Reducing Treatment-Related Mortality Did Not Improve Outcomes of Allogeneic Myeloablative Hematopoietic Cell Transplantation for High-Risk Multiple Myeloma: A University of Michigan Prospective Series

Abstract

Despite the ongoing advent of more effective immunomodulators and proteasome inhibitors, multiple myeloma (MM) remains incurable and no effective therapy is available for advanced aggressive disease. Although allogeneic (Allo) hematopoietic cell transplantation (HCT) has a curative potential, the outcomes remain poor because of high treatment-related mortality (TRM), mostly due to regimen-related toxicities and graft-versus-host disease (GVHD) in case of myeloablative conditionings, high relapse rate in case of reduced-intensity or nonmyeloablative regimens, and possibly other unknown MM-specific issues. In an attempt to improve TRM, without compromising conditioning intensity, we prospectively explored the feasibility and efficacy of a myeloablative but reduced-toxicity conditioning regimen, consisting of fludarabine and busulfan (FluBu4; fludarabine 40 mg/m(2)/day and busulfan 3.2 mg/kg/day i.v. × 4 days) in 22 patients with high-risk or advanced refractory MM. The majority (14 of 22, 64%) had prior autologous HCT. The median HCT-specific comorbidity index score was 3 (range, 0 to 6), with 46% having a Karnofsky performance score < 80%. Ten patients had unrelated donors, 3 of whom were 7/8 HLA-loci matched. GVHD prophylaxis was tacrolimus and methotrexate in 20 (91%). Most patients had active MM at transplantation, with a partial response in 12 of 22 (46%) and stable disease in 1 of 22 (4.5%). All 22 patients tolerated the FluBu4 conditioning well, without early toxic deaths or graft failure. Common regimen-related toxicities included mild to moderate mucositis (18 of 22, 82%) and mild transient liver function abnormality (9 of 22, 41%). There were no grade 4 toxicities but grade 3 mucositis occurred in 7 of 22 patients (32%). The cumulative incidence of severe, grades III and IV acute GVHD at day 180 was 23% (95% confidence interval [CI], 10% to 47%) and that of chronic GVHD was 68% (95% CI, 46% to 88%). The cumulative incidences of TRM at 100 days, 1 year, and 3 years were 9% (95% CI, 2% to 33%), 19% (95% CI, 7% to 44%), and 29% (95% CI, 13% to 55%), respectively. Two TRMs were due to idiopathic pneumonia syndrome and 1 was due to cirrhosis. They all had decreased pre-HCT corresponding organ function, with HCT-specific comorbidity index scores of > 3. With a median follow-up of 58.7 (range, 39 to 82) months, the cumulative incidences of relapse at 1 and 3 years were 37% (95% CI, 20% to 61%) and 50% (95% CI, 29% to 75%); those for 1-year and 3-year overall survival (OS) were 58% (95% CI, 40% to 83%) and 29% (95% CI, 15% to 57%), respectively, and those for the 1-year and 3-year progression-free survivals (PFS) were 40% (95% CI, 23% to 67%) and 15% (95% CI, 5% to 42%), respectively. In summary, the use of the myeloablative FluBu4 conditioning Allo-HCT for high-risk MM resulted in decreased TRM, compared with that of Allo-HCT using conventional myeloablative regimens; however, the relapse rate was high, including in those developing moderate-to-severe chronic GVHD. This suggested a less robust graft-versus-myelo...

Allogeneic stem-cell transplantation for multiple myeloma: a systematic review and meta-analysis from 2007 to 2017

“…37 [ 10 – 13 , 15 , 19 , 20 , 22 , 24 , 26 – 28 , 31 – 33 , 36 , 38 , 40 , 42 – 45 , 47 – 50 , 57 – 60 , 64 – 67 , 69 , 72 , 73 ] out of 61 trials reported the results of RR with the incidence ranging from 14.3 to 91.3%. The pooled estimate (95% CI) for RR was 50 (95% CI 45–55%).…”

Sequential systematic anti‐mold prophylaxis with micafungin and voriconazole results in very low incidence of invasive mold infections in patients undergoing allogeneic hematopoietic stem cell transplantation

“…Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the only curative treatment option for many malignant and non‐malignant hematological diseases. While treatment‐related mortality (TRM) remains a major concern of this procedure, mostly driven by infections and graft‐versus‐host disease (GVHD), several studies have shown a decrease in TRM in recent years due to a variety of factors . One such factor is the improved management of invasive mold infections (IMI), including new diagnostic tools and active drugs both in the prophylactic and treatment settings.…”

“…While treatment-related mortality (TRM) remains a major concern of this procedure, mostly driven by infections and graft-versus-host disease (GVHD), several studies have shown a decrease in TRM in recent years due to a variety of factors. 1,2 One such factor is the improved management of invasive mold infections (IMI), including new diagnostic tools and active drugs both in the prophylactic and treatment settings. These improvements have led to an apparent decrease in the mortality of these infections.…”

Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Therapies

“…In patients with HR disease or those relapsing after autologous HSCT, particularly younger patients who are fit for allografts, salvage therapy with novel agents followed by RIC allogeneic HSCT has been shown to provide significant PFS benefit [76,[118][119][120][121]. In patients lacking human leukocyte antigen (HLA)-matching sibling donors, alternate donors such as matched unrelated donors, cord blood transplantation and haploidentical forms of allogeneic HSCT have been employed and they have shown feasibility and effectiveness [115,[122][123][124].…”