Nonmyeloablative Unrelated Donor (URD) Hematopoietic Cell Transplantation (HCT) for the Treatment of Patients (pts) with Poor-Risk, Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2893-2893
Author(s):  
George E. Georges ◽  
Michael B. Maris ◽  
David G. Maloney ◽  
Brenda M. Sandmaier ◽  
Mohamed L. Sorror ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Progression Free Survival ◽  
P Value ◽  
Unrelated Donor ◽  
Refractory Disease ◽  
Refractory Multiple Myeloma ◽  
Poor Risk ◽  
Autologous Hct

Abstract We carried out HLA-matched URD peripheral blood stem cell (PBSC) transplant in 24 pts with poor-risk multiple myeloma after nonmyeloablative conditioning with fludarabine (90 mg/m2) and 2 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median age of the 19 men and 5 women was 53 (23 – 66) years. Conventional metaphase cytogenetics obtained in 14 pts showed Δ13 in 6 pts and complex abnormalities in 9 pts. Stage III disease was present in 83% and 17% had stage II disease. The median time from diagnosis to URD HCT was 25 (range, 8–130) months, and 96% were beyond 1st complete remission (CR) or had never achieved CR1, despite multiple lines of chemotherapy (median 4.5, range 2–10). At study entry, 17 pts (71%) had chemotherapy-refractory disease and 14 pts (58%) had failed autologous HCT. Thirteen pts had planned autologous-URD tandem HCT, while 11 proceeded directly to URD HCT. The median follow-up was 2.5 years after allografting. One pt experienced non-fatal graft rejection. The incidences of acute grades II, III and chronic graft-versus-host disease were 54%, 13% and 75%, respectively. Non-relapse mortality was 22% at 2.5 years. CRs were observed in 11 pts (46%) and partial remissions (PR) in 3 (13%). Best disease responses were seen in pts given tandem autologous-URD HCT with CR in 8 pts and PR in 2 pts (77% CR+PR rate). The estimated overall survival (OS) at 2.5 years for all 24 pts was 65% and progression-free survival (PFS) 41%. Pts receiving tandem autologous-URD HCT had superior OS and PFS, 76% and 63% (Fig. A), compared to pts proceeding directly to URD HCT, 52% and 14% (Fig. B), respectively (PFS p-value=.03). Risk factors for worse OS included pts with significant medical comorbidities (p=.03), chemotherapy-refractory disease prior to HCT (p=.03), and pts who had failed autologous HCT (p=.07). Pts who failed autologous HCT had 48% OS and 30% PFS at 2.5 years. For pts with poor-risk, relapsed or refractory multiple myeloma, cytoreductive autologous HCT followed with nonmyeloablative conditioning and URD HCT is very promising treatment with low non-relapse mortality, high complete remission rates and prolonged PFS. The results also suggest that URD HCT may provide improved graft-versus-myeloma effect compared with HLA-matched sibling HCT without an increase in the risk of non-relapse mortality. Figure Figure

Nonmyeloablative Unrelated Donor Hematopoietic Cell Transplantation (HCT) for Patients (pts) with Poor Risk, Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2756-2756 ◽  
Author(s):  
George E. Georges ◽  
Michael B. Maris ◽  
Brenda M. Sandmaier ◽  
Judith Shizuru ◽  
Dietger W. Niederwieser ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hematopoietic Cell Transplantation ◽  
Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Refractory Disease ◽  
Standard Chemotherapy ◽  
Refractory Multiple Myeloma ◽  
Poor Risk ◽  
Autologous Hct

Abstract We investigated the feasibility of HLA-matched unrelated donor (URD) HCT in pts with advanced stage, poor-risk multiple myeloma after nonmyeloablative conditioning. Nineteen pts, median age 52 years (range, 28–65), were treated between 5/2000 and 2/2004. Eight pts had known complex cytogenetic abnormalities including Δ13. At study entry, 12 pts had relapsed or refractory disease after a previous autologous HCT, 5 pts had refractory disease following multiple standard chemotherapy regimens, and 2 pts achieved a partial remission (PR) after standard chemotherapy. Before URD HCT, 10 pts underwent a planned high dose autologous HCT (Melphalan 200 mg/m2) to provide cytoreduction a median of 85 days prior to URD HCT, including 4 pts with relapsed/refractory disease after a prior autologous HCT. Three pts were in complete remission (CR) immediately prior to URD HCT. Nonmyeloablative conditioning consisted of fludarabine (30 mg/m2 x 3 days) and 2 Gy total body irradiation followed by PBSC grafts from URDs matched for HLA-A, −B, −C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Durable engraftment was achieved in 18 of 19 pts. One pt had graft rejection at day +56 and received a second successful nonmyeloablative HCT from another URD. Acute GVHD occurred in 13 (68%) pts and was exclusively grades II and III in 11 and 2 pts, respectively. Chronic extensive GVHD occurred in 12/17 (70%) of evaluable pts. After allografting, 9 pts (47%) were in CR and 3 (16%) in PR, for an overall response rate of 63%. Four pts (21%) died of progressive disease and 4 pts (21%) died of non-relapse causes at a median of 5.3 months. The 2-year overall survival, progression-free survival and non-relapse mortality was 62%, 51% and 24%, respectively. The median follow-up was 25 months. Eleven of 19 pts (58%) were alive, 6 (32%) in CR, 1 (5%) in PR, 2 (10%) with stable disease (SD) and 2 (10%) with relapse after initially achieving CR. Of the 10 pts who underwent a planned high dose autologous HCT for cytoreduction followed by nonmyeloablative URD HCT, 8 were alive: 6 CR, 1 SD, 1 relapse. Of the 9 pts who underwent nonmyeloablative URD HCT without planned autologous HCT, 3 were alive: 1 PR, 1 SD and 1 relapse. Of the 12 pts who entered the study with relapsed/refractory disease after a previous autologous HCT, 5 were alive: 2 CR, 1 PR, 1 SD, 1 relapse. In summary, URD HCT after nonmyeloablative conditioning is feasible with relatively low non-relapse mortality and provides a high response rate for pts with relapsed or refractory multiple myeloma, including pts with disease relapse following an autologous HCT. The data suggest that a treatment strategy consisting of two sequential transplants (1) intensive cytoreductive therapy with autologous HCT followed by (2) nonmyeloablative URD HCT, may be highly effective for treating pts with poor risk, chemotherapy-refractory multiple myeloma or after relapse following autologous HCT.

Are IPSS-R and IPSS Cytogenetic Risk Stratification Informative At the Time of Allogeneic Hematopoietic Cell Transplantation?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1400-1400
Author(s):  
Zohar Sachs ◽  
Michelle Dollan ◽  
Todd E De For ◽  
Leyla Shune ◽  
Sarah Cooley ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
P Value ◽  
Unrelated Donor ◽  
Karnofsky Performance Score ◽  
Hematopoietic Stem ◽  
Poor Risk

Abstract Abstract 1400 Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders. Cytogenetic aberrations are one of the main elements of risk stratification among published scoring systems including the International Prognostic Scoring System (IPSS) or its recent revision (R-IPSS). R-IPSS cytogenetic risk stratification has 5 cytogenetic subgroups rather than 3 in the IPSS. We hypothesized that R-IPSS and/or IPSS cytogenetic risk stratification at the time of allogeneic hematopoietic cell transplantation (alloHCT) can better predict outcome afterwards. In patients who had cytogenetic results at both diagnosis and alloHCT, we evaluated the cytogenetic changes over time and compared how well the two cytogenetic risk stratification systems predicted outcome. One hundred consecutive patients with MDS undergoing an alloHCT (52% related donor, 13% unrelated donor, and 35% umbilical cord blood) at the University of Minnesota between 1995 and 2011 were evaluated. Their median age was 52 years (range, 18–69 years). Seventy-eight percent of the patients had ≥90% Karnofsky performance score, and 60% had INT-2 or a high IPSS score. Half received reduced-intensity conditioning (RIC). Patients with IPSS good-risk cytogenetics at diagnosis had a significantly better OS (62% at 5-year) compared to patients with intermediate or poor-risk cytogenetics. However, IPSS cytogenetic stratification at the time of transplantation predicted neither overall survival (OS) nor relapse (Table). Patients with IPSS-R very poor risk cytogenetics at either diagnosis or alloHCT had a dismal outcome; no patients in this category at alloHCT survived 5 years, and their relapse rate was also significantly higher (41%) compared to other cytogenetic risk subgroups (Table). In multivariate analysis, the only factor predicting relapse was the intensity of the conditioning regimen: those patients receiving RIC had a higher risk of relapse (HR, 2.5, 95% CI 1.1–5.4, p=0.03) than those who received myeloablative conditioning regimens. This data indicate that IPSS (at diagnosis) and IPSS-R (at both diagnosis and alloHCT) cytogenetic classifications provide important prognostic information in the best and worst subgroups, respectively, but are not as helpful for patients in the intermediate subgroups. Table. OS and Relapse by IPSS and R-PSS cytogenetic stratifications at time points of diagnosis and alloHCT Factor Strata N OS @ 5 year CI 95% P-value Relapse @ 5-year CI 95% P-value IPSS Cytogenetics At alloHCT Good 30 48% 28-65% 0.16 29% 11-47% 0.82 Intermediate 21 19% 6-38% 29% 9-48% Poor 41 23% 11-38% 30% 15-45% IPSS-R Cytogenetics 
 At alloHCT Very good/Good 32 51% 31-67% <0.01 30% 13-48% 0.05 Intermediate 21 17% 5-36% 29% 9-48% Poor 41 41% 22-60% 17% 2-31% Very Poor 18 0% 41% 18-63% IPSS Cytogenetics 
 At Diagnosis Good 25 62% 39-78% <0.01 22% 5-39% 0.16 Intermediate 24 13% 3-29% 29% 10-48% Poor 47 24% 12-38% 30% 16-44% IPSS-R Cytogenetics 
 At Diagnosis Very good/Good 28 54% 33-71% <0.01 27% 9-44% 0.21 Intermediate 20 15% 4-33% 25% 6-44% Poor 29 33% 17-51% 21% 6-35% Very Poor 19 7% 0-28% 45% 22-68% Disclosures: No relevant conflicts of interest to declare.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

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.

scholarly journals ELOTUZUMAB FOR THE TREATMENT OF RELAPSED OR REFRACTORY MULTIPLE MYELOMA, WITH SPECIAL REFERENCE TO ITS MODES OF ACTION AND SLAMF7 SIGNALING

2018 ◽  
Vol 10 (1) ◽  
pp. e2018014 ◽  
Author(s):  
Masafumi Taniwaki ◽  
Mihoko Yoshida ◽  
Yosuke Matsumoto ◽  
Kazuho Shimura ◽  
Junya Kuroda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cell ◽  
Cell Activity ◽  
Adaptor Protein ◽  
Progression Free Survival ◽  
Sh2 Domain ◽  
Phase Iii ◽  
Refractory Multiple Myeloma ◽  
Pathway Activation ◽  
Signaling Lymphocytic Activation Molecule

Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone   (ELd)   for relapsed/refractory  multiple myeloma (MM) based on the findings of the phase III randomized trial  ELOQUENT-2 (NCT01239797). Four-year  follow-up  analyses  of  ELOQUENT-2 have demonstrated  that  progression-free survival was 21%  in  ELd  versus  14%  in  Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of  action:  natural  killer  (NK)  cell-mediated  antibody-dependent  cellular  cytotoxicity  (ADCC) and  enhancement  of  NK  cell  activity.  The  ADCC  is  mediated  through  engagement  between  Fc portion  of  elotuzumab  and  FcgRIIIa/CD16  on  NK  cells. Enhanced NK cell cytotoxicity results fromm phosphorylation  of  the  immunoreceptor  tyrosine-based  switch  motif  (ITSM)  that  is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2.The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+. Influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis inNK  cells. Elotuzumab  does not stimulate the  proliferation of MM cells due to a lack of EAT-2.The  inhibitory  effects  of  elotuzumab  on  MM  cell  growth  are  not  induced by  the lack  of  CD45, even  though  SHP-2,  SHP-1,  SHIP-1,  and  Csk may be  recruited  to  phosphorylated  ITSM  of SLAMF7.  ELd  improves PFS in patients  with  high-risk  cytogenetics,  i.e.  t(4;14),  del(17p),  and 1q21  gain/amplification. Since  the immune  state  is  paralytic  in  advanced  MM,  the  efficacy  of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease.

Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4445-4451 ◽  
Author(s):  
Michael Wang ◽  
Meletios A. Dimopoulos ◽  
Christine Chen ◽  
M. Teresa Cibeira ◽  
Michel Attal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Time To Progression ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Previously Treated ◽  
Survival Studies

AbstractThis analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

Sign in / Sign up

Export Citation Format

Share Document