Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma

2009 ◽  
Vol 37 (7) ◽  
pp. 791-798 ◽  
Author(s):  
Nicolaus Kröger ◽  
Anita Badbaran ◽  
Michael Lioznov ◽  
Sabine Schwarz ◽  
Silke Zeschke ◽  
...  
Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4726-4726
Author(s):  
Matthew Danish ◽  
Tabitha Copeland ◽  
Joseph Ho ◽  
Mansi Shah ◽  
Dennis Cooper

Background: Bone pain is one of the most common presentations of multiple myeloma and nearly all patients have skeletal involvement in the course of disease. Consequently, many patients require narcotics for symptom management at the time of diagnosis but the long term impact of MM treatment on pain control remains uncertain. With the advent of combination therapy for MM with novel agents followed by transplant and then maintenance therapy, clinical response is nearly universal and greater than 30% of patients achieve a serologic complete response. Therefore, we examined the impact of modern myeloma-directed therapy and high response rates on the use of narcotics up to 1 year after transplant in this group of patients. Methods: A retrospective review of data collected from the Rutgers-CINJ database was conducted. All patients who received induction inducing therapy (e.g. bortezomib, lenalidomide and dexamethasone or cyclophosphamide, bortezomib and dexamethasone) followed by high dose melphalan and autologous stem cell transplant (ASCT) and who had adequate post-transplant follow up (at least 100 days) were included. Morphine use was assessed at the time of transplant and at follow-up visits. All opiates (e.g. oxycodone, fentanyl, MS contin, etc.) where converted to morphine equivalents/day (ME/day) and recorded. Treatment responses were determined based on the International Myeloma Working Group Response Criteria. We compared the incidence and amount of narcotic use over time using one-way analysis of variance (ANOVA) and Dunn's multiple-comparison test. Results: 189 patients were included in the analysis. 38% were using opiates at the time of transplant. At 100 days post-transplant 35.5% were using opiates and at 1 year post transplant 30.9% were using opiates (p=0.04) . Average opiate use was 74.1 ME/day (95% CI: 55.2 to 92.9), 69.45 ME/day (95% CI: 50.5 to 88.3), and 70.78 ME/day (95% CI: 43.5 to 98) for each of the aforementioned time points (p=0.088) (Figure 1). For example, 74 ME/day would be equal to approximately 50 mg of Oxycodone daily. 74 patients were active opiate users at the time of transplant (Table 1). Response to myeloma treatment (remission, progression, relapse) was not different in opiate-using patients at the time of transplant or at 100 days and 1 year after transplant (Table 2). Conclusion : Early studies from the 1960's reported on the rapid reduction of bone pain in treatment responsive patients with MM (Hogstrata et al.). Recently, treatment modalities for MM have significantly improved, leading to markedly increased remission rates (>90%), progression-free and overall survival. With dramatically increased serologic responses, one would hypothesize that there would be a decline in pain and a subsequent decrease in opiate use. However, in this retrospective chart review we found that 30% of multiple myeloma patients continued to use opiates following transplant and that ongoing use of opiates appeared to be independent of clinical response. Interestingly, at the time of transplant active opiate users had a CR of 27.2% while the non-opiate using patients had a CR of 13.3%. Although there was a slight decline in the number of opiate users at the 1 year follow up, 33% of opiate users continued at their original level of opiate use and 22% increased their opiate use at 1 year post ASCT. Persistent long term use of opiates is of particular concern given that the survival of patients with MM has significantly improved with the use of novel agents and autologous transplant with an increasing number of patients surviving 10 years or more. In patients who have achieved an excellent response (e.g. serologic CR and negative PET scan), ongoing narcotic use should be addressed at each visit and other advanced pain management techniques should be considered. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5128-5128 ◽  
Author(s):  
B. Bruno ◽  
M. Ladetto ◽  
M. Astolfi ◽  
L. Veneziano ◽  
L. Cimolin ◽  
...  

Abstract New allogeneic transplant protocols with non myeloablative conditioning regimens for treatment of multiple myeloma (MM) have been developed in the attempt to reduce the transplant related toxicity associated with myeloablation. Preliminary data have been encouraging with remarkable clinical response rates (Maloney et al, Blood 2003). However, data on the achievement of molecular remission, prerequisite for eventual cure, are still lacking. We implemented a tandem transplant approach consisting of high dose melphalan (200 mg/sqm) with autografting followed by non myeloablative low dose (2.0 Gy) total body irradiation and G-CSF mobilized PBSC infusion from HLA-identical siblings. The curative potential relies exclusively upon a potent graft versus myeloma (GVM) effect through donor T cells. At diagnosis, patient specific clonal markers were generated based upon the rearrangement of the immunoglobulin heavy chain (IgH) genes and used for nested polymerase chain reaction (PCR) detection of minimal residual disease after transplant. Molecular remission was defined as the disappearance of the molecular marker post transplant in both bone marrow and blood. The sensitivity of the nested PCR-based assay was 1 in 100000 cells. A patient specific marker was generated in 11/15 (73%) patients who entered the study. After a median follow up of 16 months (range 5–50), molecular follow up post transplant showed that 3/11 (27%) reached molecular remission at 1, 3 and 7 months post allografting, respectively. Of the remaining 8 patients, 3/8 and 5/8 reached clinical complete remission, defined as the disappearance of the monoclonal paraprotein by immunofixation, and partial remission, respectively. However, minimal residual disease by nested PCR could be detected at all timepoints. The molecular remissions have been durable at 7, 30, and 48 months post transplant, respectively. In 1 case the remission was achieved and sustained in the absence of graft versus host disease (GVHD) which is consistent with the notion that GVHD is not essential for GVM. Furthermore, in 4/11 patients real-time quantification of IgH rearrangements was performed on genomic DNA samples using tumor specific primers and consensus probes. All patients showed a considerable tumor burden reduction post autografting. Samples from two patients became negative by real time PCR at 3 months post allografting, but became PCR-negative by nested PCR at 3 and 7 months, respectively. This discrepancy is explained by the greater sensitivity of nested PCR and the larger amount of IgH copies which are expected in cDNA compared to genomic DNA. The remaining two patients only obtained a clinical partial response throughout the study period. This report indicates that the tandem auto-allo transplant approach can lead to molecular remission in MM. Prospective quantitative monitoring of disease response may be helpful to design individual additional immunotherapeutic manoeuvres, such as donor lymphocyte infusions, to enhance GVM. Longer follow up on a larger series of patients is needed to determine the frequency and durability of molecular remissions.


2020 ◽  
Vol 9 (11) ◽  
pp. 3437
Author(s):  
Alberto Mussetti ◽  
Maria Queralt Salas ◽  
Vittorio Montefusco

Allogeneic hematopoietic cell transplantation (alloHCT) represents a treatment option for multiple myeloma (MM) patients. As shown in several studies, alloHCT is highly effective, but it is hampered by a high toxicity, mainly related to the graft-versus-host disease (GVHD), a complex immunological reaction ascribable to the donor’s immune system. The morbidity and mortality associated with GVHD can weaken the benefits of this procedure. On the other side, the high therapeutic potential of alloHCT is also related to the donor’s immune system, through immunological activity known as the graft-versus-myeloma effect. Clinical research over the past two decades has sought to enhance the favorable part of this balance, along with the reduction in treatment-related toxicity. Frontline alloHCT showed promising results and a potential for a cure in the past. Currently, thanks to the improved results of first-line therapies and the availability of effective second- or third-line salvage therapies, alloHCT is reserved for selected high-risk patients and is considered a clinical option. For donor lymphocyte infusion, bortezomib or lenalidomide have been used as consolidation or maintenance therapies post-transplant—none has become standard of care. For those patients who relapse, the best treatment should be evaluated considering the patient’s clinical status and the previous lines of therapy. The use of newer drugs, such as monoclonal antibodies or other immunotherapies in the post-transplant setting, deserves further investigation. However, acceptable toxicity and a synergic effect with the newer immune system could be hopefully expected.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1351-1351
Author(s):  
Farrukh Awan ◽  
Salman Osman ◽  
Samith Thomas Kochuparambil ◽  
Scot Remick ◽  
Jame Abraham ◽  
...  

Abstract Abstract 1351 Introduction: High dose therapy and autologous transplantation (HDT-AT) has shown survival benefit for (at least) young, transplant eligible multiple myeloma (MM) patients. Transplant ineligible patients who achieve complete remission (CR) with novel chemotherapy agents, have recently been shown to have superior overall survival (OS) (Harousseau JL. Blood:2010). However transplant eligible MM patients who have refractory disease in response to induction chemotherapy (not containing novel agents) before HDT-AT do not have inferior outcomes post-transplantation. A recent single institution, retrospective study has shown that <50% reduction in ‘serum M-protein’ following induction with thalidomide (T) or lenalidomide (L)-based induction therapies, predicts poor outcomes following HDT-AT (Gertz M, Blood:2010). These findings require further validation in order to refine patient selection for HDT-AT. We report here the impact pre-transplant remission status on outcomes of HDT-AT in MM patients receiving induction chemotherapy with novel agents. Methods: This multicenter outcomes study includes 121 consecutive patients who underwent a planned, single autograft within 1-year of starting induction chemotherapy with regimens containing T, L, or bortezomib (B), from 2003–2009. Peripheral blood stem cells were mobilized using a cyclophosphamide/G-CSF combination. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). The disease response pre- and post transplant was determined by using the IMWG criteria. SPSS version 13.0 was used for statistical analysis. Kaplan-Meier method was used to calculate OS and progression free survival (PFS). In order to assess the impact of chemosensitive disease, outcomes of patients achieving at least a partial remission (PR) (≥PR-group; n=105) before HDT-AT were compared with one not achieving at least a PR (<PR-group; n=16). We also compared outcomes of patient achieving at least a very good partial response (VGPR) (≥VGPR-group; n=48) with ones not achieving at least a VGPR (<VGPR-group; n=73). Results: The median age of the patients at transplant was 57yrs (range 35 –76yrs). Eighty (65%) patients were male. At diagnosis 84 (68%) had Salmon-Durie stage III disease, while 37 (31%) had stage I/II disease. At transplantation median Karnofsky performance status was 90, median number of prior therapies was 1 (range 1–4), and 31 (25%) had received radiation previously. Median follow-up of surviving patients is 24 months. KM estimates of 3 year OS of patients in ≥PR-group and <PR-group was 74% vs. 77% (p=0.94) respectively. The 3 year PFS in similar order was 44.8% vs. 45% (p=0.87). The 3 year OS of patients in ≥VGPR-group and <VGPR-group (73% vs. 75%) was also not significantly different (p=0.83). Respective figures of 3 year PFS are 54% vs. 38% (p=0.97) respectively. Of the 53 patients that entered an HDT-AT with a PR, 23 improved to a CR post transplant, 2 improved their status to a VGPR whereas 28 remained in a PR. On the other hand of the 8 patients who entered an HDT-AT with a VGPR, 2 improved to a CR whereas the rest maintained their status. Conclusion: Our limited, multicenter retrospective outcomes data suggest that response to induction chemotherapy with novel agents may not reliably predict outcome of MM patients undergoing HDT-AT. Until data from prospective studies prove otherwise, MM patients who are refractory to therapy with T/L or B-based agents should not routinely be considered ineligible for HDT-AT. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamadani:celgene: Honoraria, Speakers Bureau; otsuka: Research Funding, Speakers Bureau.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 596-596
Author(s):  
Luciano J. Costa ◽  
Xiaobo Zhong ◽  
Mei-Jie Zhang ◽  
Sagar Lonial ◽  
Amrita Krishnan ◽  
...  

Abstract Abstract 596 Background Large population-based studies have demonstrated a significant improvement in survival (OS) for patients (pts) with multiple myeloma (MM) over time since the mid-1990s. The improvement has mostly affected younger patients suggesting a beneficial impact of AHCT. The availability of novel drugs within the last decade and their impact on the utilization and outcomes of AHCT recipients is unknown. Methods We retrospectively reviewed the characteristics and outcomes of 20,278 patients undergoing AHCT within 12 months of diagnosis in USA and Canada and reported to CIBMTR in the periods of 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644) including a subgroup of 4373 individuals with detailed patient, disease and treatment information. We subsequently compared survival and analyzed patient, disease and treatment characteristics across the three periods with the time period serving as a surrogate for pre- and post-transplant exposure to novel agents. Results Across the 3 time periods, there was a marked increase in the number of upfront transplants across all age groups (Figure 1a). Patients receiving upfront HSCT in the more recent period were older, less likely to have stage 3 MM at diagnosis and more likely to have received thalidomide (<1 % vs. 22% vs. 52%), lenalidomide (0% vs. <1% vs. 21%) or bortezomib (0% vs. 2% vs. 35%) and have chemosensitive disease at the time of AHCT. The proportion of African-American patients remained low and stable across the three periods (14 vs. 13 vs. 15%). Over the 3 periods, there was a decrease in chemotherapy based stem cell mobilization and increase of single agent G-CSF based mobilization (24% vs. 24% vs. 41%). The use of single agent Melphalan conditioning increased from 54% in 1995–1999 to nearly 100% in the latest period concomitant with near disappearance of total body irradiation-based and multi-drug conditioning regimens. Compared with 1995–99 cohort, survival was superior in the 2000–04 and 2005–09 cohorts at 24 (72% vs. 79% vs. 84%, P<0.001), 48 (54% vs. 60% vs. 64%, P<0.001) and 60 months (47% vs. 52% vs. 55%, P<0.001) (Figure 1b). In multivariate analysis, we found that transplant in the 2000–04 period (HR=0.77, 95% C.I. 0.67–0.89) or in the 2005–10 period (HR=0.68, 95% C.I. 0.59–0.79) along with Karnofsky performance score of 80–100 (HR=0.59, 95% CI 0.51–0.70) and chemosensitivity (HR= 0.76, 95% C.I. 0.66–0.87) were associated with lower risk of death. Factors associated with higher risk of death were age 50–65 (HR=1.29 95% 1.13–1.47), age 65–80 (HR=1.45, 1.23–1.72), Durie-Salmon or ISS stage III at diagnosis (HR 1.56, 95% C.I. 1.39–1.76) and more than one prior line of therapy (HR=1.15, 95% C.I. 1.03–1.28). In comparison to patients transplanted in 1995–99, post relapse survival was superior for patients transplanted in 2000–04 and 2005–10 at 24 months (58% vs. 65% vs. 72%, P=0.005 and <0.001 respectively) and 48 months (33% vs. 39% vs. 40%, P=0.023 and 0.033 respectively). The use of maintenance therapy has changed with 27% in 1995–99 receiving planned interferon vs. 23% in 2005–09 receiving planned thalidomide, lenalidomide or bortezomib maintenance. Conclusions Utilization of upfront AHCT is increasing in the USA, particularly in older patients. Improvement in survival for MM patients seen in population studies results not only from greater utilization of AHCT but also from the improvement in outcomes after AHCT and a significant recent improvement in post-relapse survival. Pre- and post-transplant exposure to novel agents likely contributes to survival. AHCT and novel agents are complementary and should be combined for the optimal management of newly diagnosed MM. Disclosures: No relevant conflicts of interest to declare.


Author(s):  
Claudio Cerchione ◽  
Davide Nappi ◽  
Giovanni Martinelli

AbstractMultiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Supportive care has thus become key in helping patients to obtain the maximum benefit from novel agents. Filgrastim is a human recombinant subcutaneous preparation of G-CSF, largely adopted in hematological supportive care as “on demand” (or secondary) prophylaxis to recovery from neutropenia and its infectious consequences during anti-myeloma treatment. On the contrary, pegfilgrastim is a pegylated long-acting recombinant form of granulocyte colony-stimulating factor (G-CSF) that, given its extended half-life, can be particularly useful when adopted as “primary prophylaxis,” therefore before the onset of neutropenia, along chemotherapy treatment in multiple myeloma patients. There is no direct comparison between the two G-CSF delivery modalities. In this review, we compare data on the two administrations’ modality, highlighting the efficacy of the secondary prophylaxis over multiple myeloma treatment. Advantage of pegfilgrastim could be as follows: the fixed administration rather than multiple injections, reduction in neutropenia and febrile neutropenia rates, and, finally, a cost-effectiveness advantage.


2019 ◽  
Vol 19 (10) ◽  
pp. e180
Author(s):  
Anjali Mookerjee ◽  
Meetu Dahiya ◽  
Ritu Gupta ◽  
Rakesh Kumar ◽  
Atul Sharma ◽  
...  

Leukemia ◽  
2017 ◽  
Vol 32 (2) ◽  
pp. 252-262 ◽  
Author(s):  
C S Chim ◽  
S K Kumar ◽  
R Z Orlowski ◽  
G Cook ◽  
P G Richardson ◽  
...  

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