Killer Ig-like receptors (KIRs) are expressed on CD4+CD28null T cells, a highly oligoclonal subset of T cells that is expanded in patients with rheumatoid arthritis. It is unclear at what stage of development these T cells acquire KIR expression. To determine whether KIR expression is a consequence of clonal expansion and replicative senescence, multiple CD4+CD28null T cell clones expressing the in vivo dominant TCR β-chain sequences were identified in three patients and analyzed for their KIR gene expression pattern. Based on sharing of TCR sequences, the clones were grouped into five clone families. The repertoire of KIRs was diverse, even within each clone family; however, the gene expression was not random. Three particular receptors, KIR2DS2, KIR2DL2, and KIR3DL2, had significant differences in gene expression frequencies between the clone families. These data suggest that KIRs are successively acquired after TCR rearrangement, with each clone family developing a dominant expression pattern. The patterns did not segregate with the individual from whom the clones were derived, indicating that peripheral selection in the host environment was not a major shaping force. Several models were examined using a computer algorithm that was designed to simulate the expression of KIRs at various times during T cell proliferation. The computer simulations favored a model in which KIR gene expression is inducible for a limited time during the initial stages of clonal expansion.

Background: Renal involvement in the light chain-associated diseases multiple myeloma (MM), amyloidosis (AL) and monoclonal immune position disease (MIDD) is common and differential diagnosis usually requires renal biopsy. The aim of this study was to investigate if noninvasive methods are viable to identify and differentiate between the various types of kidney diseases. Patients and Methods: All patients with a light chain-associated disease admitted to our center from 1996 to 2008 were retrospectively evaluated. Renal biopsy data were correlated with proteinuria findings. Results: Only the ratio of free ĸ/λ light chains showed a good sensitivity for myeloma cast nephropathy (MCN), AL and MIDD. The λ light chain was characteristic for AL, the ĸ light chain dominated in MIDD. Renal function at the time of diagnosis was worst in MIDD. MCN presented with a proteinuria of >3.5 g/g creatinine. In contrast, a higher proteinuria was found in AL or MIDD. Whereas the ĸ/λ ratio in the urine was pathological for all three diseases, extremely high or low ratios indicated the presence of MCN. However, in AL or MIDD, the ratio was only moderately elevated. Conclusion: A noninvasive differentiation between MCN and other forms of renal light chain disease is possible.

Background Induction triplets utilizing at least one of the “novel drugs” and steroids with or without chemotherapy are considered current standard of care in newly diagnosed, symptomatic multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while use of allogeneic (allo) SCT remains a matter of debate. As we had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory MM, we evaluated this combination in first-line treatment. Methods The current phase II trial (DSMM XII) was designed to include a total of 190 pts up to 65 years of age with symptomatic MM. Four 4-week cycles of RAD (lenalidomide 25 mg/day, d 1-21; adriamycin 9 mg/m² as 24-hour infusion, d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) preceded stem cell chemomobilization. Low-molecular weight heparin for prophylaxis of venous thromboembolic events (VTE) was mandatory. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel200) or auto followed by allo SCT. Allo SCT (preparative regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Lenalidomide maintenance was administered for one year following both tandem auto and auto/allo SCT. This is the second pre-planned interim safety and efficacy analysis. Results Eighty-nine pts with a median age of 54 (range, 30-65) years, who were recruited between August 2009 and October 2010, are evaluable. Fifty pts (56.2%) had ISS stage II/III disease and in all except three, molecular cytogenetic analysis was performed. Incidences of chromosomal abnormalities were as follows: deletion of (del) 13q, 24.7%; translocation t(4;14), 12.4%; t(14;16), 3.4%; and del 17p, 5.6%. Treatment-related mortality with RAD induction was 0% while 61.8% of pts had treatment-emergent SAEs. Seventeen pts (19%) experienced neutropenia of grades 1 to 4. Incidences of severe (grades 3/4) and febrile neutropenia were 5.6 and 1%, respectively. Seven pts each (8%) had pneumonia and VTE, respectively. Post-RAD-induction CR/sCR and at least VGPR rates were 9% and 47.2%, respectively. All 78 pts with at least stable disease successfully mobilized stem cells. Overall response rate (at least partial response, PR) following first SCT on an intention-to-treat basis was 83%. Twelve pts each (13.5%) achieved centrally confirmed complete response (CR) or stringent (s)CR, respectively, and 54 pts (60.7%) had at least very good PR (VGPR). Conclusions This interim analysis shows RAD to be very well tolerated and effective in first line treatment of symptomatic MM. Mel200 further increased rates of deep response (at least VGPR) achieved by RAD induction. We are currently comparing this regimen to bortezomib, lenalidomide and dexamethasone (VRd) in a phase III trial. Disclosures: Knop: Celgene GmbH: Honoraria. Off Label Use: Lenalidomide and doxorubicin in newly diagnosed multiple myeloma. Engelhardt:MSD, Janssen-Cilag: Research Funding. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Bargou:Celgene GmbH: Research Funding.

8001 Background: In younger, medically fit patients (pts) with newly diagnosed (ND) multiple myeloma (MM), autologous stem cell transplant (SCT) remains a standard of care. Prior to SCT, induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks amongst the most effective treatments. VRD + SCT proved superior over VRD alone in a randomized, controlled trial (RCT). We found encouraging efficacy and low toxicity with RAD (RD and adriamycin) + SCT and decided to compare RAD versus VRD induction in an RCT. Methods: The DSMM XIV study was set up according to a double 2x2-factorial design to enroll NDMM pts up to 65 years (yrs). Post-induction (PI) CR rate was the efficacy endpoint for the initial study phase. We hypothesized CR rate with RAD would be non-inferior to an estimated 20% CR with VRD. The study was powered to confirm non-inferiority of RAD at a 10% margin with a one-sided α level of .05. Minimal residual disease (MRD) was analyzed by eight-color flow cytometry (EuroFlow standards) on marrow samples. Results: 476 pts were randomized between 05/2012 and 06/2016, 469 of whom (median age 55 (range, 32–65) yrs) received at least one dose of study drug. 18.3% of pts had ISS stage III MM and 17.2%, elevated LDH. 11.3% of pts had del17p; 11.1% had t(4;14); and 4% had t(14;16). 232 pts were randomized to 3 four-week RAD cycles and 237 to 3 three-week VRD cycles, respectively. 89.7% of RAD versus 93.2% of VRD pts completed all induction cycles. PI CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD versus 13.0% (90% CI, 8.9-18.0) with VRD, (P = .697). 72/317 pts (22.7%) with paired baseline/PI samples achieved negative MRD at a median sensitivity level of 6.73x10-6. 47 (20.3%) RAD versus 35 (14.8%) VRD pts experienced treatment-emergent SAEs (P = .144). Treatment-related induction mortality was 0% in either arm. Conclusions: To the best of our knowledge, this is the first RCT to compare two lenalidomide-based triplets prior to SCT. The endpoint was met with comparable PI CR rates for RAD and VRD, respectively. Tolerability was encouraging in both arms. Follow-up data is needed to analyze time-dependent endpoints. Clinical trial information: NCT01685814.

1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.