Efficacy of autologous stem cell transplantation in patients aged ≥ 70 years with multiple myeloma

Autologous hematopoietic stem cell transplantation (auto-SCT) is considered part of the backbone therapy for patients with multiple myeloma (MM), but this therapy is often not offered to patients aged 65 or older, despite the median age of diagnosis being 70 years old. Patients may be considered ineligible for auto-SCT due to frailty or due to the risk of complications. There have been single-center studies showing auto-SCT is a safe and effective treatment option for patients > 70 years old, though these were before the era of novel agents.¹

At the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Pashna Munshi, MedStar Georgetown University Hospital, Washington, US, presented data that evaluated the impact of older age at transplant and its effect on post-transplant outcomes.¹

Study design

• The investigators selected 15,999 patients (Table 1) who underwent auto-SCT following prior induction with regimens containing immunomodulatory drugs and proteasome inhibitors
• Data for the current analysis were retrieved from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry of transplant essential data and comprehensive report form data
• The primary objectives were to examine trends in transplant in older patients, the impact of age at transplant and post-transplant outcomes, and investigate factors associated with outcome
• The secondary objective was to assess the impact of melphalan dose on outcomes in patients ≥ 70 years old

Patient inclusion criteria

Patients were included if they:

• had undergone only a single auto-SCT
• received their transplant within 12 months of their diagnosis, between the periods of 2013–2017
• were treated within US medical centers only  
• received peripheral blood cell grafts and melphalan conditioning

Patient baseline characteristics are shown in Table 1.

Table 1. Baseline characteristics

HCT-CI, hematopoietic cell transplant comorbidity index; ISS, international staging system
Age range, years	Total	20–39	40–49	50–59	60–69	≥ 70
n	15,999	308	1,615	4,952	7,032	2,092
Median age, years (range)	62 (20–83)	37 (20–39)	47 (40–49)	56 (50–59)	65 (60–69)	72 (70–83)
Gender, male (%)	9,160 (57)	186 (60)	908 (56)	2,841 (57)	3,960 (56)	1,265 (60)
Karnofsky score < 90, n (%)	7,263 (45)	108 (35)	618 (38)	2,066 (42)	3,322 (47)	1,149 (55)
Comorbidity (HCT-CI) score > 3, n (%)	3,784 (24)	43 (14)	273 (17)	1,017 (21)	1,792 (25)	659 (32)
Durie-Salmon /ISS Stage III disease, n (%)	8,713 (54)	188 (61)	949 (59)	2,697 (54)	3,811 (54)	1,068 (51)
Cytogenetics, high-risk, n (%)	4,398 (27)	63 (20)	380 (24)	1,307 (26)	2,019 (29)	629 (30)
Melphalan dose, 200 mg/m2, n (%)	13,047 (82)	276 (90)	1,468 (91)	4,473 (90)	5,962 (85)	868 (41)
Median (range) follow-up for survivors, months	25 (< 1–72)	34 (1–64)	33 (1–71)	27 (< 1–71)	25 (1–72)	24 (1–66)

The data in Table 2 shows:

• the standard dose of melphalan (200 mg/m²) was used less with advancing age
• there is a worsening functional status and a worse hematopoietic cell transplant comorbidity index (HCT-CI) as age advances

This analysis shows that the number of transplants in patients aged ≥ 70 increased between 2013 and 2017.

Results

Statistical analysis

• Due to a large sample size (15,999), p < 0.01 was considered significant in this study
• Univariate analysis of outcomes showed patients aged ≥ 70 had a higher Day 100 non-relapse mortality (NRM) and a lower 2-year overall survival (OS)
• A multivariate analysis was then conducted to assess the mean effect of age on transplant outcome (Table 2)
  • In this analysis, age did not impact Day 100 NRM, relapse/progression (REL), progression-free survival (PFS), or OS when compared to the largest reference group of patients aged 60–69

Table 2. Multivariate analysis of outcomes looking at the mean effect of age

CI, confidence interval; HR, hazard ratio; NRM, non-relapse mortality; OS, overall survival; PFS, progression-free survival; REL, relapse/progression *statically significant
Outcome	HR (95% CI)	p value
Day 100 NRM
Main effect-age	—	< 0.0001*
60–69	1	—
40–49	0.6 (0.4–0.9)	0.007*
50–59	0.7 (0.5– 0.9)	0.003*
≥ 70	1.3 (1–1.7)	0.06
REL
Main effect-age	—	0.9
60–69	1	—
40–49	1 (0.9–1.1)	0.9
50–59	1 (1–1.1)	0.4
≥70	1 (0.9–1.0)	0.6
PFS
Main effect-age	—	0.5
60–69	1	—
40–49	1 (0.9–1.1)	0.5
50–59	1 (0.9–1.1)	0.9
≥70	1.1 (1–1.2)	0.2
OS
Main effect-age	—	0.0003*
60–69	1	—
40–49	0.8 (0.6–0.9)	0.01*
50–59	0.9 (0.8–1.0)	0.05
≥70	1.2 (1–1.4)	0.03

Primary objectives:

Day 100 NRM

Covariate factors that affected Day 100 NRM in the multivariate analysis:

• A poor functional status at the time of transplant (Karnofsky score ≥ 90 vs < 90): hazard ratio (HR) = 1.5 (95% CI, 1.2–1.9), p = 0.0001
• A HCT-CI score of ≥ 3 vs 0: HR = 2.2 (95% CI, 1.6–2.9), p < 0.0001
• Durie-Salmon/International Staging System (ISS) Stage III vs I–II disease: HR = 1.4 (95% CI, 1.1–1.8), p = 0.001
• Disease status of partial response (PR) or less at the time of transplant vs stringent complete response (sCR) or complete response (CR): HR = 2.9 (95% CI, 1.9–4.4), p < 0.0001

REL

Covariate factors that affected REL in the multivariate analysis:

• Durie-Salmon/ISS Stage III vs I–II disease: HR = 1.4 (95% CI, 1.3–1.5), p < 0.0001
• High-risk vs standard-risk cytogenetics: HR = 1.9 (95% CI, 1.7–2.1), p < 0.0001
• Disease status of < PR at the time of transplant vs sCR/CR: HR= 1.7 (95% CI, 1.5–2.0), p < 0.0001

PFS

Covariate factors that affected PFS in the multivariate analysis:

• A poor functional status at the time of transplant (Karnofsky score ≥ 90 vs < 90): HR = 1.1 (95% CI, 1.1–1.2), p = 0.0003
• Durie-Salmon/ISS Stage III vs I–II disease: HR = 1.4 (95% CI, 1.1–1.9), p < 0.0001
• High-risk vs standard-risk cytogenetics: HR = 1.8 (95% CI, 1.7–2.0), p < 0.0001
• Disease status of < PR at the time of transplant vs sCR/CR: HR = 1.8 (95% CI, 1.6–2.0), p < 0.0001

OS

Covariate factors that affected OS in the multivariate analysis:

• A poor functional status at the time of transplant (Karnofsky score ≥ 90 vs < 90): HR = 1.3 (95% CI, 1.2 –1.5), p < 0.0001
• A HCT-CI score ≥ 3 vs 0: HR = 1.3 (95% CI, 1.2–1.5), p < 0.0001
• Durie-Salmon/ISS Stage III vs I–II disease: HR = 1.8 (95% CI, 1.6–2.0), p < 0.0001
• High-risk vs standard-risk cytogenetics: HR = 2.1 (95% CI, 1.8–2.4), p < 0.0001
• Disease status of < PR at the time of transplant vs sCR/CR: HR = 2.6 (95% CI, 2.1–3.1), p < 0.0001

Secondary objective:

A second multivariate analysis was conducted to assess the outcomes for patients ≥ 70 years of age (n = 2,092), comparing melphalan doses. This analysis demonstrated a lower melphalan dose (140 mg/m² vs 200 mg/m²) was associated with:

• higher Day 100 NRM: HR = 2.2 (95% CI, 1.3–3.7), p = 0.003
• increased REL: HR = 1.2 (95% CI, 1.0–1.4), p = 0.1
• decreased PFS: HR = 1.3 (95% CI, 1.1–1.5), p = 0.008
• worse OS: HR = 1.4 (95% CI, 1.1–1.9), p = 0.02
  • Stage III disease vs Stage I/II: HR = 1.6 (95% CI, 1.2–2.1), p = 0.001

Limitations

• The data is exclusively from patients who received auto-SCT
• There was no controlled comparator group of patients who did not receive transplants
• The selection bias going into the study is unknown, as information regarding rationale behind choice of treatment regimen is missing
• Only patients receiving auto-SCT within 12 months of diagnosis were included — data does not capture patients who delayed transplant therapy and physician preferences

Conclusions

This study showed patients ≥ 70 years old receiving auto-SCT were able to achieve similar anti-myeloma benefits in comparison to younger patients. Patients with MM that are ≥ 70 years old and receiving 140 mg/m² melphalan had worse outcomes, which included a higher NRM. The authors infer this is likely due to factors such as frailty or organ dysfunction that could be present in this patient population. To read more about the management of elderly patients with MM, click here.