Presalvage International Staging System Stage and Other Important Outcome Associations in CD34+-Selected Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Abstract

Despite ongoing therapeutic advances, multiple myeloma (MM) remains largely incurable, and outcomes in patients who develop resistance to immunomodulatory drugs or proteasome inhibitors remain grim. Allogeneic hematopoietic cell transplantation (alloHCT) is an alternative option that may offer potential for cure. Although rates of transplantation-related morbidity and mortality have decreased in recent years, weighing this approach's potential benefits against nontransplantation therapies demands a thoroughly informed pre-alloHCT assessment. Here we assess the impact of pre-alloHCT variables on important clinical outcomes in a large cohort of relapsed refractory MM (RRMM) CD34 +-selected alloHCT recipients. We included all patients with MM who underwent CD34 +-selected alloHCT at our center between June 2010 and December 2015. Patients were conditioned with busulfan (0.8 mg/kg £ 10), melphalan (70 mg/m 2 £ 2), and fludarabine (25 mg/ m 2 £ 5), followed by infusion of a CD34 +-selected peripheral blood stem cell graft, without post-alloHCT graft-versus-host disease (GVHD) prophylaxis. The 73-patient cohort had a median age of 55 years (range, 37 to 66 years). Overall survival (OS) and progression-free survival (PFS) rates were 70% and 53%, respectively, at 1 year (95% confidence interval [CI], 58% to 79% and 41% to 64%) and 50% and 30%, respectively, at 3 years (95% CI, 38% to 62% and 19% to 41%). The cumulative incidence of relapse was 25% at 1 year (95% CI, 15% to 35%) and 47% at 3 years (95% CI, 35% to 58%). Nonrelapse mortality at 1 year was 22% (95% CI, 13% to 32%). The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 7% at 100 days (95% CI, 3% to 14%), and that of any chronic GVHD (cGVHD) was 8% at 1 year (95% CI, 3% to 16%). International Staging System (ISS) stage II-III assessed before salvage therapy was associated with poorer 3-year OS (30% versus 54%; P = .037) and 3-year PFS (9% versus 33%; P = .013), and increased 3-year relapse incidence (72% versus 39%; P = .004). Older age and GVHD before 6 months (aGVHD grade II-IV or cGVHD of any grade) were also associated with poorer OS, and a greater number of pre-alloHCT lines of therapy was also associated with increased relapse incidence. Our findings reinforce that CD34 +-selected alloHCT can achieve prolonged disease control and long-term survival in high-risk, heavily treated refractory MM populations. We also identified numerous pre-alloHCT variables associated with OS, PFS, and relapse. Amongst these, presalvage ISS stage II-III was consistently associated with poorer survival and relapse outcomes. Given the lack of established alternate therapies for patients with RRMM, we advocate the identification of adverse pre-alloHCT variables to inform alloHCT decision making rather than to exclude patient cohorts from this potentially curative treatment option.

Long-term survival and polyclonal immunoglobulin reconstitution after allogeneic stem cell transplantation in multiple myeloma

“…Comparable with existing data, we found only a small further increase of cumulative incidence of relapse from the third year on, indicating that relapse-free long-term survival might be possible [3,29]. With 23% in the first year, NRM was in the upper range compared with previous reports [30][31][32], with main causes of non-relapse death being GvHD and infectious complications (Fig. 1d).…”

Allogeneic Transplantation in Multiple Myeloma—Does It Still Have a Place?

“…Also, the number of patients included is in most studies are relatively small. Still, overall, the 3-year OS from the time of salvage treatment is around 50%, and the 5-year OS between 30% and 40% in most later studies [ 46 , 61 , 62 , 63 , 64 , 65 ]. Maintenance treatment may improve the results [ 61 ].…”

“…The largest multicenter prospective trial is the BMT-CTN 0102 study [ 45 , 46 ]. It included 710 patients < 70 years of age, of whom, 625 had standard risk disease.…”

“…In the updated BMT-CTN study, a subanalysis was also done on 85 high-risk patients defined as those having either del13 by conventional chromosome analysis or beta-2 microglobulin ≥ 4 mg/L [ 46 ]. At this long-term follow-up, RR (relapse rate) was significantly lower with Auto/RICAllo both at 6 and 10 years.…”

“…Reduced-intensity conditioning, introduced by the Seattle group [ 14 ], was important to reduce NRM in MM, but RR increased in comparison to myeloablative conditioning [ 23 ]. However, although higher than with myeloablative conditioning, RR was lower long term than with Auto in all the four largest prospective studies, the BMT-CTN [ 45 , 46 ], the NMAM2000 [ 47 , 48 ], the Italian [ 40 , 41 ], the HOVON [ 43 , 69 ] studies, as well as in the pooled analysis [ 70 ]. The conditioning regimen was similar in these studies, i.e., TBI 2 Gy with or without fludarabine.…”