【Cancer Med】Real-world first-line treatment model and outcome of elderly multiple myeloma in China

For elderly patients with multiple myeloma (MM), the current treatment regimen is not standardized, and older patients are mostly excluded from clinical trials due to age and comorbidities, so real-world data is particularly important
.
However, there are relatively few real-world studies in elderly MM patients, and there is a particular lack of
real-world studies on treatment patterns and survival data in elderly MM patients in China.

In a recent real-world study in Cancer Medicine, the authors analyzed the first-line treatment models of elderly MM patients from four major medical centers in China (Beijing Jishuitan Hospital, Beijing Chaoyang Hospital, Peking University First Hospital, and Peking Union Medical College Hospital), compared the impact of induction therapy regimen and maintenance therapy on clinical outcomes, and discussed the current real-world practice to provide reference
for further improving the survival rate of elderly MM patients in the future.
The corresponding author of the article is Professor Zhuang Junling, and the first author is Professor
Bao Li.

Design research

This study collected data from 362 newly diagnosed elderly MM patients (aged ≥ 65 years) from four medical centers in China (Beijing Jishuitan Hospital, Beijing Chaoyang Hospital, Peking University First Hospital, Peking Union Medical College Hospital) from January 2016 to December 2020, all of whom met IMW diagnostic criteria
.
Patients with smoke-type MM, plasma cell leukemia, or solitary plasma cell tumors, as well as conventional chemotherapy with
only a small number of patients, were excluded.

Detailed baseline data were collected, including age, sex, M protein type, hemoglobin (HGB), calcium, lactate dehydrogenase (LDH), and bone marrow plasma cell ratios, as well as
complications.
None of the patients received a transplant and were divided into 3 groups according to the type of first-line induction therapy: group 1, containing PI (bortezomib or ixazomib); Group 2, containing IMiDs (lenalidomide or thalidomide); Group 3, including PI and IMiDs
.

Research knot

Of the 362 patients, 24 (10 males and 14 females) abandoned treatment for economic reasons, and 10 (6 males and 4 females) were excluded due to traditional chemotherapy, including a total of 328 patients, and the baseline data are shown in Table 1
.
Among them, there were 177 males and 151 females, with a median age of 70 years old, and the detailed age distribution was 65-70 years old 172 cases (52.
43%), 71-79 years old 130 cases (39.
63%), ≥ 80 years old 26 cases (7.
93%)
.
ISS stage III patients accounted for 59.
76%, and R-ISS III.
patients accounted for 36.
89%.

The high-risk ratio of FISH was 18.
90%, and the proportion of patients with weak GA score was less than one-third (22.
26%)
.

Baseline differences in the three groups

As shown in Table 2, the proportion of hypoproteinemia (ALB < 30 g/L), renal failure (eGFR≤ 40 mL/min), high risk of FISH, or GA score fit was higher in group 3 than in groups 1 and 2 (p< 0.
05).

。 Other characteristics including age, sex, β2-MG level, percentage of bone marrow plasma cells, hypercalcemia (≥2.
75 mmol/L), high LDH (≥ 250 IU/L), anemia (HGB< 100 g/L), ISS or R-ISS stage distribution were not statistically significant between the three groups (p> 0.
05).

Efficacy of different first-line induction regimens

Of all 328 patients, 75 who had not completed 2 cycles were not candidates for assessment of response, and a total of 253 patients received a median of 8 cycles of induction chemotherapy with no difference in the median number of first-line cycles between the three groups (8 cycles in groups 1 and 3, 9 cycles in group 2, p=0.
133).

185 patients achieved ≥ PR remission; The ORR of all patients was 73.
12% (185/253), of which the 1st, 2nd, and 3rd groups were 71.
08%, 66.
67%, and 85.
42%,
respectively.
The proportion of patients who achieved a deep response (≥VGPR) in each group was 39.
16%, 25.
64% and 62.
50%,
respectively.
Group 3 had higher ORR and ≥ VGPR rates than groups 1 and 2 (p= 0.
016 and p=0.
018) (Table 3).

Multivariate analyses controlling for age, GA score, eGGR, ALB, ISS, and FISH risk confirmed that the type of first-line induction therapy had an independent effect
on the chances of achieving ≥ VGPR remission.
The PI+ IMiD regimen had deeper mitigation than the PI or IMiD-only regimen (corrected or, PI + IMiD vs.
PI = 0.
33; p= 0.
042; corrected or, PI + IMiD vs.
IMiD = 0.
29; p= 0.
043) (Table 4).

First-line maintenance therapy

Of the 185 patients who ≥ PR after induction therapy, 129 continued maintenance therapy, while the other 56 discontinued follow-up therapy
.
The median duration of maintenance therapy was 26 months, including 92 patients receiving IMiD (73 lenalidomide and 19 thalidomide), 20 PI patients (16 ixazomib and 4 bortezomib), and 17 PI + IMiD patients (ixazomib + lenalidomide).

The most common reasons for discontinuation during maintenance therapy were hematologic toxicity, rash, and diarrhoea, but data were not sufficiently detailed to further analyse the incidence
.

Long-term survival analysis

Results of univariate and multivariate analyses: 21 patients were lost to follow-up and 307 patients were available for survival analysis: 66 died and 241
survived.
The median PFS and OS for the entire cohort were 26 (IQR 12.
00-42.
8) months and 60 (IQR 40.
00-67.
20) months
.

Univariate analysis showed that age> 70 years, GA score frail, R-ISS stage III, hyperLDH, hypercalcaemia, induction therapy< PR, and no maintenance therapy were adverse predictors of PFS (p< 0.
05).

Age> 70 years, GA score frail, R-ISS STAGE III, HIGH LDH, HYPERCALCEMIA, EGFR≤ 40 mL/min, high risk of FISH, and lack of maintenance therapy are risk factors for predicting OS (p< 0.
05).

However, multivariate analysis showed only a GA score of frail, induction therapy at age 70 years, a GA score of frail, and an initial response

Impact of maintenance therapy on survival: PFS at 28 months, 18 months, and 26 months in groups 1, 2, and 3, respectively, did not differ significantly (p= 0.
182).

The OS for groups 1, 2, and 3 was 60 months, 59 months, and not reached (p= 0.
067), respectively (Figure 1).

PFS and OS were 26 and 40 months in patients not receiving maintenance therapy (n= 56), 48 months and not achieved in patients receiving maintenance therapy (n= 129), and PFS and OS were significantly shorter in patients not receiving maintenance therapy (p= 0.
016 and p= 0.
007) (Figure 2).

Effects of age on survival: median PFS for patients aged 65 to 70 years (n = 166), 71 to 79 years (n = 117), and ≥ 80 years (n = 24) years were 31 months, 23 months, and 14 months, respectively, and median OS was not achieved, 39 months, and 37 months
, respectively 。 PFS was significantly different across age groups (p= 0.
004); OS was significantly longer in the 65-70 age group than in the 71-79 and ≥80 age groups (n= 0.
002), but no difference in OS was observed between the 71-79 and ≥80 age groups (Figure 3).

Impact of post-induction remission status on survival: PFS for 28 months, 20 months, and 6 months in patients with different remissions (≥ VGPR [n= 105], PR [n= 80], and < PR [n= 68]), respectively, differed significantly (p= 0.
001); The corresponding OS for the three groups was not reached, 38 months, and 20 months, with also significant differences (p= 0.
001) (Figure 4).

Impact of GA score on survival: Patients with GA scores (n= 204) were divided into fit (0 points, n = 114,55.
88%), intermediate fit (1 point, n = 17,8.
33%), and frail (≥2 points, n = 73, 35.
78%), corresponding to PFS of 28, 21, and 14 months, and OS of 57, 38, and 30 months
。 Both the frail and intermediate fit groups had significantly shorter PFS and OS than the fit groups (p=0.
001 and p=0.
001) (Figure 5).

discuss

The authors analyzed the treatment patterns of elderly (≥ 65 years) MM patients at four large myeloma centers in China over the past 5 years, and showed that even though newer treatments including PI and IMiDS were already common (daratumumab was not available at the time), age > 70 years, general physical fitness frail, post-induction remission< PR, and no maintenance therapy remained independent risk factors for
OS.

Treatment options for MM patients who are not currently transplant-appropriate are not unique, and a two-drug regimen further improves ORR and PFS
compared with a regimen containing only one new drug.
Given the clinical benefit of Dara-RD in clinical trials in transplant-unsuitable MM patients (regardless of frail status), it is worthwhile to explore daratumumab in combination with PI or IMiD in the real world for older patients to further improve survival
.

Maintenance therapy after remission prolongs PFS and OS in older patients with MM, whereas approximately 30% (56/185) of remitters in this study did not start first-line maintenance therapy at the end of induction therapy
.
Although the cause has not been documented, older patients with MM are undertreated in China and urgently need to improve
.

The depth of first-line induction of remission is significantly correlated with survival, and in any case in the era of new drugs, the pursuit of deep remission in elderly patients is possible and still valuable
.
And it's not just the induction regimen itself that matters, but also first-line remission
.

Age is an important prognostic factor
in patients with MM.
In the era of traditional chemotherapy, the median OS of the elderly MM population in the 60-69, 70-79, and ≥80-year-old groups was only 20, 12, and 6 months, respectively, and after the widespread use of novel drugs, the OS in the corresponding age groups has been significantly extended in practice, such as 22 months in patients over 80 years
of age.
This study also showed that older age means poorer survival, but the new drug significantly improved outcomes in older patients of different age groups, especially OS at 37 months
≥ 80 years.

Due to comorbidities and poor physical fitness, a considerable proportion of elderly patients are excluded from clinical trials, and in fact, frailty assessment is very important because it affects not only treatment choice, but also clinical outcomes, for example, GA score is an independent predictor of OS, but GA score is not widely
used in the real world at present.
In fact, several studies have validated the prognostic value
of GA scores in practice.

In this study, factors such as high-risk cytogenetic abnormalities and stage R-ISS III did not show independent prognostic value
for OS.
Recent reports of clinical trial data suggest that the relative contribution of different prognostic factors in predicting disease risk varies by age, and that frailty score and comorbidity assessment are more important
than FISH and ISS staging in older patients with MM.
However, given that the prognostic value of these factors has been largely established through clinical trials, their real-world value may need to be further explored
.

Overall, this study cohort represents the actual treatment of older MM patients in China and found that induction therapy with PI+ IMiD alone has a deeper overall response rate than induction regimens containing PI or IMiD alone, and should be recommended to appropriate patients
.
Maintenance therapy can further improve efficacy, which also requires special attention
.

References

Li Bao, Ai-Jun Liu, Bin Chu,et al.
Front-line treatment efficacy and clinical outcomes of elderly patients with multiple myeloma in a real-world setting: A multicenter retrospective study in China.
Cancer Med .
2022 Oct 21.
doi: 10.
1002/cam4.
5234.

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