Non-Myeloablative Allogeneic Transplantation in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2759-2759
Author(s):  
Sabine Gerull ◽  
Ute Hegenbart ◽  
Martin Goerner ◽  
Axel Benner ◽  
Thomas Moehler ◽  
...  

Abstract Patients with recurrent and refractory multiple myeloma have a very limited survival expectance. Allogeneic transplantation might offer an option for cure in myeloma and the recent development of non-myeloablative conditioning regimens has reduced transplant related morbidity and mortality and rendered this treatment feasible in elderly patients. The role of non-myeloablative allogeneic transplantation for multiple myeloma however, has not yet been defined. We have analyzed the results of patients with relapsed or refractory multiple myeloma treated at our institution. Between 08/1999 and 02/2004, 56 patients with relapsed (n=54) or refractory (n=2) myeloma were treated with non-myeloablative allogeneic transplantation. The median beta2microglobulin at the time of diagnosis was 2.75 mg/l, and median age at the time of transplant was 54.5 years (39.2–67.8). The median time from diagnosis to transplant was 3.6 years. Prior to allogeneic transplantation, patients received reinduction chemotherapy which included an autologous transplantation for 30 patients. The median number of previous cycles of conventional chemotherapy was 9. The conditioning regimen was 2 Gy TBI with (n=43) or without (n=3) fludarabin 3 x 30 mg/m² for 46 patients, the remaining 10 patients received a melphalan containing regimen. Acute toxicity was low with a WBC < 500/μl and platelets < 50/μl for a median of 0 days. Engraftment was prompt with 90 % of patients having achieved > 90 % donor chimerism by day 56. Acute GvHD Grade II-IV occurred in 36 % of patients with 22 % Grade III-IV, and 61 % experienced chronic GvHD. Total transplant related mortality reached 20 %, with a day 100 TRM of 5 %. 32 patients experienced relapse or progressive disease, and 32 % of patients died due to relapse. The Kaplan-Meier estimate of overall survival and progression free survival at 18 months was 40 % and 25 %, respectively, with a median follow up of survivors of 21 months. Patients who experienced cGvHD had a significantly higher overall survival estimate (60 % vs. 20 % at 18 months, p=0.03). The number of cycles of pretreatment before allogeneic transplantation had a statistically significant negative influence on overall (p=0.02) and progression free survival (p=0.006). We conclude that non-myeloablative allogeneic transplantation is feasible in patients with relapsed multiple myeloma. The significant poor prognostic factors we identified were absence of chronic GvHD and number of cycles of pretreatment. Allogeneic transplantion should therefore be considered as an option earlier in the course of the disease.

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3591-3593 ◽  
Author(s):  
Laura Rosiñol ◽  
José Antonio Pérez-Simón ◽  
Anna Sureda ◽  
Javier de la Rubia ◽  
Felipe de Arriba ◽  
...  

One hundred ten patients with multiple myeloma (MM) failing to achieve at least near-complete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)–identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P = .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P = .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantation-related mortality (16% vs 5%, P = .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. This trial is registered at ClinicalTrials.gov ID number NCT00560053


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5742-5742
Author(s):  
Gabriele Buda ◽  
Enrico Orciuolo ◽  
Martina Rousseau ◽  
Sara Galimberti ◽  
Nadia Cecconi ◽  
...  

Abstract The pharmacology of liposomal doxorubicin gives rise to a compound with major advantages that could potentially improve response and decrease toxicity. The lower toxicity, especially less cardiotoxicity, is also related to the encapsulation of doxorubicin into microscopic liposomes, which preferentially penetrate and accumulate in tumour vasculature. In addition, because myeloma cells divide slowly, the increased exposure of these cells to doxorubicin has the potential of overcoming resistance and increasing tumour cell killing capacity, theoretically resulting in improved response rates. In our hospital we treated 40 patients (24M/16F, see Table I) with of a combination regimen of lenalidomide, non pegylated liposomal doxorubicin (NPLD, Myocet®) and dexamethasone (RMD). All the patients had relapsed multiple myeloma and the majority of them were heavily pretreated (23/40 were resistant to ≥ 2 previous therapies). RMD was administered for a median of six 28-day cycles. Lenalidomide (25mg d 1-21), NPLD 40 mg/m2 d4, Dex 40 mg d1-4 and 17-20. The median age of patients was 61 years and the ORR of the combination was 58%, with 10% of patients achieving a complete or very good partial remission. In particular a high ORR (52%) resulted also in very refractory patients in third line of treatment or more. The median progression-free survival was 9.4 months, while the median overall survival was 21 months (see Table II). The most common side effect was haematological toxicity with grade neutropenia (33%), thrombocytopenia (33%) and anaemia (18%). Under thrombosis prophylaxis with aspirin 100 mg per day we observed thrombembolic complications in only in one patients. Other non haematological side effects were pain (8%), diarrhoea (8%). Neither neurotoxicity nor constitutional symptoms of grade 3/4 were found. In our study, lenalidomide in combination with NPLD and dexamethason has shown encouraging activity in heavily pretreated patients with relapsed or refractory multiple myeloma. These schemes can be additional standard of care in the treatment of patients with relapsed or refractory multiple myeloma. The addition of NPLD can play a key role in overcoming anthracycline resistance and improving the quality of response without limiting toxicity. The pharmacology of NPLD gives rise to a compound with major advantages that could potentially improve response and decrease toxicity. Because increased angiogenic activity occurs in the bone marrow of patients with multiple myeloma, this non-pegylated formulation can enhance the delivery of doxorubicin to the tumour site. In addition, because myeloma cells divide slowly, the increased exposure of these cells to doxorubicin has the potential of overcoming resistance and increasing tumour cell killing capacity, theoretically resulting in improved response rates without limiting toxicity, especially in patients who have already received at least one prior therapy. Table Characteristics of MM Patients undergoing RMD therapy Characteristics Cases Age at diagnosis (median and range) 61 (30-73) Number of patients 40 (26 M, 14 F) Stage at diagnosis Durie-Salmon (II/III) 31/40 (78%) Number of previous therapies 1 17 (42,5%) 2 10 (25%) 3 8 (20%) 45 3 (7,5%) 2 (5%) Prognostic Markers b2-microglobulin (m/L.) 2.2 (1.1 – 35)a Creatinin (mg/dl.) 0.9 (0.5 – 4.4) a Albumin (g/dl)) 4.0 (2.1 – 4.9) a Hemoglobin (mg/dl) 11.3 (5.7 – 16.4) a .aMedian (Range) Figure 1 Figure 1. Figure 2 Figure 2. Table II Progression Free Survival and Overall Survival (in months) Disclosures No relevant conflicts of interest to declare.


2018 ◽  
Vol 36 (8) ◽  
pp. 728-734 ◽  
Author(s):  
David S. Siegel ◽  
Meletios A. Dimopoulos ◽  
Heinz Ludwig ◽  
Thierry Facon ◽  
Hartmut Goldschmidt ◽  
...  

Purpose In the ASPIRE study of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide plus dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma, progression-free survival was significantly improved in the carfilzomib group (hazard ratio, 0.69; two-sided P < .001). This prespecified analysis reports final overall survival (OS) data and updated safety results. Patients and Methods Adults with relapsed multiple myeloma (one to three prior lines of therapy) were eligible and randomly assigned at a one-to-one ratio to receive KRd or Rd in 28-day cycles until withdrawal of consent, disease progression, or occurrence of unacceptable toxicity. After 18 cycles, all patients received Rd only. Progression-free survival was the primary end point; OS was a key secondary end point. OS was compared between treatment arms using a stratified log-rank test. Results Median OS was 48.3 months (95% CI, 42.4 to 52.8 months) for KRd versus 40.4 months (95% CI, 33.6 to 44.4 months) for Rd (hazard ratio, 0.79; 95% CI, 0.67 to 0.95; one-sided P = .0045). In patients receiving one prior line of therapy, median OS was 11.4 months longer for KRd versus Rd; it was 6.5 months longer for KRd versus Rd among patients receiving ≥ two prior lines of therapy. Rates of treatment discontinuation because of adverse events (AEs) were 19.9% (KRd) and 21.5% (Rd). Grade ≥ 3 AE rates were 87.0% (KRd) and 83.3% (Rd). Selected grade ≥ 3 AEs of interest (grouped terms; KRd v Rd) included acute renal failure (3.8% v 3.3%), cardiac failure (4.3% v 2.1%), ischemic heart disease (3.8% v 2.3%), hypertension (6.4% v 2.3%), hematopoietic thrombocytopenia (20.2% v 14.9%), and peripheral neuropathy (2.8% v 3.1%). Conclusion KRd demonstrated a statistically significant and clinically meaningful reduction in the risk of death versus Rd, improving survival by 7.9 months. The KRd efficacy advantage is most pronounced at first relapse.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5857-5857
Author(s):  
Donna Fan ◽  
Waleed Sabry ◽  
Julie Stakiw ◽  
Rebecca Ellyn MacKay ◽  
Mark Bosch ◽  
...  

Abstract Introduction Reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT) offer a potential treatment for otherwise incurable cases of acute myelogenous leukemia (AML) with less associated toxicity compared to myeloablative conditioning (MAC). Eradication of malignant cells after RIC depends largely on the graft-versus leukemia effect (GVL). These regimens are becoming increasingly popular, particularly in older patients or those with comorbidities. They may also be offered to otherwise healthy patients based on personal or physician preference, as there is growing evidence that overall survival may be equivalent for both treatments. We retrospectively reviewed the charts of Saskatoon Cancer Centre patients receiving either RIC or MAC to compare the incidence and grade of graft versus host disease (GVHD), progression free survival (PFS), and overall survival (OS). Methods We identified 74 patients who underwent HSCT for AML in complete remission (CR) between January 2000- December 2013. Of these patients, 55 received MAC and 19 received RIC. Median age at HSCT was 48 years (range 18-68). In the group receiving MAC, 36% of patients were >50 years, whereas 74% of patients receiving RIC were >50 yrs of age. Results Patients receiving RIC experienced greater incidence of chronic GVHD (63% vs 41%, p=.09) and relapse (54% vs 30%, p=.07). Incidence of acute GVHD was the same for either regimen (53%). Median overall survival was similar (39 vs 38 months), with lower early mortality in RIC later overtaking MAC at 27 months. Progression free survival demonstrated a non-statistically significant advantage for MAC (median 43 vs 49 months). Conclusion RIC has been associated with greater incidence of chronic GVHD and relapse, with no difference in overall survival. Patients receiving RIC are more likely to be >50 years of age, making comparisons challenging. The results of this review suggest that MAC is the preferred regimen for patients who can tolerate its toxic effects due to reduced incidence of chronic GVHD and relapse, however the similarity in overall survival makes the choice of either conditioning regimen reasonable. Future studies to identify the best conditioning regimen are warranted. Overall Survival Figure 1 Figure 1. Progression Free Survival Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5103-5103
Author(s):  
Bruno K.L. Duarte ◽  
I.S. Valente ◽  
Afonso C. Vigorito ◽  
Francisco J.P. Aranha ◽  
Gislaine B. Oliveira ◽  
...  

Abstract From May 1998 to November 2006, 77 HD patients who used the regimen of high dose cyclophosphamide HD (CY) 7 or 4g/m2, methotretaxe 8g/m2 and etoposide 2g/m2 followed by AHSCT were analyzed. Their median age was 25.8 (8.8–71.5) years, 46 males and 31 females. At diagnosis 50 (65%) were stage III or IV disease, 10 (13%) had bone marrow involvement, 29 (37.7%) bulky disease and 55 (71.4%) B symptoms. Besides that, all patients were submitted to a mean of 2 (1–4) chemotherapy lives and their status were 3 (3.9%) complete remission (CR), 17 (22.1%) partial remission (PR), 57 (74%) progression disease (PD) or in non-specified sensitivity relapse. Concerning CY dose 30 (39%) received 4 g/m2 and 47 (61%) received 7 g/m2. After the HDCY 16 (20.8%) were in CR, 22 (28.6%) PR, 28 (36.3%) remained in DP and 11 (14.3%) died most in PD. After a median follow-up of 3.97 (1.13–55.9) months, 53 (68.8%) patients were submitted to AHSCT and their present status is 30 alive [18 CR, 2PR and 10 DP]; 23 dead [2 CR, 14PD and 7 related to the procedure]. Overall survival for transplanted patients was 55% in 8 years. Currently we have 33/77 (43%) alive patients, 19 CR, 3 PR, 11 PD. Overall Survival (OS) for whole group was 32%, Disease Free Survival (DFS) 64% and Progression Free Survival (PFS) 40%. Patients who were in DP or relapse prior to the HDCY (57) compared to their status after that had a significant improvement (P=0,001), their OS was 40% to CR-PR group (24) versus 16% PD group (33). In general, mortality was 44 (57%), their cause was 19 PD (43.2%), 8 (18.2%) related to HDCY, 2 (4.5%) related to HDMTX, 7 (16%) related to AHSCT, 6 (13.6%) infections, 1 (2.3%) chronic GVHD after a reduced intensity conditioning regimen transplant and 1 (2.2%) AML. Besides that, 3 patients developed MDS and 1 developed AML. In conclusion, although it had happened a significant number of toxicity related deaths, the sequence is feasible, mainly for sensitive patients and presents an acceptable response. The authors emphasize the high frequency of poor prognosis patients and occurrence of MDS/AML in 4 (5.2%) patients.


2016 ◽  
Vol 8 (2) ◽  
pp. 71-79 ◽  
Author(s):  
Prerna Mewawalla ◽  
Abhishek Chilkulwar

Despite recent advances, multiple myeloma remains an incurable disease. Induction therapy followed by autologous transplantation has become the standard of care. The idea of maintenance therapy in multiple myeloma is not new. Starting with chemotherapy in 1975, to interferon in 1998, to novel agents recently, a multitude of agents have been explored in patients with multiple myeloma. In spite of the novel agents, multiple myeloma continues to be an incurable disease with the progression-free survival after autologous transplant rarely exceeding 3 years. The goal of using maintenance therapy has been to improve the outcomes following autologous transplantation by increasing the progression-free survival, deepening remissions and perhaps increasing overall survival. It has been shown that patients with a stringent complete response (CR) have a better outcome [Kapoor et al. 2013]. It is becoming increasingly common to check minimal residual disease (MRD) as a means of assessing depth of response. It has also been shown that patients with no MRD have not only a better progression-free survival but also a better overall survival compared with patients who are MRD positive. This makes it even more important to find agents for maintenance therapy, which can further deepen and maintain responses. Here, we present a comprehensive review of the agents studied as maintenance for multiple myeloma and their efficacy, both in terms of overall survival, progression-free survival and toxicity.


2021 ◽  
pp. JCO.21.00972
Author(s):  
Paul G. Richardson ◽  
Shaji K. Kumar ◽  
Tamás Masszi ◽  
Norbert Grzasko ◽  
Nizar J. Bahlis ◽  
...  

PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.


Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.


2021 ◽  
Author(s):  
Junxia Huang ◽  
Juanjuan Hu ◽  
Yan Gao ◽  
Fanjun Meng ◽  
Tianlan Li ◽  
...  

Abstract Background: Advanced lung cancer inflammation index (ALI) is known to predict the overall survival of patients having some solid tumors or B-cell lymphoma. The study investigates the predictive value of ALI in multiple myeloma (MM) patients and the correlation between ALI and prognosis.Methods: A database of 269 MM consecutive patients who underwent chemotherapy between December 2011 and June 2019 in the Affiliated Hospital of Qingdao University was reviewed. ALI cut-off value calculated before the initial chemotherapy and post 4 courses treatment were identified according to the receiver operating characteristic (ROC) curve, and its association with clinical characteristics, treatment response, overall survival (OS), and progression-free survival (PFS) were assessed.Results: Patients in the low ALI group (n=147) had higher risk of β2 microglobulin elevation, more advanced ISS (International Classification System stage), and TP53 gene mutation, with significantly lower median overall survival (OS; 36.29 vs. 57.92 months, P = 0.010) and progression-free survival (PFS; 30.94 vs. 35.67 months, P = 0.013). Independent risk factors influencing the OS of MM patients were ALI (P = 0.007), extramedullary infiltration (P = 0.001), TP53 (P = 0.020), Plt (P = 0.005), and bone destruction (P = 0.024). ALI (P = 0.005), extramedullary infiltration (P = 0.004), TP53 (P = <0.001), Plt (P = 0.017), and complex chromosome karyotype (P = 0.010) were independent risk factors influencing the PFS of MM patients.Conclusions: ALI is a potential independent risk factor predicting the prognosis of newly diagnosed MM patients.


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