripheral neuropathy (10%), edema (10%) and dyspnea (6%). Arterial hypertension (71%), systemic atherosclerosis (58%), ischemic heart disease (44%) and diabetes mellitus (12%) were the most frequent recorded comorbidities. Treatment with dexamethasone was started by the nephrologist in 74% of the patients at a median dose of 128 (IQR 96, 160) mg, afterwards the patients were reffered to hematology for a bortezomib based regime. During the follow up period 58 (65%) patients died; they had higher serum creatinine (5.8 vs 2.5 mg/dL, p 0.02), needed HD at diagnosis more often (41 vs 20%, p 0.01), had lower serum albumin (3.7 vs 4.4 g/dL, p 0.001), higher LDH (236 vs 201 U/L, p 0.01) and increased inflammation (C-reactive protein: 14 vs 3 mg/L, p 0.001). In univariate logistic regression, the risk factors at diagnosis associated with mortality were increased age (OR 1.07, 95%CI1.03-1.12), atherosclerotic burden (OR 5.51, 95%CI 2.13-14.22), low serum albumin (OR 0.28, 95%CI 0.13-0.63), inflammation (OR 1.05, 95%CI 1.01-1.09), increased LDH (OR 1.01, 95%CI 1.00-1.02) and the need for HD at diagnosis (OR 2.94, 95%CI 1.04-8.26). However, in multivariate analysis only low serum albumin (OR 0.22, 95%CI 0.05-0.90) and the need for HD at diagnosis (OR 10.64, 95%CI 1.71-66.14) were significantly associated with mortality. Conclusion Patients with MM and kidney impairment at diagnosis are more frequent kappa FLC, present most often as AKI, around one third of them require HD at diagnosis, and half of them progress to CKD5D. Therefore, these patients are a distinct group of MM with a high mortality rate (>60% at five years) who need interdisciplinary care.

Analysis of Recorded Morbidity, Prevalence and Hospital Mortality of Patients with Symptomatic Multiple Myeloma in the Ryazan Region for 10 Years

INTRODUCTION: Multiple myeloma (MM) is a disease whose substrate is plasma cells; it is characterized by the production of monoclonal immunoglobulin. Epidemiology of MM in Russia is insufficiently studied. Of interest is a study of dynamics of the main epidemiological parameters of multiple myeloma in the context of a poor epidemiological prognosis for oncological diseases in the Russian Federation and in the world in general.
 AIM: To analyze the main epidemiological parameters of symptomatic MM in the Ryazan region for 10 years (20102019).
 MATERIALS AND METHODS: A total of 343 medical records of patients with symptomatic MM were analyzed, of them 146 men (age median 65 years), 197 women (age median 64 years). The patients underwent inpatient treatment in the hematology and chemotherapy department of Ryazan Regional Clinical Hospital from 2010 to 2019. The epidemiological analysis consisted in evaluation of the parameters of the registered morbidity, prevalence and hospital mortality. The criterion for inclusion in the study was the existence of symptomatic MM in the patient. For statistical processing, Microsoft information and analytical system, Office package was used.
 RESULTS: The highest amount of new cases of MM were identified in 2018 (4.19 per 100,000 population), the lowest in 2012 (1.83 per 100,000 population). In the analyzed period, the number of cases of newly diagnosed MM per year increased by 30.3%. Most patients at the time of diagnosis were in the age group of 6069 years. Morbidity with MM in the age group of 3049 years was comparable in men and women, however, among the patients 50 years women predominated. Over 10 years, the index of MM prevalence in the Ryazan region increased 1.43 times: from 6.71 to 9.6 per 100,000 population, index of hospital mortality from 1.4% to 3.3%.
 CONCLUSION: The growth of the registered mortality and prevalence of MM in the Ryazan region in 20102019 was identified, which corresponds to the dynamics in other regions of the Russian Federation. Also, during the analyzed period, an increase in hospital mortality of patients with MM was observed in the region.

Is It Time for a More Holistic Approach to the Treatment of Multiple Myeloma?

In the UK, approximately 5820 new cases of multiple myeloma (MM) are diagnosed each year. This number has increased by a third since the early 1990s. Considerable progress has been achieved in our ability to treat MM as a result of the development of new chemotherapeutic agents. MM is a disease more commonly seen in elderly individuals who frequently have pre-existing co-morbidities and are subject to social pressures that impact adversely on their quality of life (QOL). As their lives are extended by more effective treatment of MM, there is a greater need to address such issues. This review will focus on the holistic needs of a patient with MM, and how all members of the multidisciplinary team have a role. The aim is to advocate for centres to support MM patients to live well with their condition.

Multiple myeloma in Armenia during the period 2006\u20132018: facts and discussion

BackgroundIt is known that one of the reasons for the increased incidence of hematological malignancies is caused by the growth of multiple myeloma (MM). Worldwide, approximately 159,985 new cases of MM are diagnosed representing 0.9% of all cancer diagnoses and 106,105 patients will die from MM accounting for 1.1% of all cancer deaths per year. Despite significant advances in the MM treatment the mortality rates are still high. The presented study is the first accurate epidemiological study of ММ in Armenia for the period of 2006–2018.MethodsThe initial data for this retrospective cohort survey were derived from ambulance cards, hospitalization journals, and clinical data from the Registry of Blood Diseases at the Yeolyan Hematology Center.ResultsData analysis showed that during 2006–2018 the average annual incidence for the MM was 1.2 per 100,000 population. A significant increase was observed in 2018 compared to 2006, 1.9 vs. 0.7 per 100,000 population. Interestingly, there were no sex differences in the overall MM incidence during the study period.According to the received data, during the period of the 2006–2009 and 2014–2018 the 1-year survival rate for both sexes decreased dramatically from 83 to 64.1% at age group 60 years and below and from 78.5 to 68.1% in group 60 years and over. The 1-year overall survival (OS) for both sexes decreased by 18.9% for patients (≤60 age group) and 10.4% (> 60 age group) in the period of 2006–2009 to the period of 2014–2018.ConclusionsThe incidence rates for the MM increased during the analyzed period. Our study showed that males and females in the age group 60 years and below had better 5-year overall survival compared to elder ones and females have better survival.

Multiple Myeloma Patients and Risk of Skeletal Related Events - Real-World Evidence in US Oncology Clinics

Introduction: SEER estimates that 30,280 new cases of multiple myeloma (MM) will be diagnosed in the US in 2017. Osteolytic disease is a hallmark feature of myeloma at diagnosis. Skeletal related events (SRE) including pathological fractures, spinal cord compressions, radiation and surgery to bone are frequent complications for myeloma patients. However, there have been few reports of the incidence of and risk of developing an SRE in the myeloma population, particularly relative to concomitant anti-myeloma therapy.Methods: A database of oncology electronic health records (EHR) contained in Amgen's Oncology Services Comprehensive Electronic Records (OSCER) database, generated by Flatiron Health (New York, NY, April 30, 2016) were linked to administrative claims data from the Truven Marketscan database. Patients identified were individuals 18 years or older diagnosed with MM (ICD-9: 203.00; ICD-10: C90.00), had at least 1 clinic visit within 1 month of diagnosis, and at least 1 year of follow-up after MM diagnosis. The study period was from January 1, 2011 to December 31, 2016. The baseline period for co-morbidities was 12 months prior to multiple myeloma diagnosis date. Patient diagnosis, treatment dates and administrations were ascertained from the EHR. SREs were ascertained from diagnosis codes in insurance claims. Primary outcomes of interest were occurrence of and time to SRE. Multiple SRE that occurred within a 21-day span were considered as a single SRE and ordered based on the following hierarchy: 1.) spinal cord compression, 2.) pathological fracture, 3.) surgery to bone, then 4.) radiation to bone. SRE occurring within 60 days of MM diagnosis were considered as baseline SRE. Results are also stratified by line of anti-myeloma therapy.Results: A total of 343 patients were included in this study. Approximately 55% of patients were age >65, 54% male, and 70% white race. About one-third of patients had an eGFR below 60 at MM diagnosis, 69% presented with anemia, and 35% had a baseline history of SRE (includes SREs recorded within two months after diagnosis). During a median follow-up of 25.7 months after diagnosis, 34% of patients (n=117) experienced an SRE and the median time to SRE was 228 days. Among patients that experienced a SRE, 68% occurred within the first year (n=79). Among patients with a baseline history of SRE (n=119), 61% experienced a SRE during follow-up at a median of 149 days compared to 20% of patients without SRE history (n=45) at a median of 365 days. The incidence rate of SRE for these patients with a baseline history was 103/100 person-years (PY) (n=58) versus 16/100PY compared to no baseline history (n=21) one year following MM diagnosis. The incidence rate of SRE in each of line therapy within three months of the initiation of each line increased with each subsequent line (line 1: 81/100PY, line 2: 118/100PY, line 3: 150/100PY).Conclusions: Most patients experience their first SRE soon after MM diagnosis or at the beginning of each relapse. Patients with a baseline SRE had a higher risk of future SRE. Recently relapsed patients had a higher rate of SRE compared to patients who have been on therapy for an extended period, and the incidence rate was progressively higher among patients receiving later lines of therapy. Additionally, among patients experiencing SRE, multiple SRE can occur, highlighting the importance of continued surveillance and proper management of myeloma associated bone disease. The overall SRE rate was lower than expected likely due to selection bias or recording bias in the administrative claims database. [Display omitted] DisclosuresBhatta:Amgen: Employment. Fonseca:Jansen: Consultancy; Merck: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy, Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Pharmacyclics: Consultancy; AMGEN: Consultancy. Hernandez:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen, Inc.: Employment, Equity Ownership.

A Method to Identify Patients with Multiple Myeloma Who Are at Risk of Developing Concomitant Amyloidosis

INTRODUCTION : Multiple myeloma (MM) is a plasma cell dyscrasia that is characterized by the presence of both a clonal plasma cell population in the bone marrow and intact monoclonal immunoglobulin and/or free light chain (LC) proteins in the serum. It has been shown that MM may be an ominous precursor to light chain-associated (AL) amyloidosis, a devastating protein misfolding disorder characterized by the systemic deposition of extracellular amyloid fibrils composed of LC components. In the US, there are ~30,000 new cases of MM every year, and it is estimated that 10 - 15% of these patients will progress to develop amyloidosis.Light chain amyloid may deposit in any organ or tissue, but the heart, liver, spleen, kidneys and nerves are most commonly involved. The accumulation of amyloid in organs, especially the heart and kidneys, results in architectural damage leading to progressive organ dysfunction and death. It has been documented that concomitant MM with amyloidosis results in a considerably poorer prognosis than MM alone.Currently, there is no way of identifying those MM patients who will progress to develop LC-associated amyloidosis, but the ability to identify at-risk patients would be of clinical value because anti-amyloid immunotherapeutic agents are on the horizon. If such patients are identified prior to the onset of amyloid-associated clinical symptoms and organ damage, physicians could implement closer monitoring and begin a maintenance dose of amyloid-clearing antibody reagents.Early detection of amyloid is critical for enhancing patient survival; thus, we have investigated an approach to discern which MM patients have a greater likelihood of developing amyloidosis, based on the amyloid-related properties of the monoclonal light chain. We have previously shown that LC derived from MM and AL patients, when radiolabeled, can be recruited by synthetic amyloid-like fibrils. We observed that MM LC were recruited less effectively than AL LC, suggesting that there is disease specific reactivity of LC with amyloid fibrils (Martin et al . 2017 PLoS One, 12(3): e0174152.). We have since adapted this approach to a more facile and practical microplate assay measuring the ability of LC to compete with monomeric protein for fibril elongation. We have been able to discern patient populations with this technique.MATERIALS & METHODS : For these studies, 96-well microplates were coated with 0.83 μM synthetic amyloid-like fibrils (rVλ6Wil) and dried at 37°C overnight. After washing and a “blocking” step, a 100 μL solution of urinary LC protein-either AL amyloidosis or MM patient-derived-at increasing serial concentrations (0.05 - 5 µg/mL) mixed with biotinylated rVλ6Wil protein monomer (5 nM) was added to the wells. After 1 h incubation, the amount of fibril-recruited biontinyl-rVλ6Wil monomer was measured. Concentration gradients for MM and AL LC were measured and compared using a one-tailed Student's t-test.RESULTS : The data indicate that, in this competition assay, AL-associated urinary LC inhibited rVλ6Wil monomer recruitment more effectively than MM-derived LC. Our concentration-dependent gradient analysis discerned proteins from the two disease populations with statistical significance (p < 0.007). Notably, LC from a patient initially diagnosed with MM, who later developed amyloidosis, behaved as an AL LC in this assay, indicating the ability of this technique to predict the amyloidogenic propensity of LC.DISCUSSION : We have studied the capacity of intact, patient-derived LC to inhibit synthetic fibril elongation as a means of predicting the risk of amyloidosis. The assay was able to discriminate between LC proteins derived from MM and AL patients. This approach, in conjunction with other metrics, may be useful in discerning those patients with MM, or perhaps LC-associated monoclonal gammopathy of undetermined significance (LCMGUS), who are at risk of developing amyloidosis based on LC activity in our recruitment assay. We are currently adapting this technique for use with patient serum. [Display omitted] DisclosuresMartin:University of Tennessee Research Foundation: Patents & Royalties. Wall:University of Tennessee Research Foundation: Patents & Royalties.

Clinical presentation of multiple myeloma by race/ethnicity and Asian subgroup in an integrated healthcare system.

e20012 Background: Several US studies have evaluated ethnic differences in patients with multiple myeloma (MM), but few have focused on populations other than non-Hispanic Whites and Blacks. We examined ethnic differences in a contemporary cohort of MM patients and their presenting laboratory findings in a large, insured, community-based population, including findings across Asian American subgroups. Methods: Using the Kaiser Permanente Northern California (KPNC) Cancer Registry, we identified all new cases of MM from 2010-2018 and obtained data on age, sex, race/ethnicity, Asian subgroup, and presenting hemoglobin, calcium, and estimated renal function (eGFR derived from serum creatinine) from health plan databases. Moderate to severe anemia was defined by hemoglobin &lt;10 g/dL, hypercalcemia by calcium &gt;11 mg/dL, and chronic kidney disease (CKD) by eGFR: stage 3 (eGFR 30-59) and stages 4-5 (eGFR &lt;30). MM incidence was estimated using membership denominators. Results: There were 2224 new MM cases (mean age 68y, 60% male) in 2010-2018, with an annual MM incidence of 7.9-9.8/100,000. Table 1 compares presentation by race/ethnicity. Non-Whites (45%) were more likely to present at age &lt;65 than non-Hispanic Whites (30%, p&lt;0.01). Black (43%) and Asian (39%) adults were more likely to present with hemoglobin &lt;10 g/dL than non-Hispanic Whites (27%, p&lt;0.01); Black adults were more likely to present with hemoglobin &lt;10 g/dL than Hispanic adults (31%, p=0.02). Among the primary Asian subgroups, proportions with hemoglobin &lt;10 g/dL were 38% (East Asian), 43% (Filipino), and 45% (South Asian). Blacks were more likely to present with CKD stage 4-5 (19.5%) than other races/ethnicities (p=0.04); differences between White vs non-White or Asian vs non-Asian were not significant. In Asians, 12.7% (South Asian) and 19.0% (Filipino, East Asian) presented with CKD 4-5. Asians were least likely to present with hypercalcemia (6.7%, p=0.03), and this was similar for Asian subgroups. Conclusions: We observed ethnic differences in MM presentation in a large integrated healthcare system. Blacks were more likely to have CKD stage 4-5 and hemoglobin &lt;10 g/dL than non-Hispanic Whites. Asians were more likely to have CKD stage 4-5 than non-Hispanic Whites but least likely to have hypercalcemia. This is one of the first studies to identify Asian subgroups and examine variation across East Asians, Filipinos, and South Asians. Analyses examining ethnic differences in survival among MM patients are in progress.[Table: see text]

КЛИНИКО-ЭПИДЕМИОЛОГИЧЕСКАЯ ХАРАКТЕРИСТИКА МНОЖЕСТВЕННОЙ МИЕЛОМЫ В РЯЗАНСКОЙ ОБЛАСТИ

Aim. To determine the clinical and epidemiological characteristics of multiple myeloma (MM) in the Ryazan region in 2019. Materials and Methods. A retrospective analysis of medical histories of 107 patients with MM who were under observation at the hematology department of the state budgetary institution of the Ryazan region Regional Clinical Hospital (RCH) in 2019 was carried out. Registered morbid-ity implies identification of new cases of MM that were not registered before and were first de-tected in the current calendar year. Statistical analysis of the obtained data was carried out using Microsoft Office application programs and the methods of descriptive and parametric statistics. Results. In 2019, 107 patients of which 43 were men and 64 women aged 34-84 years (mean age 66.2±9.3 years), were under observation at the hematology department of the RCH. The ratio of men to women was 1.0 to 1.49, which reflects the all-Russian tendency. 3.77% Of patients with MM had IIA stage of the disease, 62.26% had IIIA stage, and 33.96% had IIIB stage of myeloma. The morbidity with MM in the Ryazan region in 2019 was 3.23 per 100 000 people. Conclusion. The incidence of the disease in the Ryazan region in 2019 was higher than the aver-age for Russia, which may be due to the diagnostic capabilities of the region with the existence of a specialized hematological department and an outpatient hematology service. In the age group of MM, patients aged 60-74 years predominated, women predominated in the gender structure. Among patients with MM in the Ryazan region, patients with III stage disease (96.22%) predominated.

Body composition analysis in patients with multiple myeloma

Rationale: Worldwide, one to five new cases of multiple myeloma (MM) are detected per 100 000 inhabitants annually. In recent years, a growing body of evidence points to obesity as a risk factor for MM. However, we have few publications related to body composition in patients already have diagnosed MM

Preclinical and Nonclinical Characterization of HPN217: A Tri-Specific T Cell Activating Construct (TriTAC) Targeting B Cell Maturation Antigen (BCMA) for the Treatment of Multiple Myeloma

About 31,000 new cases of multiple myeloma (MM) will be diagnosed in the US in 2018. In addition to chemotherapeutic agents, several targeted therapies utilizing distinct mechanisms of action, e.g., proteasome inhibitors (bortezomib, carfilzomib, ixazomib), HDAC inhibitors (panobinostat), Cullin-RING E3 ubiquitin ligase activators (thalidomide, lenalidomide, pomalidomide), and antibodies (daratumumab, elotuzumab) have become available for treating MM. However, MM remains an incurable disease. Patients who relapse after or are refractory to standard of care treatments generally have poor prognosis. In 2018, close to 13,000 patients will die of the disease in the US. Targeting the B cell maturation antigen (BCMA), a BAFF/BLyS and APRIL receptor, for treating MM patients can provide a new treatment approach complementary to existing therapies. CAR-T therapies and an antibody-drug conjugate targeting BCMA have demonstrated early clinical success in the treatment of relapsed refractory MM (RRMM).HPN217 is a tri-specific T cell activating construct (TriTAC) consisting of three binding domains: an N-terminal single domain antibody (sdAb) that binds to human BCMA, a middle sdAb that binds to human serum albumin (HSA), and a C-terminal single chain Fv (scFv) that binds to CD3ε of the T cell receptor (TCR) complex. HPN217 is a highly stable single polypeptide of ~ 53 kDa expressed by CHO cells. Simultaneous engagement of BCMA on a target MM cell and CD3 on a T cell results in T cell activation, functional differentiation and the eventual lysis of the target MM cell. Engineering of an HSA binding domain into HPN217 represents a unique strategy in extending serum half-life, giving the TriTAC molecule a small molecular size and flexibility. This approach is different from Fc-engineering applied in other CD3-based bispecific T cell engaging molecules.The KD of HPN217 binding to recombinant human BCMA, HSA, and recombinant human CD3ε was determined to be 5.5 nM, 6 nM, and 17 nM, respectively, as measured by biolayer interferometry. Flow cytometric analysis on a panel of T cells from normal donors and BCMA positive and BCMA negative tumor cell lines confirmed binding of HPN217 to its native targets expressed on cell surface. The in vitro pharmacological activity of HPN217 was evaluated by T cell-dependent cellular cytotoxicity (TDCC) assays. In co-cultures of T cells from normal human or cynomolgus monkey donors, target tumor cells, and HSA, HPN217 mediated dose-dependent and BCMA-dependent cytotoxicity with EC50 values ranging from 0.05 to 0.7 nM. Killing was dependent on expression of BCMA on target tumor cells. Concomitant with target tumor cell killing, HPN217 also mediated dose-dependent upregulation of CD25 and CD69 on T cells in the TDCC co-cultures when BCMA positive tumor cells were presence. Consistent with the mechanism of action of CD3-based T cell engaging molecules, T cell derived cytokines, e.g., TNFα and IFNγ, were detected. Similar T cell activation could be observed using human or cynomolgus monkey whole blood as a source of T cells.Nonclinical in vivo properties of HPN217 were evaluated in xenograft models and a single dose pharmacokinetic (PK) study in cynomolgus monkeys. HPN217 mediated dose-dependent growth suppression against the RPMI-8226 MM model and Jeko-1 mantle cell lymphoma model expressing relatively low levels of 5,600 and 2,200 copies of BCMA per cell, respectively. In the PK study, a single dose of HPN217 at 0.01, 0.1, or 1 mg/kg was given to cynomolgus monkeys. HPN217 exhibited linear PK behavior over this dose range. Serum half-life was in the range of 64 to 85 hours. Serum half-life, volume of distribution, and clearance appeared to be independent of dose. HPN217 was demonstrated to be stable and remained intact up to 3 weeks in vivo as demonstrated by a functional ligand binding assay using recombinant CD3ε and BCMA, respectively, to capture and detect HPN217. Importantly, serum samples collected one week after dosing were as potent as stock HPN217 in MM tumor cell killing in TDCC assays.Collectively, preclinical and nonclinical characterization suggests that HPN217 is an efficacious novel therapeutic candidate that can provide a convenient dosing schedule for patients. A first-in-human phase 1 clinical trial is planned to evaluate HPN217 in RRMM. DisclosuresLaw:Harpoon Therapeutics: Employment. Aaron:Harpoon Therapeutics: Employment. Austin:Harpoon Therapeutics: Employment. Barath:Harpoon Therapeutics: Employment. Callihan:Harpoon Therapeutics: Employment. Evans:Harpoon Therapeutics: Employment. Gamez Guerrero:Harpoon Therapeutics: Employment. Hemmati:Harpoon Therapeutics: Employment. Jones:Harpoon Therapeutics: Employment. Kwant:Harpoon Therapeutics: Employment. Lao:Harpoon Therapeutics: Employment. Lemon:Harpoon Therapeutics: Employment. Patnaik:Harpoon Therapeutics: Employment. Sexton:Harpoon Therapeutics: Employment. Wesche:Harpoon Therapeutics: Employment. Xiao:Harpoon Therapeutics: Employment. Yu:Harpoon Therapeutics: Employment. Yu:Harpoon Therapeutics: Employment.

The Characteristics, Treatment Patterns, and Outcomes of Older Adults with Multiple Myeloma

Background: Advances in the treatment for multiple myeloma (MM) have dramatically improved outcomes for younger patients. Older adults, particularly those 80 years of age or older at diagnosis, have seen more modest gains. MM incidence increases with age, and as more of the population is living later into life, the segment of the MM population over 80 will continue to grow. In this study, we sought to better understand the characteristics, treatment, and outcomes of older patients with MM.Methods: We identified all patients diagnosed with MM at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER) database from 2007-2013 to determine incidence and outcomes. Subset analysis was then performed on patients included in the SEER-Medicare linked database who were enrolled in Medicare Parts A, B, and D to further explore patient characteristics and treatment patterns.Results: The incidence of MM increases over age, peaking after age 80. The annual incidence for those aged 65-69, 70-74, 75-79, 80-84 and 85+ was 24.4, 32.7, 39.5, 42.8 and 36.4 per 100,000, respectively. Based on 2010 US population estimates, approximately 4,500 new cases of MM were diagnosed annually 2007-2013 in patients age 80 or older. In that period, 8,093 cases, approximately 1,150 per year, were reported to SEER. The estimated median overall survival (OS) of these patients was 14 months (95% CI 13.2-14.8). The estimated relative 12 month survival was 58.9% (95% CI 57.4-60.4) compared to their peers without cancer.Of the 8,093 cases of MM reported to SEER during the study period, 2,385 were present in the SEER-Medicare linked dataset. Of these, 225 were identified as smoldering MM using a previously established algorithm (Fiala, et al, JCOCCI, 2018) and excluded leaving 2,160 for the analyses. The median age was 84 (range 80-100) and 55% were female. 81% were white, 13% black or African-American, and 6% another race. At disease presentation, 22% had claims indicating hypercalcemia, 61% renal failure or chronic kidney disease, 59% anemia, and 34% MM bone involvement. The estimated median OS was 13.4 months (95% CI 12.2-15.1).Only 52% of patients had claims indicating they received systemic MM treatment within 6 months post-diagnosis. Nearly all that did received novel agents; 38% received bortezomib-based treatment, 41% immunomodulatory drug (IMID)-based, and 14% both. The others received antineoplastic chemotherapies such as melphalan or cyclophosphamide. Interestingly, bortezomib utilization increased incrementally from 25% of patients treated in 2007 to 62% in 2013 while IMID utilization declined from 67% to 49%.The median OS of those receiving treatment was 21 months (95% CI 18.5-23.1) compared to 6.3 months (95% CI 5.3-7.3) for those who did not (p <0.0001). MM treatment was associated with a 26% decrease in hazard for death (aHR 0.74; 95% CI 0.67-0.82; p < 0.0001) independent of age, race, gender, poverty, comorbidities, and proxy measures of performance status. Outcomes improved for patients in more recent years; the hazard for death decreased by 3% (HR 0.97; 95% CI 0.94-0.99; p = 0.0096) each year 2007-2013. This can be attributed to increasing treatment rates. In 2007, only 41% of patients received treatment compared to 61% in 2013. After controlling for MM treatment, the year of diagnosis was no longer a significant predictor of survival.Conclusions: The outcomes of patients with MM over 80 years old are still relatively poor; nearly half of the patients do not receive systemic treatment and for those who do the median OS is just 21 months. The population over 80, when MM incidence peaks, is projected to triple over the next few decades. It is imperative that we improve our understanding of the needs of this vulnerable subgroup of patients of MM. DisclosuresSchroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract A43: [Advocate Abstract:] Dot4life multiple myeloma for Caribbean patients

Abstract The population of Puerto Rico decreased from 3,808,610 on April 1, 2000 to 3,725,789 on April 1, 2010. Population estimates for 2011 indicate that the population continues to decrease. The population structure of Puerto Rico got older. The population 65 years of age and older increased from 11.2% in 2000 to 15.2% in 2011. The poverty level in all people in Puerto Rico for 2011. In 2011, 7.6% of the noninstitutionalized civilian population in Puerto Rico had no health insurance coverage. Puerto Rico has 250 new cases of multiple myeloma every year. The Veterans Hospital has 15 new cases every year for the same cause. Between 2008-2012 we had 1053 new cases of multiple myeloma. Puerto Rico does not have any specialists for multiple myeloma, although it receives a support from one of the hospitals in Florida that came 1 or 2 times a month to see these patients. Giving the patient education, the correct therapy, helping them with financial programs; we will have the engagement for any clinical trials that exist for this cause. Note: This abstract was not presented at the conference. Citation Format: Marisel Brignoni. [Advocate Abstract:] Dot4life multiple myeloma for Caribbean patients [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A43.

A phase 1 multicenter study evaluating KITE-585, an autologous anti-BCMA CAR T-cell therapy, in patients with relapsed/refractory multiple myeloma.

TPS3103Background: In the United States there are > 30,000 new cases of multiple myeloma (MM) and an estimated > 12,000 deaths annually (Howlader et al. SEER Cancer Statistics Review. 2017). Despit...

Epidemiology of Multiple Myeloma in the Czech Republic

Multiple myeloma (MM) is a cancer of plasma cells with an incidence of 4.8 cases per 100,000 population in the Czech Republic in 2014; the burden of MM in the Czech Republic is moderate when compared to other European countries. This work brings the latest information on MM epidemiology in the Czech population. The Czech National Cancer Registry is the basic source of data for the population-based evaluation of MM epidemiology. This database also makes it possible to assess patient survival and to predict probable short-term as well as long-term trends in the treatment burden of the entire population. According to the latest Czech National Cancer Registry data, there were 504 new cases of MM and 376 deaths from MM in 2014. Since 2004, there has been a 26.9% increase in MM incidence and an 8.3% increase in MM mortality. In 2014, there were 1,982 persons living with MM or a history of MM, corresponding to a 74.4% increase when compared to MM prevalence in 2004. The 5-year survival of patients treated in the period 2010-2014 was nearly 40%. The available data make it possible to analyse long-term trends in MM epidemiology and to predict the future treatment burden as well as treatment results.Key words: multiple myeloma - epidemiology - Czech National Cancer Registry - Registry of Monoclonal Gammopathies - Czech Republic.

Temporal Trends in Survival Among Multiple Myeloma Patients in the US: Impact of Age and Cardiac Comorbidities

Introduction: Approximately 27,000 new cases of multiple myeloma (MM) are diagnosed in the United States each year, and over 11,000 deaths annually are attributed to MM (http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf). In the past decade, the introduction of new drugs has markedly changed the treatment paradigm and outcomes for patients with MM (Kumar et al. Leukemia 2014;28:1122-1128). However, it is not clear whether the improvements have been sustained in more recent years and if improvements were also experienced by patients with additional risk factors for death. This study examined temporal changes in MM survival among patients with additional factors known to be associated with death (i.e. older age and cardiac conditions).Methods: This was a retrospective observational cohort study using the Truven Health MarketScan® Commercial and Medicare Supplemental Databases. Study patients included those with at least 1 inpatient or 2 outpatient claims with an MM diagnosis between January 1, 2006 and December 31, 2014, who were at least 18 years old at diagnosis, were continuously enrolled in a health plan for at least 12 months before and at least 30 days after the first diagnosis, and had no prior history of any malignancies. Patients were followed from the date of the first MM diagnosis through the earliest event including death, end of enrollment, or end of the study period (September 30, 2015). All-cause mortality data were obtained from inpatient admissions with a discharge status of "death," and from Social Security Administration death records. Mortality rates were calculated overall, for patients <65 years-old and ≥65 years-old, and for patients with and without a cardiac comorbidity (heart failure, dysrhythmia, myocardial infarction, other ischemic heart disease) indicated in the 12-month baseline period grouped within two time periods according to the date of MM diagnosis (2006-2010 and 2011-2014). Kaplan-Meier survival curves were created for each group and compared using log-rank tests.Results: A total of 5,199 MM patients met all eligibility criteria and were included in the analysis. There were significant differences in survival between patients stratified by age and time period of diagnosis (Figure 1). The overall mortality rate was substantially lower among all patients <65 years-old, compared to those ≥65 (0.18 vs. 0.43 per 1,000 person-days, p<0.05), and mortality rates improved among both age groups from the 2006-2010 to the 2011-2014 time period (<65 years: 0.19 vs. 0.15 per 1,000 person-days, p<0.05; ≥65 years: 0.47 vs. 0.35 per 1,000 person-days, p<0.05). Over 41% of MM patients ≥65 years-old had a cardiac comorbidity, compared to approximately 17% of those <65 years-old. There were significant differences in survival between patients stratified by the presence of a cardiac comorbidity and time period of diagnosis (Figure 2). The mortality rates improved from the 2006-2010 to the 2011-2014 time period among both groups (no cardiac comorbidity: 0.26 vs. 0.20 per 1,000 person-days, p<0.05; cardiac comorbidity: 0.48 vs. 0.37 per 1,000 person-days, p<0.05) (Table 1). Patients who were ≥65 and with a cardiac comorbidity had the worst survival in both time periods; however, mortality rates improved from the 2006-2010 to 2011-2014 time period for all groups stratified by age and presence of a cardiac comorbidity (Table 1).Conclusion: This real-world analysis showed improved survival over time in patients with MM. Improvements in survival were most pronounced for older patients with a cardiac comorbidity, suggesting that changes in disease management over time may have contributed to better outcomes even among the most vulnerable MM patients. With the recent FDA approval of new MM treatment options, tailoring treatment plans for patients based on specific risk factors is even more feasible and may help to further optimize disease management and continue the improvements in survival. [Display omitted] [Display omitted] DisclosuresMaiese:Janssen Scientific Affairs, LLC: Employment. Evans:Truven Health Analytics: Employment. Irwin:Truven Health Analytics: Employment.

Abstract IA07: Outcome disparities in multiple myeloma: The role of race/ethnicity

Abstract Approximately 27,000 new cases of multiple myeloma (MM) will be diagnosed and more than 11,000 deaths will occur from it in 2015. Overall, 5-year relative survival rates have improved from 26.5% in 1975 to 44.9% in 2010, and this has been attributed to the introduction of novel therapeutic agents, widespread utilization of autologous stem cell transplant (ASCT), and improvement in supportive care modalities. However, studies evaluating the role of race/ethnicity in MM have shown marked disparities in incidence and outcomes of MM among patients of different racial subgroups. Traditionally, it has been known that African-Americans (AA) have a higher incidence of MM than Whites and that it occurs in AA at a younger age. Despite this difference in incidence, AA patients are known to have a better overall survival (OS) than Whites. Recent population-based outcomes analyses of MM patients beyond just Whites and AA has shown that Asians have the best median OS, while Hispanics have the worst, in a population that is more representative of the current US racial/ethnic mix. Additionally, the cumulative survival benefit over time as per a recent report was most pronounced among Whites (1.3 years) and least among Asians (0.5 years), suggesting a possible differential access as well as utilization of therapeutic modalities. Thus, despite overall improvement in MM outcomes over years, racial disparities exist. While majority of the data so far has reported the existence of these outcome disparities, a few reports have explored the potential causes of these differences. With regards to disease biology, there is some data suggesting that MM patients belonging to different races may have variability in the incidence of high-risk mutations, with AA MM patients having a lower incidence of such mutations, supporting the better OS seen in AA patients as compared to Whites. Another suggestion supporting differences in an interaction between biologic and environmental factors in MM patients is the variability in incidence of second primary malignancies in patients after they have developed MM, which may affect their outcome and OS. Other causes of outcome disparities may include a differential access to certain treatment options, especially more complex ones like stem cell transplants, as well as certain novel therapeutic agents that may depend on the patient's insurance payer status, which brings up differences in socioeconomic status, education level and barriers in accessing healthcare. It has also been reported recently that access to comprehensive cancer centers has benefitted Whites more than racial minorities. While access issues are being reported for MM patients belonging to different races, it has been suggested that outcome disparities by race are not noted in equal access healthcare systems. The potential shortcomings for these studies in equal access healthcare systems though, have been small size, mostly single-institution and focusing primarily on Whites and AA, without much representation yet of Hispanics and Asians, despite these two racial subgroups being the fastest growing ones in the US. Outcome disparities in MM by patient race have been established. The factors affecting these outcome disparities may be complex and interrelated, making it difficult to identify specific factors that may be modifiable. Yet, it is important to explore outcome disparities and their potential causes, especially in large cohorts prospectively, so that healthcare resources may be utilized efficiently and furthermore, the disadvantaged population subgroups may be benefitted by targeted interventions. Citation Format: Sikander Ailawadhi. Outcome disparities in multiple myeloma: The role of race/ethnicity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA07.

Multiple myeloma cell lines and primary tumors proteoma: protein biosynthesis and immune system as potential therapeutic targets.

Despite great advance in multiple myeloma (MM) treatment since 2000s, it is still an incurable disease and novel therapies are welcome. Therefore, the purpose of this study was to explore MM plasma cells' (MM-PC) proteome, in comparison with their normal counterparts (derived from palatine tonsils of normal donors, ND-PC), in order to find potential therapeutic targets expressed on the surface of these cells. We also aimed to evaluate the proteome of MM cell lines with different genetic alterations, to confirm findings obtained with primary tumor cells. Bone marrow (BM) samples from eight new cases of MM and palatine tonsils from seven unmatched controls were submitted to PC separation and, in addition to two MM cell lines (U266, RPMI-8226), were submitted to protein extraction for mass spectrometry analyses. A total of 81 proteins were differentially expressed between MM-PC and ND-PC - 72 upregulated and nine downregulated; U266 vs. RPMI 8226 cell lines presented 61 differentially expressed proteins - 51 upregulated and 10 downregulated. On primary tumors, bioinformatics analyses highlighted upregulation of protein biosynthesis machinery, as well as downregulation of immune response components, such as MHC class I and II, and complement receptors. We also provided comprehensive information about U266 and RPMI-8226 cell lines' proteome and could confirm some patients' findings.

Differences in the Original Diagnostic Markers Including the "CRAB" Criteria in Multiple Myeloma Patients from Different Ethnicities: A Single Center Experience

LEARNING OBJECTIVESDetermine if there are any differences in the original diagnostic markers, including the “CRAB” criteria, in Multiple Myeloma patients from different ethnicities. BACKGROUNDAbout 24,050 new cases of Multiple Myeloma are expected to be diagnosed in 2014. In a metropolitan institution, such as Henry Ford Hospital, newly diagnosed patients are drawn from multiple ethnic backgrounds. While several epidemiological studies have demonstrated a positive correlation between race and values of several diagnostic markers (such as hemoglobin, creatinine and albumin), most of the research focused on molecular and genetic, as opposed to clinical, differences in patients from multiple ethnicities.Our study, therefore attempted to offer a more customized diagnostic approach to patients with newly diagnosed Multiple myeloma, based on their ethnicity, and to determine if there was a correlation between the patients’ races and common diagnostic elements, including the CRAB criteria, at time of diagnosis. METHODSWe conducted a retrospective study. Data from 300 patients over 5 years (2007-2012) with newly diagnosed with Multiple myeloma was collected. Only 197 patients fulfilled the diagnostic criteria and were included in the final analysis. The following data was extracted: Age at diagnosis, gender, diagnostic elements according to the CRAB criteria (serum Calcium, serum Creatinine, Anemia, Bone lytic lesions) at date of diagnosis, serum beta-2-microglobulin level, M-protein serum concentration, and whether Urine monoclonal protein excretion was present. The patients were divided into two groups by race: African American and Caucasian. An overall score was created by summing the incidence of each diagnostic marker. RESULTSCategorical data was compared between the two groups using chi-square tests, and CRAB score was compared using a Wilcoxon rank-sum test due to its ordinal nature. Our study demonstrated that there were no statistically significant differences between the two groups in any of the components collected, or in the final total score CONCLUSIONS1.Our study demonstrated that there was no statistically significant difference in the original diagnostic markers, including the CRAB criteria, in Multiple Myeloma Patients from Different Ethnicities presenting to our Institution.2.The effect of baseline cytogenetic characteristics on the diagnostic markers between multiple myeloma patients from different ethnicities is still not fully understood, and might be a factor that needs to be studied further. DisclosuresNo relevant conflicts of interest to declare.