ALBERT

Description: Background: Increasing evidence suggests that the depth of response in myeloma (MM) correlates with delayed time to progression1.We have previously shown that lenalidomide (Len) can augment vaccine efficacy to the pneumococcal conjugate vaccine (PCV), Prevnar2.We extend those observations to examine whether vaccinating patients on Len in a near complete remission (nCR) (negative M-spike, IFE positive) could further deepen the clinical response and generate measurable myeloma specific immunity in a small Phase II study. Design:Patients needed to be on a Len-containing regimen and needed to be in one of the following categories for enrollment: 1) in a stable nCR for at least 4 months; 2) converting from IFE negative to IFE positive; or 3) showed signs of early relapse from a nCR to an M-spike

Description: Key Points The tumor microenvironment drives myeloma cell clonogenic growth and self-renewal through GDF15.

Description: Background AlloBMT is a potentially curative treatment for multiple myeloma (MM). However, its effectiveness has been compromised by high transplant related mortality (TRM) and acute and/or chronic graft-versus host disease (GvHD). Our development of PTCy has reduced the incidence of GvHD allowing safe and effective related haploidentical alloBMT. PTCy promotes tolerance in both alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloBMT. Patients and Methods As part of an IRB-approved study we performed a retrospective analysis on all patients with MM who underwent alloBMT followed by PTCy. A total of 39 patients who were transplanted between 2003 and 2011 were identified. All patients received 2 doses of PTCy 50mg/kg on days 3 and 4 after alloBMT. High risk MM was defined as having any one of the following: del(13q) by cytogenetics or t(4;14), t(14;16), t(14;20), -17p ,+1q21 on FISH/cytogenetics. International Staging System (ISS) stage was based on beta2 microglobulin and albumin at diagnosis of symptomatic MM. The definitions of progression, stable disease and response were as per the International Myeloma Working Group criteria. Survival probability was determined using Kaplan-Meier method and differences assessed with the log-rank test. Cox regression was used to model prognostic factors with respect to progression-free (PFS) and overall survival (OS) rates. Results The median follow-up for living patients was 80 months (22-115). The minimum follow up was 23 months. The median age at BMT was 54 (range 37-70). 30 patients (77%) received a transplant from a matched sibling donor. Of the remaining 9 patients, 7 (18%) received a transplant from a haploidentical donor and 2 (5%) from a matched unrelated donor. 28 patients (72%) were in 〉 PR at the time of alloBMT. Only 1 patient (3%) was in a CR prior to alloBMT. Thirty patients (77%) received reduced intensity conditioning and the remaining 9 patients (23%) received myeloablative conditioning. 28 patients (72%) received unmanipulated bone marrow, while remaining 11 patients (28%) received mobilized peripheral blood cells. The median time between diagnosis and alloBMT was 10.6 months (4.1-178.7). Cytogenetics and FISH for evaluating high risk MM were available for 26 patients (66.6%) and of those 15 patients (58%) had high risk features. 28 patients (72%) were evaluable for ISS at diagnosis and of those 13 patients (46%) had ISS III at diagnosis. 36 patients (92%) had been treated with either bortezomib based or immunomodulatory (Imid) based therapy prior to alloBMT. 7 patients (18%) had received an autologous transplant prior to alloBMT. 20 patients (51%) are alive after a median follow up of 〉 6 years after alloBMT. Only 1 (2.5%) patient died from complications related to alloBMT. At last follow up, 6 patients (15%) are in sustained first complete remission after alloBMT. Of the 9 patients who received myeloablative prep, 6 are alive and 3 are in sustained CR. At 6 months following alloBMT, 12 patients (31%) were in a deeper response compared to their pre-transplant status. 15 patients (38%) developed 〉 grade 2 acute GvHD at a median of 1.5 (range 0.6-4.5) months. Only 3 patients (8%) developed grade 3 acute GvHD and there was no grade 4 acute GVHD. 14 (36%) patients received systemic treatment for acute GvHD. 5 (13%) patients developed chronic GvHD. The median OS was 96 months, and the median PFS was 14 months (95% CI 6.2-32.8). Chronic GvHD was significantly associated with PFS, with a median PFS of 90 months in patients who developed cGvHD compared to 11 months in patients who did not (hazard ratio = 0.3, 95% CI 0.07-1.25). The major cause of death was disease progression. Conclusion The use of PTCy led to a very low TRM in MM, including with related haploidentical donors. Although only a minority of patients maintained long-term PFS, the prolonged OS allows incorporation of novel post-alloBMT strategies to improve disease control. Disclosures: Off Label Use: Outcomes of Allogeneic Blood Or Marrow Transplantation (AlloBMT) In Multiple Myeloma With Post-Transplantation Cyclophosphamide (PTCy).

Description: Because of its potent immunosuppressive yet stem cell–sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)–matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell–replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).

Description: Key Points Posttransplantation cyclophosphamide is effective as sole GVHD prophylaxis for myeloablative HLA-matched–related or –unrelated BMT. Despite low chronic GVHD with PTCy, relapse and survival are comparable with outcomes reported using other GVHD prophylactic approaches.

Description: Abstract 4002 African-Americans (AA) have a 2–3-fold higher risk of multiple myeloma (MM) relative to Whites (Gebregziabher, 2006). We have formed a consortium and are conducting a multi-center study with 9 clinical centers and 4 NCI Surveillance, Epidemiology and End-Results (SEER) Program population-based cancer registries to determine the causes of the disease in this population and explain the excess risk (Myeloma in African-American Patients, MAP). Participation involves providing a blood or saliva specimen for DNA and answering a lifestyle and medical history questionnaire. At the end of the data collection period, a genome-wide scan will be performed and our results compared to those from 2,000 African-American controls participating in cohort studies. Patients with African ancestry (predominantly African-Americans) are identified from outpatient clinic rosters or from population-based cancer registries. For patients recruited at clinics, information on subtype, cytogenetics, FISH and lytic bone lesions is abstracted from medical records. To date, 601 patients have agreed to be in the study and we have received DNA samples from 592 patients; 54.6% are female and 45.4% are male. The mean age at diagnosis is 57 years (SD =11.2) with a median age at diagnosis of 58 years (range 27 to 90 years of age). Of the 514 subjects who completed a questionnaire, 7.8% were obese at age 20 (body mass index 〉 30) and 39% were obese 5 years prior to diagnosis. A first-degree relative with MM was reported by 17 cases (3%), 74% higher than the lifetime risk of 1.7% in the general population based on SEER data. In addition, cases reported 21 first-degree relatives with leukemia (4%), 7 with non-Hodgkin lymphoma (1%) and 14 with Hodgkin lymphoma (3%). To date, clinical information has been abstracted for 351 patients. Of these, 207 (58%) have active disease with the following distribution: stage I (30%), stage II (27%) and stage III (43%). The remainder have relapsed (13%), refractory (1%), relapsed and refractory (4%), or smoldering myeloma (6%), or are in remission (18%). The subtype distribution is: IgG (74%), IgA (11.4%), IgD (0.9%) and IgM (0.3%), and light chain only (13.5%); a distribution significantly different from that observed in a predominantly White population (P

Description: Introduction: As single agents, Bortezomib (V) and thalidomide (T) have activity in less than 50% of newly diagnosed myeloma (MM) patients whereas combinations with dexamethasone (D) with T (TD) and V (VD) demonstrated response rates of 63% and 85%, respectively. We sought to examine the anti-myeloma activity of VT, a steroid-free regimen. Considering the neurotoxicity of both agents, we examined the baseline neuropathy and progression of neurotoxicity post-VT. Methods: Eligible patients had untreated Salmon-Durie Stage II/III MM and an ECOG performance status ≤2. V was given 1.3mg/m2 i.v. on days 1, 4, 8, 11 every 21 days. T was started at 50mg daily and increased weekly to 150mg. Patients were treated for a minimum of 4 (evaluable), but to a maximum of 8 cycles. The neurologic evaluation utilized the reduced Total Neuropathy Score (rTNS), a validated scoring system combining symptoms, signs and nerve conduction studies. The rTNS was measured at baseline and after every 2 cycles. rTNS scores range between 0 to 32. Results: 30 patients have been enrolled and 27 are evaluable for response. Median age is 59 (37–83), b2-microglobulin 3.3 (1.2–36.9), and albumin 3.6 (2.3–5.2). The mean dose of V was 1.11mg/m2 and of T 110 mg/d. A dose reduction for ≥1 agent was required in all patients. Treatment was discontinued in 5 patients due to neurotoxicity, and 1 due to disease progression. A ≥ 50% reduction in M-spikes was observed in 82% of patients with 31% achieving undetectable levels. Median time to best response was 5 cycles (range 2–8). Clinical evidence of baseline peripheral neuropathy (PN) was noted in 15%, whereas 67% had abnormal baseline skin biopsies. By cycle 5 all patients developed PN: rTNS 2–8, (grade 1) 50%; rTNS 9–16 (grade 2) 31%; rTNS 17–24 (grade 3) 15%; and rTNS 25–32 (grade 4) 4%. There was no correlation between severity of PN and the cumulative V/T doses. Neuropathic symptoms improved with T/V dose reductions. Additional common adverse events (≥ grade 2) included fatigue 57%, constipation 52%, generalized pain 44%, and leg cramps 23%. Although the incidence of thromboembolic events with steroid-containing regimens ranges between 15–20%, no deep vein thromboses occurred in this study. Conclusions: The VT combination achieved an 82% response rate in previously untreated multiple myeloma patients. No DVTs occurred with this steroid-free combination. This study established the baseline PN in newly diagnosed, untreated myeloma patients and demonstrated progression of neuropathy post-VT therapy. Future studies utilizing neuropathic preventive agents, lower doses of VT, or V in combination with other agents may yield similar disease responses with reduced neuropathic toxicities.

Description: Although most patients with cancer respond to therapy, few are cured. Moreover, objective clinical responses to treatment often do not even translate into substantial improvements in overall survival. For example, patients with indolent lymphoma who achieved a complete remission with conventional-dose therapies in the prerituximab era did not experience a survival advantage over similar patients treated with a “watch and wait” approach. Several studies have also shown that neither the magnitude nor the kinetics of clinical response has an impact on survival in multiple myeloma. Recent data suggesting many malignancies arise from a rare population of cells that exclusively maintains the ability to self-renew and sustains the tumor (ie, “cancer stem cells”) may help explain this paradox that response and survival are not always linked. Therapies that successfully eliminate the differentiated cancer cells characterizing the tumor may be ineffective against rare, biologically distinct cancer stem cells. New methods for assessing treatment efficacy must also be developed, as traditional response criteria measure tumor bulk and may not reflect changes in rare cancer stem cell populations. In this article, we discuss the evidence for cancer stem cells in hematologic malignancies and possible ways to begin targeting these cells and measuring clinical effectiveness of such treatment approaches.

Description: We recently demonstrated that multiple myeloma (MM) is organized in a hierarchical manner in which clonogenic MM progenitors or stem cells resembling post-germinal B cells give rise to MM plasma cells (PC). To study the potential biologic differences between MM stem cells and MM PC, we examined each cellular subset for characteristics found in normal stem cells as well as their responses to various antitumor agents. The human MM cell lines RPMI 8226 and NCI-H929 were initially studied as we previously found that they recapitulate clinical MM specimens and consist of distinct cell populations based on the expression of the PC surface antigen CD138; CD138+ cells resemble typical MM PC, whereas CD138neg cells express B cell surface antigens and have greater clonogenic capacity. Examination of these cellular subpopulations by flow cytometry demonstrated that CD138neg cells were smaller and less granular by light scatter than CD138+ PC and expressed higher levels of the intracellular enzyme aldehyde dehydrogenase that is present in normal hematopoietic progenitors with self-renewal potential. Furthermore, cells expressing the side population phenotype after staining with the DNA binding dye Hoechst 33342 were exclusively CD138neg. We also investigated the effects of different clinically applicable agents on CD138+ and CD138neg cells. CD138+ and CD138neg cells isolated from RPMI 8226 and NCI-H929 cells by fluorescence activated cell sorting were treated with dexamethasone (dex, 100nM), bortezomib (velcade, 10nM), CC5013 (revlimid, 1μM), rituximab (10μg/ml) or alemtuzumab (campath,10μg/ml) for 72 hours followed by plating in methylcellulose to assess clonogenic capacity. CD138+ PC were significantly inhibited by dex (27 ± 11% recovery compared to untreated control cells), velcade (14 ± 6%) and revlimid (44 ± 27%), whereas rituximab (92 ± 25%) and campath (97 ± 18%) had little activity. In contrast, clonogenic growth of CD138neg cells was not significantly inhibited by dex (82 ± 19%), velcade (88 ± 29%), or revlimid (91 ± 14%), but was significantly decreased by rituximab (63 ± 22%) and campath (47 ± 27%). Similarly, clonogenic MM growth of CD138neg cells from 4 clinical MM samples was not affected by dex (84 ± 9%), velcade (82 ± 24%), or revlimid (93 ± 11%), but was significantly inhibited by rituximab (19 ± 7%) or campath (15 ± 11%). Clonogenic MM precursors may be distinguished from MM PC by a variety of biological parameters typically expressed by normal stem cells. Furthermore, these cellular subsets have different susceptibilities to a variety of clinical agents, and agents with activity against MM PC may be ineffective against MM stem cells. Moreover, agents without activity agasint MM PC may have major activity against MM stem cells. The divergent sensitivities of MM stem cells and PC may explain the dramatic, but transient, responses seen with many agents. Therapeutic strategies that result in long-term remissions may require the inhibition of both MM PC to reduce clinical symptoms and MM stem cells responsible for relapse.

Description: Abstract 5090 Lymphoplasmacytic lymphoma (LPL) is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells, which does not fulfill criteria for any of the other small B-cell lymphoid neoplasms (WHO 2008). Neuropathy has been described in association with Waldenstrom's macroglobulinemia, but less so with LPL. We present 7 cases of neuropathy and LPL to highlight the variable presentations. 1) A 56 year old man developed sensory ataxia with an IgM kappa non-MAG paraprotein. CSF protein was 97. Stabilized on MMF, he slowly worsened. Plasma exchange (PE) was given with improvement. Bone marrow (BM) 4 years into his course revealed LPL. Rituximab was given, and his PE reduced. 2) A 49 year old woman developed progressive weakness with rapid decline in January 2010. NCS showed demyelinating polyneuropathy, and CSF protein was 179. An IgM kappa non-MAG paraprotein was found. BM was normal. PE was given with improvement but later prednisone, IVIg and rituximab twice did not help. Repeat BM revealed 2% clonal CD20+ CD5negCD10neg B cells by flow cytometry. PE was given with modest improvement. Cyclophosphamide 1 gm/m2 monthly was given with improvement. 3) A 53 year old man noted imbalance and distal weakness. NCS showed absent SAPs and prolonged distal and F wave latencies. An anti-MAG positive, IgM kappa paraprotein was found. In 2002 BM was normal. He received rituximab weekly × 4 doses. 7 years later, he developed anemia and worsening neuropathy. Repeat BM showed 0.5% CD20+CD5negCD10neg kappa-restricted B cells by flow cytometry and weekly rituximab was reinitiated. 4) A 62 year old man developed weakness and areflexia. NCS showed asymmetric demyelinating polyneuropathy. Biclonal gammopathy of IgM kappa and IgG kappa was found. BM showed LPL by histopathology. Prednisone was given with improvement. Later two courses of weekly rituximab were given. 5) A 55 year old woman developed asymmetric weakness. NCS showed asymmetric demyelinating polyneuropathy. MRI showed enlargement, abnormal signal intensity, and abnormal enhancement of bilateral radial, median, and ulnar nerves. She was found to have an IgG kappa paraprotein and LPL on BM biopsy. She was treated with rituximab, cyclophosphamide, fludarabine, and PE. In each case, the primary feature driving the need for therapy was the neuropathy and not the underlying hematologic process. Further, worsening neuropathy in 3 cases led to repeat bone marrow biopsies revealing a clonal B cell process and a diagnosis of lymphoplasmacytic lymphoma. Thus, in the presence of an IgM monoclonal gammopathy and peripheral neuropathy, we suggest bone marrow examination for LPL and then consideration of therapy directed toward the abnormal B cell clone. Disclosures: No relevant conflicts of interest to declare.