Remission Of Multiple Myeloma Research Articles

Secondary extramedullary plasmacytoma in the absence of active multiple myeloma: a rare cause of small bowel obstruction

A 75-year-old woman with a history of multiple myeloma in remission presented with signs, symptoms and imaging findings consistent with a small bowel obstruction secondary to an intussusception. She underwent operative management, and intraoperative findings were consistent with an intussusception of mid small bowel as the cause of the small bowel obstruction. The offending portion of small bowel was resected, and histopathology confirmed a plasmacytoma deposit in the small bowel at the lead point of the intussusception. Secondary extramedullary plasmacytomas in the gastrointestinal system are rare but can have significant consequences like small bowel obstruction requiring operative management. We present a rare case that emphasizes the need to be highly suspicious for uncommon sequelae of multiple myeloma like secondary extramedullary plasmacytomas when managing patients with history of multiple myeloma in remission with concerning abdominal symptoms.

Alternating the Administration of Ixazomib and Lenalidomide As Maintenance Therapy after Autologous Transplant for Multiple Myeloma

Autologous transplant (ASCT) can cause remissions in Multiple Myeloma (MM) patients (pts), but relapse remains a major problem. Currently, lenalidomide alone for as long as tolerated post ASCT is the standard maintenance utilized in the USA. Since the use of an alternating schedule of an Immunomodulatory drug (IMiD) with a proteasome inhibitor (PI) might decrease the emergence of resistant dominant clones, we designed a study to investigate treating with a regimen alternating IMiD lenalidomide with PI ixazomib post ASCT. We report here on the toxicity and efficacy of this all-oral maintenance regimen. Thirty to 120 days after recovery from toxicity of ASCT, pts began study therapy. Treatment regimen consisted of alternating ixazomib 4mg po on days 1, 8 and 15 per each 28-day cycle for two consecutive cycles followed by lenalidomide 10mg po daily for two consecutive cycles until MM progression, intolerable toxicity or maximum of 24 cycles. Dose adjustment for toxicity occurred. Pts remained on anti-VZV and PJP prophylaxis throughout therapy and until 2 months after stopping therapy. Pts got bisphosphonate therapy. Pts also received DVT prophylaxis therapy as clinically indicated. The primary endpoint was toxicity. Secondary endpoints were ability to deliver planned therapy, initial response, overall progressive free and survival rates. Thirty pts were enrolled and treated on the study with at least 1 cycle of therapy. Twenty-three pts were male (77%), 13% were members of minority groups. The median age was 60 years (range 44-70 years). Three pts (10%) were over 65 years old. Fourteen pts (47%) had high-risk cyclogenetic MM per IMWG, including 6 pts (20%) that had multiple high-risk changes. Pts started study therapy at a median 107.5 days post ASCT (range 53-120 days). Thirteen pts (43%) stopped therapy before completing 24 cycles for the following reasons: relapse (n=8), patient's decision (n=2), secondary cancer treatment (n=1) and elective surgery that was complicated by infections (n=2). No pts met stopping rules for toxicity in the first 4 months of therapy. There were no deaths due to study therapy. The most common AE grades (gr) 2-4 were: abnormal glucose (10%, 100% gr 2), lymphocyte decreased (70%, 37% gr 2, 33% gr 3), low phosphate (17%, 100% gr 2), WBC decreased (53%, 33% gr 2, 20% gr 3), Platelet (PLT) decreased (33%, 23.3% gr 2, 6.7% gr 3 and 3.3% gr 4), ANC decreased (60%, 30% gr 2, 23.3% gr 3, 6.7% gr 4). The following infectious episodes were also seen in 27 patients (90%): non-identified upper respiratory tract infection (URTI) (n=34), identified URTI (n=9, included metapneumovirus (n=1), rhinovirus (n=2), RSV (n=1), influenza A (n=1) parainfluenza (n=2), RSV and COVID-19 (n=1) and COVID-19 (n=1)), nonneutropenic fever (n=1), thrush (n=1), conjunctivitis (n=1), shingles (n=1), cellulitis (n=3 include one case of MRSA), giardia (n=1), strep pneumonia with sepsis (n=1), bacterial pneumonia (n=2), viral gastroenteritis (n=2), urine tract infection (n=1), bronchitis (n=2) and tinea of the skin (n=1). The most frequent gr 3-4 AEs were hematological, with decreased WBC in 20%, decreased PLT in 10% and decreased ANC in 30% of pts. Twenty-four (80%) of the pts still had detectable MM disease after ASCT before starting study therapy. At completion of study therapy, 29.2% had progressed, 21% had stable disease, 4.2% were in PR, 29% in nCR, 8.3% in sCR and 8.3% in CR. Overall, 50% of patients converted to a deeper response (≥ PR). Four pts have developed a secondary cancer, localized skin cancer (n=3) and metastatic lung cancer (n=1). Only 1 pt was still receiving study therapy when the secondary cancer developed. Median follow-up is 3.95 years (range 3.18-6.7 years). Sixteen (53%) of the pts have relapsed. Eight pts (37%) have died including 6 pts with relapsed MM and 2 pts without relapse (metastatic lung cancer (n=1) and non-COVID infection (n=1). To date, 9 pts (30%) are alive in relapse and 13 pts (43%) are alive in remission. Post ASCT, the all oral regimen of alternating ixazomib and lenalidomide is overall well tolerated and has high initial response rates. Hematological toxicity as expected was the most significant toxicity. Significant gastrointestinal and peripheral neuropathy toxicity were not seen. The most common infection was non-specified URTI. A larger randomized trial comparing the alternating oral med schedule of ixazomib and lenalidomide to single agent lenalidomide is warranted.

Maintenance Therapy Cessation for Sustained MRD Negative Multiple Myeloma Patients

Introduction Maintenance therapy with lenalidomide (len) and other drugs is a cornerstone therapeutic strategy for sustaining deep durable remissions in multiple myeloma (MM). However, indefinite treatment, as currently recommended, may lead to financial, emotional, and physical toxicity. Current guidelines lack data on optimal duration of maintenance in MM patients (pts) who have achieved sustained negative minimal residual disease (MRD) status. Here, we present the first pre-planned interim results from a phase II study evaluating maintenance cessation in patients with sustained MRD negative status for at least 3 years at the time of enrollment on study. Methods The current two-stage designed study of fifty MM pts, having already demonstrated >3 years of durable MRD negative responses, will be evaluated for MRD negative sustainability after ceasing maintenance therapy. Enrolled pts stop maintenance therapy and undergo active surveillance for three years, including serum protein testing every 3 months, bone marrow MRD testing by multiparametric flow cytometry (single 10-color tube with limit of detection of at least 6x106 (6 cells in 1 million) every 6 months, and annual PET-CTs. Primary endpoint includes sustained MRD negative rate after 1 year. Secondary endpoints include sustained MRD negative rate 3 years of cessation, re-treatment responses, microbiome and immune studies, health-related quality of life outcomes (HRQoL), and progression-free survival (PFS). The first stage includes 15 pts, and if 8 or more remain MRD negative at the end of 1 year, study enrollment continues to stage two (n=35). Results At data cutoff, on July 31, 2022, twenty-three pts (15 - stage 1; 8 - stage 2) have been enrolled on study. Median follow-up was 14.8 months (95% LL-UL: 11.1 - 25.1) after study enrollment, included 17(74%) male and 6(26%) female; 19(83%) ISS-stage 1, 2(9%) ISS-stage 2, and 2(9%) ISS-stage 3; and 4(17.3%) pts with high-risk cytogenetics [1 - t(4,14) and t(14,16); 1 - t(4,14) and +1q21gain; 2 - +1q21gain]. All pts enrolled onto study were receiving lenalidomide maintenance at the time. For stage 1, 13/15 (87%) remained MRD negative at 12 months of stopping maintenance therapy, and study accrual is ongoing with enrollment of 8 additional pts onto second stage. Overall, MRD negative sustained rates at 6 months and 12 months are 17/18 (94%) (95% CI: 73%-99%) and 14/16 (88%) (95% CI: 62%-98%), respectively. Progression free survival at 12 months was 94% (95% CI: 83%-100%). Two pts converted from MRD negative to MRD positive disease states while meeting clinical progression criteria with new FDG avid bone lesions. These pts have transitioned to new regimens: Pt 13 initiated carfilzomib, pomalidomide, and dexamethasone with VGPR; Pt 2 with a plan to initiate daratumamab-based therapy locally. Pt 10 converted to MRD positivity without clinical progression and opted to restart maintenance therapy with repeat MRD testing pending. Among the three MRD converters, one pt demonstrated standard risk cytogenetics and two pts had unknown risk cytogenetics. Additional HRQoL outcome data will be presented at the time of the meeting. Conclusions Initial first stage results of stopping maintenance in sustained MRD negative patients (>3 years) warrants further investigation and study continuation. This study and similar ones, such as MRD2STOP (NCT04108624), set a benchmark for future trials investigating maintenance cessation. One such trial includes SWOG 1803, which randomizes maintenance continuation vs. discontinuation in two-year MRD negative sustained patients. While maintenance therapy demonstrates clear benefit for MM patients, feasibility of treatment-free periods remain an unanswered critical question in the field. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Value of P-selectin in the prognosis of cardiovascular events in patients with multiple myeloma

Multiple myeloma (MM) survival has greatly improved in recent decades. MM is usually diagnosed in elderlies. Patients do not necessarily die from MM, so cardiovascular health may be a key factor threatening long-term survival. The aim of the research: to evaluate the prognostic value of circulating P-selectin for cardiovascular events in patients with multiple myeloma in full or partial remission. Materials and methods. 97 patients with MM with complete or partial remission were enrolled in the study. None of the patients had received any lipid-modulating medications, including statins or fibrates, before enrollment. The observation period was up to 1 year. Blood samples for biomarkers measurements were collected. ELISA method for measurements of circulating level of P-selectin was used. Results. During the observation period progression of MM was proved in 25 patients, 5 persons were excluded for poor follow-up. 67 patients were included in the statistical analysis. Thirty-six cumulative clinical events occurred in 18 patients (26.9 %) within the follow-up, with their distribution being as follows: 2 cardiovascular deaths, 16 cardiac arrhythmias, 3 cardiac ischemic events, 1 stroke, 4 chronic heart failures, and 10 hospital admissions for cardiovascular reasons. 2 deaths were not related with cardiovascular pathology. Medians of circulating levels of P-selectin in free-events subject cohort and subjects cohort with cardiovascular events were 58.24 ng/ml (95 % confidence interval (CI) = 32.27–77.48 ng/ml) and 87.57 ng/ml (95 % CI = 51.12–114.89 ng/ml) (Р < 0.01). In multivariate logistic regression circulating P-selectin independently predicted cumulative cardiovascular events (odds ratio (OR) = 1.11; 95 % CI = 1.08–1.15; Р = 0.02) in patients after sever coronavirus disease (COVID-19) within 1 year of observation period. Conclusions. Among patients with documented multiple myeloma in remission increased circulating P-selectin was associated with increased cumulative cardiovascular events.

Clinical images: Cinematic rendering of tophaceous gout

A 77 year-old-man with a complex medical history, notable for multiple myeloma in remission and gout, presented for noncontrast Computed Tomography (CT) of the right upper extremity using dual energy technique, from which cinematic rendered images were created (Figure 1). The cinematic rendered images provide a unique, photorealistic, three-dimensional representation of the extensive tophi and their relationship to the adjacent structures within the hand.

CHANGES IN MYOCARDIAL BIOELECTRIC ACTIVITY IN PATIENTS WITH PROGRESSIVE MYLTIPLE MYELOMA

Introduction. Long-termed oncohematological course with periods of progression and remission of multiple myeloma, an increase in the cumulative dose of cytostatic drugs usually lead to a growing risk of chemotherapy-induced cardiotoxicity in patients with high cardiac risks. The aim of this study is to investigate changes in myocardial bioelectric activity of patients with progression of multiple myeloma and concomitant ischemic heart disease. Materials and methods. 42 patients with multiple myeloma were examined. The patients were divided into groups according to presence of concomitant coronary heart disease: І (n=15) included patients with multiple myeloma without concomitant cardiovascular diseases; II (n=27) involved patients with multiple myeloma and concomitant coronary heart disease. The patients were assessed before chemotherapy. We analyzed general and biochemical blood count findings. Based on Holter electrocardiography monitoring findings, we assessed heart rate, PQ interval, corrected QT interval. Results: Grade 3 and 4 of anaemia were detected only in the group of patients with multiple myeloma and concomitant coronary heart disease, in 4 (14,80%) and in 1 (3,70%) patients, respectively. Serum creatinine level above 177 μmol / l was found in 1 (6%) patient in the group I and in 2 (7%) patients in the group II. An inverse correlation was found between creatinine levels and erythrocyte counts in patients with multiple myeloma and concomitant coronary heart disease (R=-0,58, p<0,05). Rhythm disorders were found in 3 (20%) patients with multiple myeloma without cardiovascular diseases and in 8 (29.6%) patients with multiple myeloma with concomitant ischemic heart disease, conduction disorders was found in 5 (33%) patients in group I and in 14 (52%) patients in group II. Tendency in increasing the incidence of myocardial bioelectrical activity has been found out in case of concomitant coronary heart disease.

Impact of Daratumumab-Containing Induction on Stem Cell Mobilization and Collection, Engraftment and Hospitalization Parameters Among Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Introduction: Advances in induction regimens have significantly improved depth of response and duration of remission in multiple myeloma (MM) patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT). Proteasome inhibitor-based induction regimens are standard as part of induction and it has been shown not to have any detrimental effect on stem cell (SC) collection and engraftment. Daratumumab (DARA) is an IgG1k monoclonal antibody directed against CD38 with potent antimyeloma activity. Based on the results of prospective studies DARA is now approved as part of induction therapy. Available data indicate a potential impact of DARA on SC collection but there is limited data on engraftment, duration of hospitalization and infection risk. In this retrospective analysis we evaluated the effect of DARA-based induction on ASCT parameters.Methods: The analysis included consecutive newly diagnosed MM patients that received ASCT between 2016 and 2020, as part of their upfront treatment regimen in our institution (Department of Clinical Therapeutics, Athens, Greece). Per institutional protocol, after 4-6 cycles of induction, pts received low dose cyclophosphamide (2.5 g/m2) followed by G-CSF (10 mcg/Kg/day) to mobilize and collect SCs. Plerixafor was administered on-demand in case of poor mobilization and insufficient first day collection. Large volume leukapheresis was performed in pts with low CD34+ counts in order to increase CD34+ yield. Pts received G-CSF 480 μcg once daily from day +4 after SC reinfusion to ANC >1500/mm3. All pts received antiviral and antifungal but no anti-bacterial prophylaxis.Results: 200 eligible pts were included in the analysis; 40 (20%) pts received DARA as part of PI-based upfront treatment and 160 (80%) pts received PI-based upfront treatment without DARA. Baseline demographics (age, gender, performance status) and disease characteristics (ISS and R-ISS stage, cytopenias, eGFR, lytic bone disease etc) were not different between the two groups. Response after induction was also similar (CR+VGPR rate was 93% vs 95% for non-DARA and DARA-containing regimens respectively).Use of DARA at induction was associated with lower total mean number of collected CD 34+ SCs (10.48 x 10^6/kg vs 16.58 x 10^6/kg, p<0.0001), or SC collection on day 1 (7.99 x 10^6/kg vs 16.27 x 10^6/kg, p<0.0001). Fewer pts in the DARA-treated group achieved the planned yield of at least 5 X 10^6 CD34+/kg, compared to DARA-untreated group (87.5 % vs 96.2%, p=0.047). DARA-treated pts required more often additional SC mobilization with on demand administration of plerixafor (42.5% vs 7.6%, p<0.0001). In order to compensate for a poorer mobilization and lower quality graft (CD34% 0.66% vs 1.26% in apheresis product, p<0.0001) DARA-treated group underwent more often >1 day of SC collection (37.5% vs 6.3%, P <0.0001), resulting in longer duration of collections (689 vs 452 min, p<0.0001) and larger total apheresis volumes (723 vs 557 ml, p<0.0001). However, 97% and 98% of pts in the two groups respectively were able to move to at least a single ASCT. Following ASCT, DARA-treated pts had a slightly delayed hematopoietic recovery (11 vs 10 days to PMN>500/mm3, p<0.001 and 12 vs 11 days for PLT counts> 25x10^9/mm3, p<0.001) and required more transfusions (2 vs 1 for RBCs, p=0.031 and 4 vs 2 for platelets, p<0.001). Rates of neutropenic fever were higher (80% vs 67%, p=0.182), required antibiotics for longer duration (10 vs 8 days, p=0.042) and more often 2 or more lines of antibiotic therapy (53% vs 39%, p=0.003), experienced more often septic shock (12.5% vs 1.3%, p=0.003) and as a results DARA-treated pts had a slightly prolonged hospitalization (21 vs 19 days, p=0.02). However, D100 mortality was not statistically different (<2% in both groups).Conclusion: DARA-containing induction before ASCT is associated with poorer mobilization and frequent need for use of plerixafor. However, similar percentage of patients can move to at least a single ASCT. The use of DARA-containing induction was also associated with slightly increased risk of infectious complications, antibiotics use and blood product transfusions but no increase in the risk of D100 mortality. These data point to the need for certain modifications to ASCT protocol for patients treated with DARA-containing regimens at induction, such as preemptive use of plerixafor, and perhaps prophylactic antibiotics. DisclosuresTerpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Takeda: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding.

Découverte fortuite d’une récivide myélomateuse lors d’une scintigraphie osseuse réalisée dans le cadre d’une suspicion d’algodystrophie

We report the case of a 51-year-old patient with a history of multiple myeloma in remission after several courses of chemotherapy and an autologous transplant in April 2019, referred by the pain center of the hospital in December 2020 for the performing of a bone scintigraphy in the context of a suspected algodystrophy of the left upper limb, after surgery for a cervical disc herniation in September 2020. Early whole body acquisition following the injection of 630 MBq of 99mTc-sodium oxidronate demonstrated an intense hyperhemic mass in the left shoulder, associated with diffuse hyperemia in the rest of the left upper limb. Hybrid SPECT-CT imaging confirmed the presence of a large tissue density mass associated with major lysis of the left humeral head. There was also a diffuse reactive hyperfixation of the entire left upper limb as well as two unknow lytic lacunar frontal hyperfixing lesions. Faced with these results, the patient also underwent a PET-CT scan with 18F-FDG finding the large left humeral lesion as well as several hypermetabolic osteolytic lesions. The patient was finally hospitalized in internal medicine and presented for regional multidisciplinary meeting (RCP), which concluded in a myeloma recurrence with left humeral plasmacytoma. Although bone scintigraphy is not one of the examinations recommended in the assessment of myeloma (1,2), it has proven to allow the correction of the diagnosis and the detection of recurrence. 18-FDG-PET-CT was found in our case to be a more sensitive examination in the detection of myeloma lesions, allowing a more complete assessment of the disease and the detection of lesions that went unvisualized on bone scintigraphy.

Unusual Long Term Remission in Multiple Myeloma Using Conventional Therapy Combined with Danazol

Introduction and Case studies. The treatment of multiple myeloma (MM) has drastically changed over the past decade with significantly improved progression free as well as overall survival. Despite the advent of multiple treatment options, MM still has the inherent ability to become resistant. Relapses are frequent and the disease becomes refractory to treatment, leading to significant morbidity and mortality. Long term remissions lasting over a decade without relapses are rare in MM with conventional treatment.We report here prolonged remission lasting for decades in two patients with MM who were treated with conventional alkylating agents and steroids, combined with danazol as adjuvant and maintenance therapy. Both achieved complete remissions with undetectable M proteins and remarkable clinical improvement and better quality of life. The remissions were maintained now over two decades.Our first case was a 51 year old man who presented with severe back pain and noticeable loss of height. Work up revealed many lytic lesions and multiple collapsed vertebrae with diffuse osteoporosis on skeletal bone survey. Hematologic studies revealed high levels of IgG-lambda M protein of 6 grams. He was treated with melphalan, prednisone, monthly Aredia and danazol 200 mg three times daily (TID). He achieved a complete remission (CR) with marked clinical improvement. His remission was maintained with danazol 200 mg TID and Intron-A (interferon alfa-2b, recombinant) 5 million units three times a week. Danazol was later reduced to three times a week in combination with interferon, doses of which he remains on today. He remains in CR now for over 21 years without signs of relapse. He resumed all of his normal activities and is currently working without any limitation as a full time college professor. He refuses to stop danazol nor Intron-A.Our second case was a 41 year old man with 3 year history of progressive polyneuropathy that rendered him severely paraplegic, bedridden and unable to feed himself because of weakness. Work up revealed an IgG lambda M protein and multiple sclerotic bone lesions on bone survey. Excisional bone biopsy showed neoplastic plasma cell proliferation. Diagnosis of osteosclerotic multiple myeloma with POEMS syndrome was made. He was treated initially with plasmapheresis and infusions of IVIG without any long tern benefit. Subsequently, he received palliative radiation therapy to relieve bone pain and was treated with chlorambucil 3 mg PO daily, hydrocortisone 20 mg PO daily, danazol 200 mg PO TID and monthly Aredia which was later changed to Zometa. He achieved a CR with remarkable clinical recovery. His strength improved significantly with the ability to walk and feed himself as well as resumption of his normal daily activities (Muscle Nerve. 1997, 8:1035). He stopped danazol and remains in remission now over 22 years.Conclusion/Discussion: The use of immunomodulators (IMiDs) have changed the approach to the treatment of MM. While the mechanism of action is not fully understood, IMiDs appear to possess anti-myeloma properties including immunomodulation, anti-angiogenesis, and anti-proliferative activities (Leukemia. 2010, 24:22).Danazol, an attenuated androgen, is widely used in the treatment of ITP (NEJM. 1983, 308:1396). We previously showed that danazol carries inherent immunomodulatory action, increasing T-helper cells as well as the proportion of T-helper to T-suppressor cells among patients treated for ITP (Clin Imm Immunopath. 1987, 42:287). Administration of danazol in patients for ITP for over a year, even with withdrawal, yielded long term remissions while relapses were more frequent in those that took it for less than 6 months (Ann Intern Med. 1989, 111:723). Similar observation was made in other autoimmune disease such as immune hemolytic anemia (Acta Hematol. 1990, 84:122). Collectively, long term administration of danazol appears to induce prolonged unmaintained remission in autoimmune diseases like ITP. We postulate that danazol may induce similar immunomodulation in MM and contributed to decades of remission in our patients. Danazol has not yet been tested in the treatment of MM systematically but deserves further investigation through a large prospective clinical trial. DisclosuresNo relevant conflicts of interest to declare.

Multiple myeloma remission following COVID-19: an observation in search of a mechanism (a case report).

Coronavirus disease 2019 (COVID-19) represents a major challenge in the management of patients with hematologic malignancies. Individuals with plasma cell dyscrasias, including multiple myeloma, are at increased risk of developing severe disease. Furthermore, immunosuppressant agents, which represent an important component of multiple myeloma treatment, may increase the risk of serious infection; thus, treatment regimens may need to be modified in some patients. The pathogenesis of COVID-19 is incompletely understood and much remains to be established regarding cancer care in the setting of this new global health threat. We report a case of multiple myeloma remission that occurred after a single cycle of chemotherapy in a patient with COVID-19. In addition, we discuss possible mechanisms underlying this surprising observation. The findings warrant further investigation and may have important implications for the management of multiple myeloma and other plasma cell dyscrasias in the age of COVID-19.

Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells.

Simple SummaryMultiple myeloma (MM) constitutes the second most common hematological malignancy and is caused by aberrant plasma cell proliferation in the bone marrow. While recent improvements in the treatment of MM has been observed using immunomodulatory drugs (IMiDs), patients often relapse due to acquired drug resistance and no cure for the disease is currently available. In this report, we profile circular RNA (circRNA) expression patterns in cultured MM cells being sensitive to IMiDs and their resistant counterparts. CircRNAs constitute a large class of non-coding RNA molecules with emerging roles in cancer development and progression, but have not previously been explored in this context. We found that global circRNA expression patterns reflect IMiD sensitivity, but the most downregulated circRNA in IMiD resistant MM cells did not seem to be a direct driver of IMiD resistance. Future studies should investigate other circRNA candidates identified here in the context of IMiD resistance.Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs with important roles in cancer. Here, we profiled genome-wide expression patterns of circRNAs in IMiD-sensitive MM cells and their resistant counterparts as well as in IMiD-resistant cells treated with specific epigenetic drugs alone or in combination. We found that genome-wide circRNA expression patterns reflect IMiD sensitivity and ciRS-7 (also known as CDR1as) was the most downregulated circRNA upon acquired resistance. The depletion of ciRS-7 correlated with increased methylation levels of the promoter CpG island of its host gene, LINC00632. Expression of LINC00632 and ciRS-7 was partly restored by treatment with a combination of an EZH2 inhibitor (EPZ-6438) and a DNA methyl transferase inhibitor (5-azacytidine), which also restores the IMiD sensitivity of the cells. However, knockdown of ciRS-7 did not affect IMiD sensitivity and we found that ciRS-7 also becomes epigenetically silenced after prolonged cell culture without drug-exposure. In conclusion, we found that genome-wide circRNA expression patterns reflect IMiD sensitivity in an in vitro model of acquired resistance.

Bone marrow plasma cell ratio, is it must to evaluate before autologous stem cell transplantation in multiple myeloma?

Objective: Complete remission in multiple myeloma (MM) is a defined as having a &lt;5% bone marrow plasma cell (BMPC) ratio plus negative serum and urine immunofixation tests. However, it is necessary to reassess whether or not the bone marrow plasma cell ratio should be determined before transplantation in secretory multiple myeloma patients. A significant decrease in monoclonal protein levels or having negative serum and urine immunofixation tests after induction therapy might be enough to indicate chemo-sensitivity.&#x0D; Material and Methods: In this study, the data of 177 multiple myeloma patients that underwent autologous stem cell transplantation (ASCT) in our center were retrospectively evaluated.&#x0D; Results: We found a statistically significant difference in the post-ASCT response rates between the patients with a pre-ASCT BMPC ratio &lt;5% vs BMPC ratio ≥5% (p:&lt;0.001*). The 2-year progression-free survival (PFS) of the patients with BMPC ratio &lt;5% and ≥5% post-ASCT was found 24% and 25% (median PFS 11 months (95% CI; 6,68-15,31) vs 12 months (95% CI; 9,47-14,53)) respectively (p: 0.900). The 2-year overall survival (OS), was 67% and 63% (median OS 35 months (95% CI; 25,59-44,41) vs 40 months (95% CI; 27,52-52,47)) respectively (p: 0.341).&#x0D; Conclusion: Patients with decreasing monoclonal protein in serological tests, the pre-ASCT BMPC ratio was not found to have an impact on neutrophil and platelet engraftment durations, transplantation related mortality (TRM), PFS and OS. Our study suggests that in MM patients with measurable disease, it is not required to evaluate the BMPC ratio if serologic response exists.

Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma

Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma

Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

110 Testicular Plasmacytoma With Features of Testicular Germ Cell Tumor in a Patient With Multiple Myeloma Remission for Years

110 Testicular Plasmacytoma With Features of Testicular Germ Cell Tumor in a Patient With Multiple Myeloma Remission for Years

CAR T-Cell Therapy Leads to Durable Remissions in Multiple Myeloma

CAR T-Cell Therapy Leads to Durable Remissions in Multiple Myeloma

Circulating VE-catherin and prognosis of cardiovascular events in remission of multiple myeloma

Circulating VE-catherin and prognosis of cardiovascular events in remission of multiple myeloma

A Case of Internal Carotid Artery Thrombosis associated with Thalidomide Administration in Multiple Myeloma

Thalidomide is an effective chemotherapeutic agent used to achieve remission in multiple myeloma. However, its administration is associated with several adverse effects including venous thromboembolism, while arterial thrombosis has also, although rarely, been described in the literature. We report a case of internal carotid artery occlusion within 1 week of starting thalidomide with prophylactic low molecular weight heparin in a patient who had no other prothrombotic risk factors. It is not known why this complication occurs despite the administration of anticoagulant prophylaxis. The role of factor VIII, von Willebrand factor antigen levels and fibrinogen in multiple myeloma patients should be studied in order to determine if these factors should be targeted in future prophylactic treatment.LEARNING POINTSThalidomide increases risk of arterial thrombosis in multiple myeloma (MM), even if no other procoagulant risk factors are present.All patients starting thalidomide must be assessed before commencing venous thromboprophylaxis, although its efficacy in preventing arterial thrombosis has not yet been proven.Further research is required to target anti-thrombotic factors in order to prevent arterial thrombosis in patients with MM being treated with thalidomide and its derivatives.

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long-term follow-up in a single institution.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce long-term remission in multiple myeloma (MM), but the role of allo-SCT in MM is controversial due to the high rate of treatment-related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high-risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo-SCT. We therefore analyzed the outcome of one hundred and forty-seven patients with MM who received an allo-SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow-up of 88.8 months. For the first-line setting, median progression-free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10-yr OS of 51%. We found no difference in outcome for patients with high-risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high-risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto-SCT. Therefore, if applied at all in these patients, improvement of allo-SCT is needed, focusing on reduction of TRM and more effective immunotherapy.

The importance of the number of transplanted cells with dipeptidyl peptidase-4 expression on the haematopoietic recovery and lymphocyte reconstitution in patients with multiple myeloma after autologous haematopoietic stem-cell transplantation.

Autologous haematopoietic stem cell transplantation (AHSCT) remains recommended treatment in the first remission in multiple myeloma (MM). In earlier research it has been suggested that there is an influence of the expression of dipeptidyl peptidase-4 (CD26) on both the homing and lymphocyte reconstitution after AHSCT. The aim of the study is to investigate the influence of transplanted cells CD26+ on the haematopoietic recovery and lymphocyte reconstitution after AHSCT in MM. Forty eight patients with MM underwent AHSCT in our centre. Number of all CD26+ cells, CD26+ lymphocytes, CD26+ monocytes and CD26+ and CD34+ cells were measured in the harvested material. Number of lymphocyte's subpopulations (all lymphocytes CD3+, helpers, suppressors, natural killer (NK), cytotoxic NK and lymphocytes B) were measured in peripheral blood during regeneration after AHSCT. In both flow cytometry was used. On the basis of the analysis there was, as regards regeneration of haematopoietic cells after AHSCT, it was shown that a higher number of monocytes CD26+ improves the reconstitution of helper, suppressor and NK lymphocytes. A higher number of transplanted CD26+ lymphocytes accelerates the reconstitution of NK lymphocytes, whereas a higher number of all the cells CD26+ has a positive impact on the regeneration of cytotoxic NK lymphocytes. Copyright © 2015 John Wiley & Sons, Ltd.