We compared the outcomes of multiple myeloma (MM) patients aged 21-40 and 41-60 years in the novel agent era. This case-control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high-risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P < 0·001). Five- and 10-year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P < 0·001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P < 0·001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21-40 years, treated in the era of novel agents have a better OS than their counterparts aged 41-60 years, but the survival advantage observed in younger patients was lost in more advanced stages of MM.

Background: Pomalidomide is a distinct IMiD¨ immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide (LEN) treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report on the clinical benefit of ClaPd with regard to the presence of the negative prognostic features of adverse cytogenetics and prior resistance to novel agents. Methods: One hundred twenty patients (pts) with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included LEN. ClaPd is clarithromycin 500 mg twice daily, pomalidomide 4mg for days 1-21, and dexamethasone 40 mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81 mg aspirin daily. Disease response evaluation was performed monthly with serum and urine protein electrophoresis, immunofixation, and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Cytogenetic testing was performed on CD138-selected cells. Treatment was continued as tolerated by the patient until disease progression. Results: One hundred seventeen pts had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All pts were included in the survival analysis. Median time on study was 7.2 months (range 0.3-55.8). Patients had undergone a median of 5 (range 3-15) prior lines of therapy. High risk cytogenetics were present in 72 patients (64%, n =113) as per IMWG definition. The proportion of patients who were refractory to LEN, refractory to bortezomib (BORT), and double (LEN+BORT) refractory were 84%, 78%, and 68%, respectively. The median number of ClaPd cycles was 8 (range 1-56). Median progression-free survival (PFS) and duration of response for the entire cohort was 7.7 and 9.3 months. Overall response rate for the overall, LEN-refractory, BORT-refractory, and double-refractory cohorts did not differ significantly, Table 1. Median PFS for high vs low-risk cytogenetic groups did not differ significantly: 7.7 vs 8.3 months (P = 0.5038); however, subjects with del17p (n=27) had significantly shorter PFS at 3.73 vs 8.67 months (P = 0.0036). The presence of t(4;14) (n= 11), t(14;16) (n = 7), gain 1q (n = 46) in the absence of concurrent del 17p had no significant impact on PFS. Median PFS was not affected by LEN-refractory, BORT-refractory, or double-refractory MM status at 7.7 (P = .5193), 6.5 (P = 0.2618), and 5.8 months (P = 0.2163) respectively. Median overall survival (OS) for the group was 19.3 months (CI 14.2, 26.7). Loss of 17p was associated with significantly shorter survival at 13.2 vs 25 months (P = .0008). Other adverse cytogenetic factors did not affect OS. Median OS was not affected by LEN-refractory, BORT-refractory, or double-refractory MM status at 19.2 (P = .9355), 16.8 (P = 0.5983), and 16.8 months (P = 0.3893) respectively. Conclusions: ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response rates are higher and survival outcomes are longer than expected from prior reports of Pom/Dex activity in similar populations. The presence of double refractory disease did not significantly impact clinical outcomes. Known adverse cytogenetic factors did not affect observed PFS and OS with the exception of del 17p leading to approximately 50% decrease in PFS and OS. This 17p OS result is consistent with previously reported data by Leleu (2015, OS = 12 months); however for ClaPD, t(4;14) had no impact while Leleu 2015 reported decrease in OS to 9.2 months with Pom/Dex. This finding may be due to sampling error due to the relatively low % of pts with t(4;14) (10%) in our study as opposed to the 64% in the Leleu report. Table 1. Best Response (IMWG Criteria) n (%) Overall (N = 117) Lenalidomide-refractory (n = 101) Bortezomib-refractory (n = 94) Double-Refractory (N = 81) ORR (>= PR) 70 (60) 59 (58) 52 (55) 44 (54) CBR (>= MR) 78 (67) 66 (65) 83 (88) 51 (61) sCR 6 (5) 6 (6) 5 (5) 5 (6) CR 1 (1) 1 (1) 1 (1) 1 (1) VGPR 20 (17) 15 (15) 14 (15) 9 (11) PR 43 (37) 37 (37) 32 (34) 29 (36) MR 8 (7) 7 (7) 7 (9) 7 (9) SD 29 (25) 23 (23) 24 (26) 20 (25) PD 10 (9) 10 (10) 8 (9) 8 (10) Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Off label use of clarithromycin in combination with pomalidomide for treatment of relapsed myeloma. . Rossi:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Huang:Celgene: Research Funding. Chen-Kiang:Celgene: Consultancy. Niesvizky:Celgene: Consultancy, Speakers Bureau.

Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) for years but utilization remains limited. We recently developed a novel immunohistochemical (IHC) co-staining technique for CD138 and Ki67 expression to quantify plasma cells in active cycling. Previously presented results from newly diagnosed patients demonstrate that having an elevated ratio of plasma cells in active cycle by co-expression of CD138 and Ki67 (>5%) is associated with aggressive disease and poor outcomes including shorter overall survival (OS). The expansion of subclones with higher proliferative capacity following initial therapy may be an indicator of a higher risk relapse event and indicate poor prognosis. Here we assess MM patients (pts) with Ki67/CD138 co-staining on bone marrow samples both at diagnosis and relapse to assess the impact of changes in cell cycling ratio on outcomes with subsequent therapy and overall clinical course. Methods: A retrospective cohort study of pts with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital (WCMC/NYPH). For inclusion in the analysis, pts must have had bone marrow evaluation with double-staining for Ki67 and CD138 by immunohistochemistry both at diagnosis and relapse. Pts must have completed their first line and relapse treatments at WCMC/NYPH. The Ki67% was calculated as the ratio of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on alterations in Ki67% between diagnosis and relapse. Results: We identified 37 pts with bone marrow sampling that was evaluated for CD138 and Ki67 co-expression both at diagnosis and at the time of relapse. These pts had undergone a median of 2 lines of prior treatment at the time of relapse bone marrow biopsy (range 1-7). 19 pts were identified to have a rising Ki67% between diagnosis and relapse defined at a 5% or greater increase, the other 18 pts had stable or decreased Ki67%. Pts with a rising Ki67% at relapse had a shorter OS with a median of 72 months vs not reached (p=0.0069), Figure 1. Pts who had rising Ki67% at relapse had shorter progression free survival (PFS) on first line treatment with a median of 25 vs 47 months (p=0.036), Figure 2. Additionally pts with rising Ki67% had a trend towards shorter PFS with the treatment they received after relapse with median of 12.5 vs 3.5 months (p=0.09). Relapse regimens were most commonly carfilzomib (n=9), pomalidomide (5) or ixazomib (4) based. 37% of pts (7/19) with rising Ki67% achieved PR or better on relapsed treatment vs 67% (12/18) with stable Ki67%. Discussion: The presence of clonal evolution and selection of higher risk clones under therapeutic pressure in multiple myeloma is a key feature of disease progression. The ability to improve risk stratification at the time of relapse may help guide clinical decision making to best suit individual patient needs. We have identified rising plasma cell proliferation through quantification of Ki67/CD138 co-expression at relapse to be a useful marker of high risk disease evolution. This appears to help identify the emergence of higher risk clones which are ultimately responsible for treatment resistant disease. Patients with rising Ki67% were more likely than patients with stable Ki67% to have early relapses to initial therapy, were less likely to achieve responses to relapse regimens or to maintain their response and had shorter overall survival. Further evaluation is needed to identify if different approaches to patients with increasing proliferation may improve outcomes in these patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rossi:Calgene: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau.

Background:Rickettsial diseases are reemerging in many parts of our country. Scrub typhus is a rickettsial disease caused by Orientia tsutsugamushi. It is difficult to diagnose Scrub typhus because of nonspecific clinical presentation and lack of availability of specific tests (ELISA) in all centres. Aim: Our aim was to study the clinical features, lab parameters and outcome of patients diagnosed with Scrub typhus. Materials and Methods: A retrospective hospital based study was done in Mangalore (Karnataka) to identify cases of scrub typhus. Patients who had an acute febrile illness and IgM antibodies against O. tsutsugamushi were included in our study. Results: 10 cases of Scrub typhus were identified. Among them 7(70%) patients were females and 3(30%) were males. Major symptoms on admission were fever10(100%), dyspnea or cough-2(20%), rashes1(10%), altered sensorium1(10%). The major signs were fever10(100%), eschar 2(20%), and signs of meningial irritation in 1(10%). Lab parameters showed leukocytosis in 4(40%), thrombocytopenia in 3(30%), raised liver enzymes in 3(30%) and renal failure in 3(30%). Chest X-ray showed consolidation in 2(20%) patients. There was no mortality in our study. Conclusion: Scrub typhus can present with varying clinical manifestations and eschar can be absent in majority of cases as shown in our study. Therefore diagnosis should be based on a high index of suspicion and empirical treatment with doxycycline must be started whenever there is a strong suspicion of Scrub typhus.

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