Salvage Therapy For Multiple Myeloma Research Articles

Pomalidomide and dexamethasone until progression after first salvage therapy in multiple myeloma.

Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response.

Second Autologous Stem Cell Transplant As Salvage Therapy in Multiple Myeloma - the Oregon Health and Science University Experience

Background: Though the available number and efficacy of novel agents for multiple myeloma (MM) have improved in recent years, it remains an incurable disease with relapse inevitable in nearly all patients. Autologous stem cell transplantation (ASCT) as consolidation after induction remains the standard of care for transplant-eligible patients with randomized studies showing progression-free survival (PFS) greater than 4 years (Atttal et al., N Engl J Med 2017; 376:1311-1320). Relapse outcomes are also improving with PFS now greater than 3 years in some settings (Bahlis, et al., Leukemia 2020 Jul;34(7):1875-1884). For fit patients with good response to a first ASCT, a second autologous transplant (SAT) can be considered. The American Society for Blood and Marrow Transplantation (ASBMT) and the International Myeloma Working Group (IMWG) guidelines suggest SAT should be considered for those whose first ASCT resulted in remission duration >18 months (Giralt et al., Biol Blood Marrow Transplant 2015; 21:2039-2051). CIBMTR data note 600-700 SATs are performed annually. Most data on SAT come from single-center retrospective series, though pooled analyses note median PFS >1 year and median OS >30 months (Hagen and Stiff, Biol Blood Marrow Transplant 2019 Mar;25(3):e98-e107). Here we present our institution's experience with salvage SAT for MM analyzing treatment outcomes and toxicities. Methods: We performed a single-center retrospective review of all MM patients at Oregon Health and Science University who received SAT for myeloma as salvage therapy. Planned tandem transplants were excluded. Demographic and disease characteristic data at time of original diagnosis and at time of SAT were extracted and responses assessed by IMWG criteria. OS and PFS from SAT were calculated by Kaplan Meier method with progression or death from any cause counted as events for PFS and censoring at last known follow-up for live patients. Results: Baseline characteristics: Sixty-eight patients were identified who received SAT between 1999 and 2020. Durie-Salmon staging at diagnosis was available for 30 patients; 16 (24%) 3A, 7 (10%) 2A, 1 1B (1%), 6 (9%) 3b. The median age at time of SAT was 61 (range 45 -74). The median time between first and second ASCT was 5.5 years, (range 1.1 -15.2 years). Median PFS after first ASCT could be calculated for 53 patients and found to be 2.5 years (range 0.3 - 10). First ASCT conditioning regimen and dosing were available for 56 patients; 55 (81%) received melphalan with 53 (78%) receiving 200mg/m2, 2 (3%) receiving 140mg/m2, 1 (2%) received busulfan + TBI. The average number of lines of therapy prior to SAT was 2.8 (range 1-14). SAT preparative regimens were available for 67 patients: 59 (87%) received melphalan 200mg/m2, 6 (9%) received melphalan 140mg/m2, 1 (2%) received BEAM, 1 (2%) received melphalan 200mg/m2 and bortezomib. All SAT patients received peripheral blood stem cell mobilization. Outcomes: 37 (54%) patients have died at time of data collection. Median OS after SAT was 3.09 years while median PFS was 1.65 years. Treatment related mortality (TRM, defined as death not due to progression within 100 days of SAT) occurred in 1 patient (2%). Long term complications included 10 patients found with other malignancies after SAT (5 with basal or squamous cell skin carcinoma, 2 with MDS, 2 GI malignancies, 1 prostate). Conclusion: Our institution's experience with SAT for MM suggests it's an effective salvage treatment with low treatment-related mortality, though with a shorter PFS than after first transplant. Most patients were able to receive and tolerate full dose melphalan 200mg/m2 for SAT. Disclosures Silbermann: Sanofi-Aventis: Consultancy, Research Funding; Janssen: Consultancy; Karyopharm: Consultancy. Maziarz:Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding; Novartis and Athersys: Other: DSMB participant; Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Athersys: Patents & Royalties.

Is re-challenge still an option as salvage therapy in multiple myeloma? The case of REal-life BOrtezomib re-Use as secoND treatment for relapsed patients exposed frontline to bortezomib-based therapies (the REBOUND Study).

Therapeutic re-challenge is currently a debated issue in the field of multiple myeloma (MM), given the recent availability of several new drugs and combinations. However, very few specific evidences are available about bortezomib re-use at first relapse. This multicenter, observational, retrospective study enrolled 134 MM patients with significant response after bortezomib-based frontline regimens and who had received a first salvage treatment containing bortezomib at relapse. The overall response rate was 71%, including 40% partial responses, 24% very good partial responses, and 7% complete responses. Re-treatment was well-tolerated, with no significant new or unexpected toxicities observed. The median duration of second progression-free survival (PFS) was 15months, while median PFS2 was 55months. With a median follow-up of 56months, overall survival was 94months for the entire series, without significant differences between patients undergoing or not undergoing transplant procedures. This real-life survey indicates that re-treatment including bortezomib as a first salvage therapy could be still considered in MM patients achieving durable response after initial exposure to bortezomib.

Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party

We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.

Outcome of first salvage therapy for multiple myeloma (MM) in real-world clinical practice: Results from the third interim analysis of the multinational, observational, non-interventional EMMOS study

Outcome of first salvage therapy for multiple myeloma (MM) in real-world clinical practice: Results from the third interim analysis of the multinational, observational, non-interventional EMMOS study

Salvage Therapy for Multiple Myeloma with Lenalidomide-Based Regimens: Impact of Single Nucleotide Polymorphisms Related to miRNA Pathways

Introduction: Multiple myeloma (MM) remains an incurable disease for most patients. Thus, sequential therapy when relapse or progression after first line is almost always needed. Immunomodulatory agents derived from thalidomide such as lenalidomide, has several antitumoral effects including anti-proliferative and immune-modulation by binding the intracellular protein cereblon. Lenalidomide has been approved for the treatment of relapsed or refractory MM in Europe and USA. The possibility of using biological predictors of response with this regimen could be promising. A group of genetic normal variations in DNA, mainly single nucleotide polymorphisms (SNPs), have been described in association with response to treatment in MM. A distinctive group of polymorphisms is constituted by SNPs in microRNAs (miRNA) processing machinery in miRNA precursor molecules and in miRNA binding sites, known as miRSNPs, that we have associated with response to autologous transplantation and bortezomib. The aim of this study was to ascertain the outcome of patients with relapsed myeloma treated with lenalidomide in a tertiary hospital as to investigate the prognostic impact of 9 miRSNPs located either in MM related miRNAs target genes or in miRNA biogenesis pathway proteinsMethods: One hundred and three patients (54M/49F; median age 65 years, range 30 to 86) with relapsed MM after at least one treatment regimen were treated from November 2003 to January 2014 with lenalidomide plus dexamethasone. Median follow-up for alive patients was 3 years. Patients had received a median number of 2 treatment lines (range 1 – 6), but with no lenalidomide-based regimens.Genomic DNA was isolated from bone marrow slides using a commercial kit (Qiagen). The genes and SNPs evaluated in genomic DNA by allelic discrimination (TaqMan assays) were KRT81 (rs3660), FAM179b (rs1053667), MIR146A (rs2910164), MIR196A2 (rs11614913), MIR149 (rs2292832) and MIR423 (rs6505162) for miRNA target genes, and RAN (rs14035), TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. These genes were selected based on their potential impact on prognosis in solid tumors in previous reports.Results: Overall response (OR) was achieved in 55.4% of the patients (complete remission 6.8%, partial response 40.8% and minor response 7.8%), while 16 (15.5%) and 26 (25.2%) showed no response (NR) or progressive disease (PD), respectively. 4 patients (3.9%) died before response could be evaluated. The median progression-free survival (PFS) after lenalidomide therapy was 8.1 months (95% CI 7.3 to 8.9), with a median overall survival (OS) of 2.3 years (95% CI 1.5 to 3.2). OS was significantly shorter in those patients not reaching at least MR (1 vs. 3.7 years; p<0.0001). Six patients did not progress during the first 5 years of treatment: two have died for unrelated causes; two progressed biologically but no requiring further treatments and the remaining two are in continued response while on therapy. Only 8 responding patients (7.8%) in whom therapy with lenalidomide was discontinued received re-treatment with lenalidomide at progression.OS was significantly longer in patients with SNP in FAM179b (p=0.041) (Figure 1) and MIR196A2 (p=0.01) (Figure 2), with a trend for MIR149 (p=0.117). In the two first SNPs, there were also a significant impact in PFS after lenalidomide regimen (p=0.024 and p=0.018). Interestingly, these miRSNPs have not shown the same impact as previously reported when autologous transplantation or bortezomib are used, where XPO5 is the crucial gene. Other factors associated with longer OS included lenalidomide at first relapse vs. subsequent lines (p=0.002), IgG isotype (p=0.044), normal serum LDH (p=0.032) and a trend for creatinine lower than 2 mg/dL (p=0.08) at diagnosis. In a multivariate analysis for OS, only the use of lenalidomide at first relapse (HR 2, 95% IC 1.04-3.9; p=0.039) and SNP in MIR196A2 (HR 1.86, 95% IC 1.03-3.4; p=0.04) remained at significant level.Conclusions: Lenalidomide plus dexamethasone is a very active regimen when used in daily clinical practice, particularly at the time of first relapse. A small subgroup of patients can remain disease-free for more than 5 years. Some SNPs in miRNA target genes (FAM179b and, particularly, MIR196A) could be useful as potential predictors of response. [Display omitted] DisclosuresFernández de Larrea:Celgene: Consultancy, Honoraria. Cibeira:Celgene: Consultancy, Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Jiménez:Janssen: Honoraria. Bladé:Janssen: Grant support Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Bortezomib‐Induced Sweet's Syndrome Confirmed by Rechallenge

Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized predominantly by fever, elevated neutrophil count, and erythematous skin lesions composed of plaques and nodules that appear on upper extremities, face, or neck. The incidence of Sweet's syndrome in the general population is unknown due to the rarity of the condition and potential lack of reporting. Bortezomib, an antineoplastic agent that is the standard of care in patients with multiple myeloma, has been reported to be associated with Sweet's syndrome. We describe a 69-year-old man who developed Sweet's syndrome during his initial course (after cycle 4) of bortezomib for treatment of multiple myeloma; he again experienced Sweet's syndrome 3.5 years later when rechallenged with bortezomib (after cycle 5) for treatment of relapsed multiple myeloma. The patient's signs, symptoms, and biopsy results were identical during both presentations of Sweet's syndrome. In both instances, the syndrome spontaneously resolved without incident and without supportive treatment with corticosteroids or antihistamines. To our knowledge, this is the first case report of a patient who developed Sweet's syndrome during an initial course of treatment with bortezomib and after rechallenge with bortezomib for relapsed disease. As proteasome inhibitors continue to be a mainstay of therapy for both treatment and salvage therapy for multiple myeloma, this case demonstrates that rechallenge with bortezomib is an option for patients who develop Sweet's syndrome.

Second autologous transplant as salvage therapy in multiple myeloma

High-dose chemotherapy followed by autologous haematopoetic stem cell transplantation (ASCT) is a standard frontline therapy for multiple myeloma (MM). Unfortunately, there are no randomized clinical studies examining the role of a second ASCT in patients who relapse after the initial autotransplant. Analysing all available retrospective studies, it seems that salvage ASCT can safely be performed in most patients with an overall treatment-related mortality rate <5%. Approximately 65% of patients will achieve an objective response and progression-free and overall survival will be around 12months and 32months, respectively. Retrospective data suggest that patients with a progression-free survival of ≥18months after initial ASCT are most likely to benefit from a salvage autotransplant. However, patients with a <12-month duration of response after initial ASCT should not be considered for a second autograft in the relapsed setting because this group will probably only experience ASCT-related toxicity without any clinical benefit. Quality of response after initial ASCT and number of therapies preceding salvage ASCT may also have a predictive value. Importantly, these findings need to be verified by randomized clinical trials in order to firmly integrate salvage ASCT into a global therapeutic concept for myeloma patients including optimized induction, consolidation, and maintenance approaches.

Autologous Stem Cell Transplantation: An Effective Salvage Therapy in Multiple Myeloma

Eighty-one patients treated with high-dose therapy and autologous stem cell transplantation (ASCT) as part of salvage therapy after a frontline ASCT were included in a retrospective analysis. The median time between the first and the salvage ASCT was 47 months. After salvage ASCT, 75 patients (93%) achieved at least a partial response, including 67% very good partial responses, and no toxic death was reported. Sixteen patients (20%) underwent consolidation therapy, whereas 30 patients (37%) underwent some form of maintenance therapy after salvage ASCT. For all patients, the median overall survival (OS) was 10 years from diagnosis and 4 years from salvage ASCT. The median progression-free survival (PFS) from the date of the first ASCT to the date of the first relapse was 40 months, and the median PFS from the date of salvage ASCT to the date of subsequent progression was 18 months. In the multivariate analysis of prognostic factors, three independent factors unfavorably affected PFS: a short duration of response to the first ASCT (cut-off value of 24 months), a response less than a very good partial response after salvage therapy, and no maintenance treatment after salvage ASCT. Age over 60 years and a short duration of response after the first ASCT were the two factors adversely affecting OS from the time of diagnosis and OS from the time of salvage ASCT. Our data show that salvage ASCT is a feasible option that should be routinely considered at the time of relapse for patients with a response duration of more than 2 years to frontline high-dose therapy.

Bendamustine As Salvage Therapy in Multiple Myeloma: A Retrospective, Multicenter Study From the Italian Compassionate Use Program in 78 Heavily Pre-Treated Patients.

AbstractAbstract 2971 Introduction:Bendamustine is a bifunctional alkylating agent approved for the treatment of several lymphoproliferative disorders. Studies have evidenced its efficacy in multiple myeloma (MM), but data so far available in this setting are scarce. We performed a retrospective analysis of Italian patients with relapsed/refractory MM, who had received bendamustine as salvage therapy within a national compassionate use program. Patients and methods:Seventy-eight patients (42 males, 36 females) were collected in 19 hematological centers. Mean age was 64.2 years (range 38–84). ISS was equally distributed, with about one third of patents being represented in single stages. Twenty-three of 43 analyzed patients had cytogenetic abnormalities, the most frequent being del13q (14 patients); t(4;14) and t(11;14) were observed in 4 and 2 patients, respectively, while t(6;14), del17p or complex karyotype occurred in single patients. The median number of prior lines of therapy was 4 (range 1–10). Ninety-seven percent of patients had previously received bortezomib, 94% IMIDs, 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, 33% radiotherapy. Sixty percent of patients had undergone autologous and 4% allogeneic stem cell transplantation. The last treatment before bendamustine was a bortezomib-based regimen in 31%, an IMIDs-based regimen in 42%, a combined bortezomib/IMIDs-based regimen in 9%, while 18% of patients had received other therapies. Seventy-three percent of patients were resistant to last therapy received, while 27% had relapsed. Median duration of response to last treatment received before bendamustine was 9 months (range 2–46). Median Hb value was 10.1 g/dl (range 7.6–14.9), WBC count 2.700/μl (range 550–15.200), PLT count 130.000/μl (range 6.000–410.000). Serum creatinine, calcium, beta2-microglobulin and LDH levels were increased in 12 (15%), 4 (5%), and 44 (56%) patients, respectively, while albumin levels were decreased in 27 patients (35%). The median percentage of marrow plasma cells (as evaluated in 57 cases) was 60% (range 1–100). Seventy-six percent of patients had osteolytic bone involvement and 78% extramedullary localizations, with 13% showing secondary plasma cell leukemia and 7% documented amyloidosis or proteinuria. Finally, 45% of patients presented with at least one severe comorbidity, mainly cardio-vascular, liver or pulmonary dysfunction, and diabetes. Results:A total of 236 cycles was administered (median 3, range 1–9). In 47% of patients bendamustine was variously associated to bortezomib (23%), or IMIDs (21%), or to a combination of both (3%). In 80% of patients receiving bendamustine +/− steroids, a median dose of 90 mg/sqm for two consecutive days every 28 days was employed; the median dose was 80 mg/sqm when bendamustine was combined with bortezomib, 60 mg/sqm with IMIDs (total range: 40–140 mg/sqm). The remaining patients received single, monthly doses ranging from 60 to 150 mg/sqm. According to IMWG uniform response criteria, 21 out of 73 evaluable patients achieved a response after a median time of 3 months. In particular, there were 16 PR, 1 VGPR, 1 sCR, and 3 CR; overall response rate (ORR) was, therefore, 29%. Response rate was 10% (4/39) in bendamustine single agent +/− steroids, 38% (5/13) in bendamustine + bortezomib and 62% (10/16) in bendamustine + IMIDs subgroups, respectively. Responders had received a lower number of previous treatments than non responders (median 3 vs 4). Response rate was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months. After a median follow-up of 8 months, median PFS duration was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non responders, range 0–27). Grade 3–4 hematological and non-hematological toxicities occurred in 56% and 15% of patients, respectively, causing three interruptions of the treatment. Conclusions:Though with the clear limits due to the high heterogeneity of treatments applied and of population analyzed, our data indicate that bendamustine may be a therapeutic option in heavily pretreated MM, suggesting a possible non cross-resistance with other agents. Its earlier use with appropriate doses and combinations might further improve the results obtained in this study. Disclosures:Musto:Mundipharma: Honoraria. Off Label Use: Bendamustine in relapsed/refractory myeloma. Fragasso:Mundipharma: Honoraria. Baldini:Mundipharma: Honoraria. Storti:Mundipharma: Honoraria.

Management of myeloma-associated renal dysfunction in the era of novel therapies

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.

The Impact of Co-Morbidities on the Outcome of Autologous Stem Cell Transplantation for Multiple Myeloma

Abstract 4511 Introduction:Autologous stem cell transplantation (ASCT) is used as an upfront and salvage therapy for multiple myeloma (MM). We assessed the prognostic value of pre-transplant co-morbidity on the transplant outcome. Method:We analyzed the data of 162 patients with MM who underwent single ASCT between 2004 and 2009 in our center. Pre-transplant co-morbidity was scored according to the hematopoietic cell transplant co-morbidity index (HCT-CI). Data were tabulated and statistical difference was calculated using t-test and Chi square test. Correlation coefficiency test was used to correlate HCI-CI with data of continuous variables. Probabilities of overall survival were analyzed using Kaplan-Meier analysis. Result:The median follow up after transplant was 23 months (range: 0.7–78). The median age at transplant was 60 years (range: 34–77), males were 64%. A total of 130 patients (80%) had transplant at ≤ 12 months from diagnosis. The proportion of IgG, IgA and free light chain subtypes was 54, 24 and 17% respectively. Durie Salmon stage at diagnosis was stage I (8%), II (12%), III (60%) respectively. The median HCT-CI was 2 (range: 0–8). HCT-CI was 0, 1–2, >2 in 27%, 32%, and 41% respectively. There was no significant correlation between HCT-CI and time to engraft or length of stay. Patients with HCT-CI of 0–2 (group 1; n= 95) and >2 (group 2; n=67) had a re-admission rate (within 30 days) of 13.7% and 21% respectively (p=0.23). Group 1 had non-relapse mortality (NRM) of 0% at 18 months, while group 2 had NRM of 2% and 2.5% at 6 months and 18 months respectively (p= 0.02). There was no significant difference in the OS; not reached and 60 months in group 1 and 2 respectively (p=0.3). Conclusion:These data show that high pre-transplant HCT-CI is associated with higher NRM following ASCT for multiple myeloma. This finding needs to be validated in a large cohort of patients. Disclosures:No relevant conflicts of interest to declare.

Second Autologous Stem Cell Transplantation as Salvage Therapy for Multiple Myeloma: Impact on Progression-Free and Overall Survival

The role of a second autologous stem cell transplant (ASCT) as salvage therapy is unclear, particularly with the availability of novel agents to treat progressive multiple myeloma (MM). We retrospectively reviewed all MM patients who received a second ASCT as salvage therapy at our center from March 1992 to December 2009. Eighty-one MM patients received a second ASCT for relapsed MM. The median time to relapse after first transplant was 39 months (9.83-100). All patients received reinduction therapy before the second ASCT. The high-dose regimen given before the second ASCT consisted of melphalan (MEL) alone in the majority. Complete response, very good partial response, and partial response were seen in 7.7%, 39.7%, and 50%, respectively, at day 100 post-ASCT; the median time to relapse after the second ASCT was 19 months. Early deaths occurred in 2.6%. Median progression-free survival (PFS) based on the time to myeloma relapse after first ASCT was 9.83 months (relapse ≤ 24 months) and 17.3 months (relapse ≥ 24 months) (P < .05). Median overall survival (OS) was 28.47 months (relapse ≤ 24 months) and 71.3 months (relapse >24 months) (P = .006). Second ASCT is a feasible and safe option for salvage therapy in MM. The best outcome was observed in patients whose time to progression was >24 months after first ASCT, as these patients had a subsequent PFS lasting over 1 year and an OS of almost 6 years.

Plasma cell leukemia

Plasma cell leukemia (PCL) is a rare, yet aggressive plasma cell (PC) neoplasm, variant of multiple myeloma (MM), characterized by high levels of PCs circulating in the peripheral blood. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of MM (secondary PCL). Presenting signs and symptoms are similar to those seen in MM such as renal insufficiency, hypercalcemia, lytic bone lesions, anemia, and thrombocytopenia, but can also include hepatomegaly and splenomegaly. The diagnostic evaluation of a patient with suspected PCL should include a review of the peripheral blood smear, bone marrow aspiration and biopsy, serum protein electrophoresis (SPEP) with immunofixation, and protein electrophoresis of an aliquot from a 24h urine collection (UPEP). The diagnosis is made when a monoclonal population of PCs is present in the peripheral blood with an absolute PC count exceeding 2000/μL and PC comprising 20% or more of the peripheral blood white cells. The prognosis of PCL is poor with a median survival of 7 to 11 months. Survival is even shorter (2 to 7 months) when PCL occurs in the context of refractory or relapsing MM. There have been no prospective randomized trials investigating the treatment of PCL. Recommendations are primarily based upon data from small retrospective series, case reports, and extrapolation of data from patients with MM. In general, patients are treated with induction therapy followed by hematopoietic cell transplantation (HCT) in those who are appropriate candidates for this approach. The best induction regimen for PCL is not known and there is great variability in clinical practice. Newer agents that are being incorporated into frontline and salvage therapy for MM have also demonstrated activity in PCL such as Immunomodulatory agents and the use of bortezomib with different combinations.

Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma

The purpose of this study was to evaluate the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone (CP) as a salvage therapy for multiple myeloma (MM). A total of 27 consecutive patients with MM received a treatment regimen that consisted of oral cyclophosphamide 50 mg and prednisone 15 mg daily. Nineteen patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy as a result of severe infection associated with the conventional chemotherapy. Patients had received 1 to 4 chemotherapeutic regimens before the enrollment. The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival (PFS) has not been reached. In the nonresponding patients, the median PFS was 4 months. Continuous low-dose CP is an effective and well-tolerated salvage therapy for MM.

Influenza (flu) Vaccine Administration to Patients with Multiple Myeloma (MM) Prior to Autologous T-Cell Harvest Leads to Better Reconstitution of Flu Immunity After High Dose Melphalan and Autologous Stem Cell Transplant (ASCT) and Reinfusion of Primed Ex-Vivo Co-Stimulated Autologous T-Cells and Post-ASCT Second Flu Vaccination Than Post-ASCT Flu Vaccination Alone.

Abstract 797 Introduction:Epidemics of influenza A virus strains have been associated with a mortality rate of 0.1% and hospitalization of approximately 200,000 people per year in the United States. The recent pandemic of swine-origin H1N1 has further emphasized the need to protect the population. Patients with multiple myeloma (MM) are particularly vulnerable to flu infection from altered humoral and cellular immunity from the disease as well as from the immunosuppressive chemotherapies, corticosteroids and radiation frequently used for treatment. In particular, high dose melphalan and ASCT, a common and efficacious treatment as part of first-line or salvage therapy for MM, is associated with post-ASCT immune suppression by virtue of low T-cell numbers, poor T-cell function and immune paresis. Despite anti-infection vaccination after ASCT, pneumococcal pneumonia and influenza are common. In an attempt to improve this outcome we previously showed that adoptive transfer of in-vivo PCV vaccine-primed and ex-vivo (anti-CD3/anti-CD28) co-stimulated autologous T cells (aT-cells) early (within 14 days) post-ASCT increased CD4 and CD8 T cell counts and induced pneumococcal conjugate vaccine-directed T and B-cell responses [Rapoport et al, Nature Medicine, 2005]. Patients who did not receive pre-collection vaccination did not show this response despite infusion of co-stimulated T-cells and post-ASCT vaccination. In the current clinical trial we investigated whether pre-harvest flu vaccination would result in a similar improvement in immunity. Methods:We performed a randomized open-label single center study of two influenza vaccine schedules for patients with high-risk MM responding after conventional induction therapy. Of 21 patients enrolled, 11 were randomly assigned to Group X and received pre- and d+14 post-transplant flu vaccine with the commercially available influenza vaccine (Fluzone) produced by Aventis Pasteur. The 10 patients in Group Y received only post-transplant vaccination. All patients received T-cell harvest, high dose melphalan and ASCT and aT-cell infusion. Immunological assessment (T-cell and B-cell subsets, T-cell repertoire, T-ELISPOT, CFSE-CBC, antibody HAI, B-ELISPOT) was conducted d+60, 100 and 180. The primary study endpoint is the immune response to influenza as measured by the serotype-specific influenza antibody response on day 100 using a standard hemagglutination inhibition assay (HAI) optimized for the vaccine administered each year. Results:The median age was 55 (range 37-68), 13 M, 8 F, 18 Caucasian, 2 African American, 1 Hispanic, IgG 57%, IgA 33%, light chain 10%. With a median follow-up of 1 year, 86% (18/21) patients are alive with 48% (10/21) alive in remission. No difference in these parameters was seen between both Groups. HAI titers, however were higher at all three time points (d+60, 100, 180) for Group X when compared to Group Y both for H3N2 (p= 0.04) and for H1N1 (p=0.07). HAI titers for Group Y remained near baseline throughout all time points while Group X peaked day 60 and remained elevated day 180. Analysis of other immune assessment is ongoing and will be presented. Conclusion:Preliminary analysis of this randomized trial of flu vaccine schedule for MM patients undergoing ASCT suggests superior flu immune reconstitution when vaccine is administered to prime autologous T-cells prior ASCT and aT-cell infusion. This result adds to our observation that an approach of vaccine priming and co-stimulated autologous T-cell infusion after high dose melphalan and ASCT for MM augments an otherwise poor response in this patient population to pneumococcal and influenza vaccination. Investigation of this approach as a platform for anti-myeloma immune therapy is ongoing. [Display omitted] Disclosures:June:University of Pennsylvania: Patents & Royalties.

Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma.

Abstract 4962 ObjectiveTo assess the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone regimen (CP) as a salvage therapy for multiple myeloma (MM). MethodThe CP regimen consisted of oral cyclophosphamide at 50 mg and prednisone at 15 mg daily. A total of 27 consecutive patients received the CP regimen: 19 patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy due to severe infection associated with conventional treatment. All patients had received 1-4 chemotherapeutic regimens prior to the current study. ResultThe overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival has not been reached. In the non-responding patients, the median progression-free survival was 4 months. In patients with severe comorbid conditions and unwilling to accept conventional chemotherapy because of severe infection, the physical conditions improved significantly. ConclusionContinuous low-dose CP regimen is an effective and well-tolerated salvage therapy for MM. DisclosuresNo relevant conflicts of interest to declare.

Antitumour Activity of Bortezomib-Pegylated Liposomal Doxorubicine Association as Salvage Therapy in Multiple Myeloma Patients.

Background. There are evidences supporting the existence of a synergism between the proteasome inhibitor bortezomib and anthracyclines. In addition, several in vivo data show synergic-additive effect of bortezomib and pegylated liposomal doxorubicine (Peg LD). Recently these findings were confirmed by the results of a phase III study.Patients and therapy. Based on these findings we are using this combination as salvage therapy in active multiple myeloma (MM) in current patient care. So far, 23 MM patients (F:M 14:9, median age 66 years, range 45–74) with a disease resistant to or relapsing after high or conventional dose chemotherapy have been enrolled. Patient distribution according to disease status and previous therapy was as follows: three and 11 patients with a disease resistant to(including PR cases)or relapsing after high dose chemotherapy with PBSC support, respectively; four and 5 patients with a disease resistant to or relapsing after conventional chemotherapy, respectively. Bortezomib1,3mg/m2 was given as a bolus IV injection on days 1,4,8 and 11 for 8 cycles(induction therapy), then administered on days 1,8,15 and 22 for 3 cycles. PegLD was given at a dose of 40mg/m2 every 3 weeks. In the 1st cohort, Peg LD was employed after the completion of the 8th cycle of bortezomib, during maintenance therapy. In the second cohort, Peg LD was combined with bortezomib starting from the 4th induction cycle. Sequential drug administration was chosen in order to evaluate if PegLD increases the antitumor of bortezomib employed as single agent.Results. The1stcohort included 5 patients. Two with resistant disease to high dose(1) or conventional dose chemotherapy(1) and 3 with relapsing disease after high dose(2)or conventional dose(1). Bortezomib therapy resulted in 4 objective responses(2 nCR,2 PR) and 1 disease stabilization. However, the addition of PegLD did not induce any significant improvement of response in 3 cases. In 2 patients PD was documented, after an initial response, before and during the maintenance therapy respectively. The 2ndcohort included 5 patients resistant to high (2 pts)or conventional (3 pts) dose chemotherapy and 13 with relapsing disease. Response was evaluated in 17/18 cases. One patient still on induction therapy was in a therapeutic phase too early to be evaluated. Myeloma progression was documented in 3 istances during the first three cycles of bortezomib. After the1stcycle in1 and after the 2ndcycle in 2 cases. Of the remaining 14 patients, 9 reached PR, 3 nCR and 2 CR after the first 3 cycles of bortezomib. One patient developed cardiac failure and did not receive PegLD. In the13 patients who completed the planned therapy a conversion of 4 PRs into CRs and 3 nCRs into CRs was documented. No improvement was reported in the other 2 PR cases. One of the CR patients showed an isolated bone progression during the 11th cycle of treatment. Overall, bortezomib or PegLD-bortezomib combination, were well tolerated. Grade1–2 thrombocytopenia was the most common hematological toxicity. All patients complained mild to moderate asthenia and grade 1–2 paresthesias. Conclusion. It is not possible to achieve any firm conclusion regarding the effect of bortezomib-PegLD combination on the control of resistant-relapsing MM, mainly because of the small sample size of treated patients. However, our findings suggest that this combination therapy may exert in some cases a significant antitumor activity.

Polychemotherapy in Combination with Thalidomide Followed by Autologous or Allogeneic Transplantation for Rescue after Autograft or Induction Therapy Failure in Patients with Multiple Myeloma.

BACKGROUND: Most patients (pts) undergoing high-dose therapy and autologous transplant for multiple myeloma (MM) develop disease recurrence. The optimal salvage treatment for these patients is not well defined. Autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (SCT) have been used for salvage therapy.METHODS: We performed a retrospective analysis of pts with MM (n=118) treated in our institution who had failed after 1st-line therapy or relapsed after auto-SCT. Re-induction was performed with TCED (thalidomide, cyclophosphamide, etoposide and dexamethasone, median number of cycles 3). Seventy-four pts (median age, 59 yrs) received auto-SCT as salvage therapy, whereas 44 pts (median age, 53 yrs, p=0.43) underwent a reduced-intensity allo-SCT (related in 23 pts), using conditioning with 2 Gy total body irradiation and fludarabine in 40 pts or melphalan 140 mg/m2 / fludarabine in 4 pts. The majority of the pts (37 / 44) received allo- SCT a median of 59 (range 33–186) days after auto-SCT. Twenty pts in the auto-group and 9 pts in the allo-group were primary progressive, respectively (p=0.42).RESULTS: 89 pts (75%) responded to TCED chemotherapy (CR 4 pts, PR 65 pts, MR 22 pts, SD 13 pts). The number of pts progressing after TCED was equal in both groups (p=0.54). Remission status improved in 30 pts after auto-SCT (7 CR) and in 20 pts after allo-SCT (16 CR, p=0.001). After a median follow-up of 24 months for the auto-group and 21 months for the allo-group since the end of TCED therapy, the median event-free survival (EFS, figure 1) and overall survival (OS, figure 2) were 14 months in both groups (p=0.37) and 27 months versus 35 months (p=0.75), respectively. Incidence of chronic GvHD was 82% (62% extensive). TRM was 20% in the allo-group and differed significantly from the auto-group (1%, p=0.007). Three years after end of TCED 12/44 pts are alive (6 pts in CR) in the allo-group compared to 15/74 pts (1 pt in CR) in the auto-group. All but 1 pt with CR > 3 years after allo-SCT have extensive cGvHD.CONCLUSIONS: Both auto- and allo-SCT are feasible as salvage therapy for MM. Disease recurrence or progression remains the major cause of treatment failure. More CRs and more long term survivors in CR have been observed after allo-SCT confirming the contribution of the GvM-effect. Further concepts are necessary to maintain CR, to prevent relapse or progression and to reduce TRM after allo-SCT. [Display omitted] [Display omitted]

Weekly Cyclophosphamide and Alternate-Day Prednisone: An Effective, Convenient, and Well-Tolerated Oral Treatment for Relapsed Multiple Myeloma After Autologous Stem Cell Transplantation

To assess the efficacy and tolerability of weekly oral cyclophosphamide in combination with alternate-day prednisone (CP) as salvage therapy for patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (ASCT). We retrospectively reviewed the medical records of all patients identified in our clinical database as having received CP as treatment for relapsed MM after ASCT at Princess Margaret Hospital between July 1998 and May 2004. The CP regimen consisted of oral cyclophosphamide at 500 mg once weekly and oral prednisone at 100 mg on alternate days. A total of 66 patients received the CP regimen, with a median of 2.0 prior therapies (range, 1.0-5.0) from time of diagnosis to initiation of CP. The median time from relapse after ASCT to start of CP therapy was 1.5 months (range, 0.0-23.5 months). Because of nonsecretory disease in 7 patients, only 59 patients were evaluable for response. The median duration of CP treatment was estimated at 5.8 months (95% confidence interval [CI], 4.6-7.8 months). With a median follow-up of 15.9 months (range, 1.4-67.2 months), 36 patients (61%) responded to treatment, 24 (41%) of whom had a partial response. The 1-year progression-free survival of all evaluable patients was estimated at 66% (95% CI, 54%-80%), with a median progression-free survival of 18.6 months (95% CI, 13.9-29.9 months). The median overall survival from time of initiation of CP was estimated at 28.6 months (95% CI, 22.1-not available months). Our data show that CP is an effective, well-tolerated, and convenient regimen as salvage therapy for MM after ASCT.