IgD Myeloma: Clinical Features and Outcome In The Era Of Novel Agents

Abstract IgD multiple myeloma is a rare variant of the disease and in various series accounts for about 2% of patients with symptomatic myeloma. It has been suggested that patients with IgD myeloma may have an inferior outcome when compared to other patients. However, data on IgD myeloma patients treated in the novel agent era are lacking. In order to assess the frequency and evaluate the outcome and the specific characteristics of patients with IgD myeloma we analyzed the database of the Greek Myeloma Study Group to identify such patients. Between January 2000 and December 2012, among the 1239 patients with previously untreated, symptomatic, myeloma, 31 patients (2.5%) were diagnosed with IgD myeloma. Of interest, 84% of patients with IgD myeloma had lambda light chain (versus 38% of the patients with other subtypes of MM, p<0.001). The median age of patients with IgD myeloma was 65 years (range 26-80 years) versus 68 years (range 23-96 years) for patients with other subtypes of MM (p=0.073), while 10% of patients with IgD versus 28% of the other patients were >65 years (p=0.023) and 10% of patients with IgD versus 3.8% of the other patients were ≤40 years of age. Patients with IgD myeloma presented more often with significant renal dysfunction (serum creatinine ≥2 mg/dl in 52% versus in 19%, p<0.001 or eGFR <30 ml/min/1.73m2 in 42% versus 18% in patients of other subtypes, p=0.001) and excreted larger amounts of Bence Jones protein (59% excreted ≥2 gr per day versus 17% of the other patients, p<0.001). Patients with IgD myeloma had also more often features of high risk disease including ISS-3 disease (60% versus 37% for the other patients, p=0.011) and elevated serum LDH (≥300 IU/L) in 29% versus10% of the other patients (p=0.001). Response to primary therapy for patients with IgD myeloma was similar to other patients (at least PR in 77% versus 72% respectively), although there was a trend for better quality of responses in patients with IgD myeloma (sCR and CR in 26% versus 15% of patients, and at least VGPR in 53% versus 29% in patients of other subtypes, respectively, p=0.059). However, more patients with IgD myeloma had received primary therapy with bortezomib-based regimens (40% versus 22%) and less often IMiD-based therapy (20% versus 35%), while similar proportions of patients received conventional chemotherapy-based regimens (40% versus 44%; p=0.043). Despite the increased frequency of features of high risk disease in patients with IgD myeloma, the median survival of these patients was 51.5 months versus 50.7 months for patients of other subtypes (p=0.850). In a multivariate model to adjust for differences in prognostic features, IgD myeloma was not associated with a different prognosis. We also compared the outcome of patients with IgD myeloma treated before and after January 1st, 2000. The survival of the patients with IgD myeloma who started therapy before versus after 2000 was 44 months (p=0.018). In conclusion, in a large series of patients with symptomatic multiple myeloma, the incidence of IgD myeloma is 2.5%. The vast majority of patients with IgD myeloma is associated with lambda light chain and present more often with significant Bence Jones proteinuria, significant renal dysfunction and features of advanced disease. However, their outcome in the era of novel agents is similar to that of patients with other myeloma subtypes. Disclosures: No relevant conflicts of interest to declare.

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Multiple Myeloma Patients ≤40 Years Of Age: Clinical Characteristics and Outcome In The Era Of Novel Agents

Blood ◽

10.1182/blood.v122.21.3226.3226 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3226-3226

Author(s):

Argiris S. Symeonidis ◽

Efstathios Kastritis ◽

Sosana Delimpasi ◽

Charikleia Kelaidi ◽

Anastasia Sioni ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Dysfunction ◽

Median Survival ◽

Advanced Disease ◽

Age Groups ◽

The Other ◽

Novel Agents ◽

Primary Therapy ◽

Younger Patients ◽

The Difference

Abstract Multiple myeloma (MM) is a disease of the elderly and the median age at diagnosis is 65 to 68 years; MM is rarely diagnosed in patients ≤40 years of age. Reports on the characteristics of the disease and the outcome of patients ≤40 years of age are limited. Thus, we sought to identify patients ≤40 years of age who were treated for symptomatic myeloma and describe their characteristics and outcome in the era of novel agents. Among 1239 consecutive patients who started therapy for symptomatic MM within the Greek Myeloma Study Group centers, between January 2000 and December 2012, 49 patients (3.95%) were ≤40 years of age. We compared their characteristics and outcome to that of patients 41-65 years of age, who are usually eligible for autologous transplantation and to patients >65 years, who are usually treated without high dose therapy. Most patients ≤40 years were males (67% vs. 55% of patients 41-65 and 52% of patients >65 years, p=0.069). Osteolytic bone disease at diagnosis was present in 81% (vs. 74% in each of the other two groups, p=0.553) and 65% had an ECOG performance status (PS) ≤1 (vs. 66% of patients 41-65 and 44% of patients >65 years, p<0.001). Anemia at diagnosis (Hb <10 gr/dl) was less frequent in patients ≤40 years than in older ones (29% vs. 44% in patients 41-65 and 47% in patients> 65 years, p=0.037), while low platelet counts (<130x109/l) were similar (10% vs. 13% and 12%, respectively, p=0.871). Severe renal dysfunction (eGFR <30 ml/min/1.73m2) was less common in younger patients (8% vs. 16% vs. 21%, p=0.025). Advanced disease stage (ISS-3) was present in 22% (vs. 32% and 42% for the other age groups, respectively) and most patients ≤40 years were rated as ISS-1 (55% vs. 29% vs. 20% for the other age groups; p<0.001). IgA MM was less common in patients ≤40 years (14% vs. 20% vs. 27% of patients 41-65 and> 65 years) and IgD MM was more common (6% vs. 3% vs. 2%, respectively; p=0.003). Other features of advanced disease such as LDH ≥300 IU/L were similar although bone marrow infiltration was less extensive in patients ≤40 years (52% had plasma cell infiltration <40% vs. 29% and 35% of patients of the other age groups, p=0.002). There were significant differences in the type of primary therapy among age groups: most patients ≤40 years received primary therapy with novel agents (47% bortezomib-based and 10% IMiD-based regimens), while patients in the other age groups received less often bortezomib at first line (38% of patients 41-65 years and 10% of patients >65 years received bortezomib but 17% and 47%, respectively, received primary therapy with IMiDs; p<0.001). Response to primary therapy was achieved in 75.5% vs. 76% vs. 69% of patients ≤40 years, 41-65 and <65 years respectively, but the quality of response was better in the younger patient group (sCR/CR in 33% vs. 19% vs. 11% and ≥ VGPR in 43% vs. 36% vs. 24% in the three age groups respectively, p<0.001). The calculated median survival for patients ≤40 years was 11.5 years (95% CI 7-16 years) vs. 7 years (95% CI 6-8.4 years) for patients 41-65 years (the difference was not significant p=0.162) and 3.2 years (95% CI 2.8-3.4 years) for patients >65 years (p<0.001 for comparison to the other two age groups). The survival curve indicates that only after 5 years there is a difference in the survival rate between patients ≤40 years and patients 41-65 years (74% vs. 64%). Compared to the survival of patients ≤40 years who started therapy between January 1990 and December 1999 (median survival 5 years) there has been a major improvement in the survival of younger patients (p<0.001). In order to adjust for differences in the characteristics of the disease between the three age groups (ECOG PS, ISS stage, anemia, renal dysfunction, IgA type) we performed a multivariate analysis in which the difference in the risk of death for patients ≤40 years vs. those 41-65 years was not significant (HR: 1.3, 95% CI 0.76-2.22, p=0.335); however, further follow up is needed in order to see a survival difference between these two groups of patients under the age of 65. In conclusion, about 4% of our myeloma patients were ≤40 years of age; these patients are more often males, have more often IgD MM or ISS-1 disease and less often anemia or renal dysfunction. The median survival of these young patients exceeds 10 years in the contemporary era of novel agents and has more than doubled compared to the pre 2000 era. Disclosures: No relevant conflicts of interest to declare.

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A Prospective Observational Study of Clinico-Pathological Features, Prognostic Factors and Treatment Response to Primary Therapy in Multiple Myeloma at a Tertiary Care Centre

Blood ◽

10.1182/blood-2019-125752 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5559-5559

Author(s):

Saurabh Mishra ◽

Ashok K Vaid ◽

Nitin Sood ◽

Manorama Bhargava ◽

Bhuvan Chugh ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Response ◽

Light Chain ◽

Prospective Observational Study ◽

Tertiary Care ◽

High Dose ◽

Primary Therapy ◽

Lambda Light Chain ◽

Tertiary Care Centre ◽

Cell Support

Title: "A prospective observational study of clinico-pathological features, prognostic factors and treatment response to primary therapy in Multiple Myeloma at a tertiary care centre" Background: Multiple myeloma (MM) is characterised by the neoplastic proliferation of plasma cells leading to excess monoclonal immunoglobulins. The incidence of multiple myeloma in India ranges from 1.2 to 1.8 per 100,000. There is paucity of cytogenetic data from this part of subcontinent. The aim of our study is to report various clinicopathological features, evaluate biological markers of prognostication including cytogenetic variables and assess treatment response after standard primary therapy. Methods and Materials: The study was carried out at a tertiary care center in Northern India. After final diagnosis of multiple myeloma was established, each patient was risk stratified via FISH cytogenetic analysis as per the revised ISS. Definitive management plan was individualised, including assessment for high dose therapy with peripheral blood stem cell support. Treatment response were recorded as per standard IMWG response criteria. Significant toxicities associated with treatment were also recorded. Results: Eighty consecutive patients with newly diagnosed multiple myeloma were enrolled prospectively from April 2017 to November 2018. The median age at diagnosis was 63 years, and number of males & females were equal. The most common presenting symptom was back pain (67.8 % patients) and most frequent clinical sign was pallor (86.4 %). All four CRAB features were documented only in 16.9% patients. M-Band was present in 96.6% patients and on SFLC assay 59.3% and 40.7% were kappa and lambda light chain restricted respectively. Most common heavy chain abnormality detected was IgG. Seventy percent patients had lytic lesions on imaging while only 3% suffered skeletal related events. Cytogenetic evaluation by interphase FISH was carried out in all patients upfront. No chromosomal abnormality was documented in 61.25 % while among those with chromosomal abnormalities, most commonly detected was del13q14.3 (23.75 %). Overall, 66.6% patients were stratified as standard risk, 28.1% as intermediate risk and only 3 (5.3%) patients were categorised as high risk. Most common induction regimen was VRD. Overall response rate was 94.9 % and VGPR or better responses were observed in 77.9% patients. Most common adverse effect of therapy was peripheral neuropathy of all grades. Of the 77 patients who completed primary therapy, 21.4% patients underwent high dose therapy with peripheral blood stem cell support while 67.7% patients were started on maintenance therapy. Four (5.1 %) non-responder was started on 2nd line treatment. On univariate analysis, higher deeper responses (VGPR or better) were observed in patients with IgA & IgG related myeloma and better overall response rates were seen in IgG related myeloma. Those with kappa light chain myeloma had 5.67 times higher likelihood of achieving response as compared to lambda light chain myeloma. Also, patients with kappa light chain myeloma achieved higher VGPRs as compared to lambda light chain myeloma. There was 17 times high risk of non-response in the presence of local bony tenderness. None of the findings were found to be significant on multivariate analysis. Conclusions: Use of interphase FISH to identify various cytogenetic markers help in stratification & staging of the disease which in turn act as a marker for prognostication. They should be a part of standard care in multiple myeloma. In majority we could administer treatment in accordance to standard practice guidelines and response rates were similar to those reported my seminal studies. Our study in a longer follow up will yield some useful information which will help in the better care of the patients. Disclosures No relevant conflicts of interest to declare.

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Novel agents improve survival of transplant patients with multiple myeloma including those with high-risk disease defined by early relapse (<12 months)

Leukemia & Lymphoma ◽

10.3109/10428194.2010.531409 ◽

2010 ◽

Vol 52 (1) ◽

pp. 34-41 ◽

Cited By ~ 27

Author(s):

Christopher P. Venner ◽

Joseph M. Connors ◽

Heather J. Sutherland ◽

John D. Shepherd ◽

Linda Hamata ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Novel Agents ◽

Early Relapse ◽

Transplant Patients ◽

High Risk Disease

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Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents

Haematologica ◽

10.3324/haematol.2012.065698 ◽

2012 ◽

Vol 97 (11) ◽

pp. 1761-1767 ◽

Cited By ~ 154

Author(s):

S. Z. Usmani ◽

C. Heuck ◽

A. Mitchell ◽

J. Szymonifka ◽

B. Nair ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Poor Prognosis ◽

Novel Agents ◽

Extramedullary Disease ◽

High Risk Disease

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Comprehensive evaluation of the revised international staging system in multiple myeloma patients treated with novel agents as a primary therapy

American Journal of Hematology ◽

10.1002/ajh.24891 ◽

2017 ◽

Vol 92 (12) ◽

pp. 1280-1286 ◽

Cited By ~ 10

Author(s):

Hyungwoo Cho ◽

Dok Hyun Yoon ◽

Jung Bok Lee ◽

Sung-Yong Kim ◽

Joon Ho Moon ◽

...

Keyword(s):

Multiple Myeloma ◽

Comprehensive Evaluation ◽

Staging System ◽

Novel Agents ◽

Primary Therapy ◽

International Staging System

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Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease

Blood ◽

10.1182/blood-2013-12-546077 ◽

2014 ◽

Vol 123 (16) ◽

pp. 2504-2512 ◽

Cited By ~ 23

Author(s):

Jeffrey R. Sawyer ◽

Erming Tian ◽

Christoph J. Heuck ◽

Joshua Epstein ◽

Donald J. Johann ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Copy Number ◽

High Risk Disease ◽

Key Points ◽

Gains And Losses

Key Points Jumping translocations of 1q12 (JT1q12) provide a mechanism for the deletion of 17p in cytogenetically defined high-risk myeloma. Sequential JT1q12s introduce unexpected copy number gains and losses in receptor chromosomes during subclonal evolution.

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Real-World Experience with Minimal Residual Disease Testing with Next Generation Flow Cytometry and Functional Imaging in Multiple Myeloma

Blood ◽

10.1182/blood-2020-140772 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

David Böckle ◽

Paula Tabares Gaviria ◽

Xiang Zhou ◽

Janin Messerschmidt ◽

Lukas Scheller ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

High Risk ◽

Functional Imaging ◽

Real World ◽

Research Funding ◽

Residual Disease ◽

Focal Lesions ◽

High Risk Disease ◽

Minimal Residual

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

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Outcomes with early response to first-line treatment in patients with newly diagnosed multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2018022806 ◽

2019 ◽

Vol 3 (5) ◽

pp. 744-750 ◽

Cited By ~ 4

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

S. Vincent Rajkumar ◽

Morie A. Gertz ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Light Chain ◽

Progression Free Survival ◽

Early Response ◽

Stage Iii ◽

Newly Diagnosed ◽

Best Response ◽

Light Chain Disease ◽

The Impact

Abstract We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and <VGPR after 2 cycles (PFS, 28 vs 30 months, P = .6; OS, 78 vs 96 months, P = .1) and 4 cycles (PFS, 31 vs 29 months; OS, 89 vs 91 months, P = .9), although both were improved, with ≥VGPR as best response (PFS, 33 vs 22 months, P < .001; OS, 102 vs 77 months, P = .003). On multivariate analysis stratified by transplant status, achievement of ≥VGPR after 2 cycles was not associated with improved PFS (hazard ratio [95% confidence interval]; transplant cohort, 1.1 [0.7-1.6]; nontransplant cohort, 1.2 [0.8-1.7]) or OS (transplant cohort, 1.6 [0.9-2.9]; nontransplant cohort, 1.5 [1.0-2.4]). Covariates in the model included high-risk cytogenetics, ISS stage III, triplet therapy, creatinine ≥2 mg/dL, light chain disease, and age. Although patients with high-risk disease are more likely to achieve early response, a rapid achievement of a deep response by itself does not affect long-term outcomes.

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Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_159016 ◽

2016 ◽

pp. 210-221 ◽

Cited By ~ 2

Author(s):

Amrita Krishnan ◽

Ravi Vij ◽

Jesse Keller ◽

Binod Dhakal ◽

Parameswaran Hari

Keyword(s):

Multiple Myeloma ◽

Disease Control ◽

Minimal Residual Disease ◽

Residual Disease ◽

The Other ◽

Novel Agents ◽

Patient Specific ◽

High Dose ◽

Hematopoietic Stem ◽

Minimal Residual

For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, significant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also increasing rates of minimal residual disease–negativity with additional consolidation therapy. On the other hand, maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy maintenance, and patient-specific maintenance—a concept that utilizes minimal residual disease as the primary driver of decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and immune checkpoint manipulations. In the future, personalized minimal residual disease–driven treatment strategies following ASCT will help overcome the residual disease, restore multiple myeloma–specific immunity, and achieve sustained disease control while minimizing the risk of overtreatment.

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Regulation of Selected MicroRNAs in Multiple Myeloma,

Blood ◽

10.1182/blood.v118.21.3916.3916 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3916-3916

Author(s):

Reinhold Munker ◽

Tetsuro Setoyama ◽

Madeleine Duvic ◽

Robert Z. Orlowski ◽

George Calin

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Ionizing Radiation ◽

Cell Lines ◽

Expression Profiles ◽

Early Time ◽

Pegylated Interferon ◽

Protective Mechanism ◽

Time Points ◽

High Risk Disease

Abstract Abstract 3916 Introduction: Multiple myeloma is clinically and biologically heterogeneous. Certain translocations and chromosomal losses (t{14;16}, t{14;20}, del 17p) and gene expression profiles define high-risk disease. Recently, several groups found microRNAs (miRs) dysregulated in multiple myeloma. A profile composed of 28 miRs was found to define high-risk disease. Among the dysregulated miRs, miR15a, miR16 were down-regulated, miR19b, miR20a, miR181b were increased according to most publications. MiR-21 was generally upregulated in high-risk disease and inducible by interleukin-6. We hypothesized that commonly administered treatments for multiple myeloma would alter the expression pattern of these miRs. Materials and Methods: For these in-vitro experiments, 4 established cell lines were used: RPMI8226, OPM-2 (t4;14), Kas-6 (IL-6-dependent) and MM1-S (t14;16). The cells were treated with ionizing radiation (3- 6 Gy), lenalidomide (10 μM), doxorubicin (50 ng/ml), bortezomib (2- 50 nM), SAHA (1–3x 10−6 M), pegylated interferon α (3–300 ng/ml) and nutlin-3 (10 μM) between 2 and 48 hours. RNA was extracted and quantitative real-time RT-PCR was performed for miR-15a, miR-16, miR19b, miR-20a, miR21, miR-181b and a control gene (U6). The expression was calculated and compared by the ΔΔ CT method. Results: Ionizing radiation increased miR15a in 1/2 cell lines at early time points, increased miR-19b at early time points in 2/2 cell lines (decreased later) and increased MiR20a in 2/2 cell lines at early time points. Lenalidomide induced miR15a in 2/4 cell lines, miR19b in 3/ 4 cell lines and miR-20a in 3/ 4 cell lines. Doxorubicin increased miR-16 in 2/3 cases and miR-20a in 2/3 cases (in 1 cell line decreased). Bortezomib overall induced few changes in miR-expression. SAHA induced miR-15a in 2/3 cell lines and decreased miR-16 in 1/3. MiR-19a was decreased with SAHA in 2/4 and increased in 1/4 cell lines. MiR-20 decreased in 1/4 and increased in 1/4. MiR-21 decreased in 1 and increased in 1/4 SAHA-treated cell lines. MiR-181b increased in 2/4 cell lines. Pegylated interferon decreased MiR-15a in 3/4 cell lines, decreased miR-16a in 3/4 cell lines, increased miR19b in 2/4 cell lines. MiR-20a was increased in 2/4 and decreased in 1/4 cell lines. MiR-181b was decreased in 2/ 4 cell lines. Nutlin-3 increased miR16 in 1/3 cell lines, increased miR-20a in 2/4 cell lines, increased miR-181b in 2/4, decreased miR-181b in 1/4 cell lines. Most changes observed are in the range of −50 – + 200%. Conclusions: Many miRs are induced at early time points under non-cytotoxic conditions. The variability observed in these experiments may be due to the genetic heterogeneity of the cell lines. Interferon mostly down-modulates the expression of the miRs studied. Previous experiments, for example using endothelial cells also showed an induction of certain miRs after cytotoxic or cytostatic treatments. This can be explained as a stress response or protective mechanism enhancing tumor cell survival. However, the functional relevance of our data was not investigated. The downregulation of miRs following interferon treatment is surprising and would argue for a combination of interferon with cytostatic treatments. If confirmed using CD138 selected samples from patients with multiple myeloma, our data may be used to develop a treatment profile which ultimately might prognosticate treatment response. Our results are also relevant for future miR-based treatments for multiple myeloma. Disclosures: Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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