Improve the survival prognosis and improve the quality of life, CD38 monoclonal antibody helps to break the dilemma of MM treatment for the elderly

Multiple myeloma (MM) is a malignant disease with abnormal proliferation of cloned plasma cells, with a median age of up to 69 years at the time of MM diagnosis, and the number of elderly MM patients is growing
rapidly as the current population ages more severely.
Frailty is particularly prevalent in older patients with MM, and an accurate assessment of frailty in older patients and the selection of appropriate treatment options for them is critical
to improving disease outcomes.
The small editor of this article will sort out the diagnosis and treatment strategies of elderly weak MM patients for everyone, the specific content is as follows
.

MM is more common in the elderly, and older MM patients are often in a frail state due to disease-related symptoms, decreased physical status, comorbidities, previous multiple medications, nutritional status and cognitive impairment, and a large proportion of these patients are poorly tolerated to conventional treatment regimens, and are more likely to stop treatment
due to toxicity and early death.
In real-world clinical practice, due to the lack of accurate identification of frailty, the risk of overtreatment, undertreatment, discontinuation of treatment, and adverse events in elderly patients with frail MM is often higher, which will have a negative impact on
their survival and quality of life.
At the same time, since most clinical trials exclude elderly frail patients, participating patients are generally younger and better in physical condition than typical MM ^patients1
.
Under many factors, the treatment of frail MM in the elderly faces great challenges
.

Therefore, clinicians should assess the patient's frailty when developing treatment strategies, stratify and individualize the patient's ^frailty2
.
Patient frailty status needs to be dynamically monitored during treatment and re-evaluated to further adjust subsequent treatment
.
The currently widely used frailty assessment tool is the International Myeloma Working Group (IMWG) frailty scoring system, which combines age, comorbidities, and functional status to classify patients into healthy (fit; score = 0), intermediate fitness (intermediate fitness; Score = 1) and frail (frail; Score ≥2) three groups and have been shown to predict mortality and toxicity risk
in older MM patients.
Other commonly used assessment tools include the revised Myeloma Comorbidities Index (R-MCI) and the UK Myeloma Research Consortium Risk Prediction Model (MRP
).
The scoring parameters and assessment methods of different frailty assessment tools are not exactly the same
.
R-MCI specifically considered lung function, renal function, and cytogenetic abnormalities, and there were significant differences in progression-free survival (PFS) and overall survival (OS) in patients based on the R-MCI ^grouping2
.

The First Affiliated Hospital of Sun Yat-sen University developed a new frailty prediction model more suitable for MM patients in China, TM Frailty Score ³, based on the IMWG frailty scoring system, which combined the stand-up walking test (TUG) and the Brief Table of Micro Nutritional Assessment (MNA-SF) to further distinguish the risk of adverse events between the health (fit) group and the frail group (Figure 1).

More research is underway to optimize and refine frailty assessment tools that are expected to help identify patients with frail MM more accurately and develop more appropriate treatments
.

Figure 1 Grade 3 adverse event incidence and OS ≥ by IMWG frailty scoring system (a/b) and TM frailty score (c/d).

For the treatment of elderly patients with frail MM, it is necessary to comprehensively assess the patient's factors, disease factors and social factors before treatment, and carefully select a treatment plan
that takes into account both efficacy and tolerable toxic side effects 。 Therefore, elderly patients with weak MM receive low-intensity chemotherapy regimens, and can usually consider a combination of two drugs to reduce the dose of treatment regimens, such as bortezomib combined with dexamethasone (Vd), lenalidomide combined with dexamethasone (Rd), isazomib combined with dexamethasone (Id), etc.
, to achieve better tolerability, improve quality of life as the main treatment goals, but its survival improvement for patients is still limited, the clinical need for efficient and low-toxicity treatment drugs, in order to ensure that toxic side effects can be tolerated as much as possible to deepen the depth of remission, Improve response rates
.

The addition of new drugs such as CD38 monoclonal antibody darleturumab (Dara) and Isatuximab (Isa) provides more treatment options
for elderly patients with frail MM.
MAIA Study ⁴ divided 737 newly diagnosed MM (NDMM) patients who were not suitable for transplantation into 3 groups based on frailty scores, and the results showed that the Dara combined Rd (DRd) regimen resulted in significantly better PFS benefits than Rd regardless of frail states (fit, intermediate fitness, and frail) (Figure 2).
The median PFS in the DRd and Rd groups was not achieved and 30.
4 months, respectively, in the frail subgroup, and the rates of complete or better response (≥CR) and minimal residual disease (MRD) negative rates (23.
8% vs 10.
1%) were both improved
.
ALYCONE Study ⁵ Debilitating Subgroup Analysis (Figure 3) also confirmed that the addition of Dara to bortezomib in combination with mevalin and prednisone could benefit more
from PFS in frail patients.
Two studies have shown that the combination of CD38 monoclonal antibody can be used as the preferred treatment for elderly patients with frail NDMM and have good application prospects
.

Figure 2 MAIA studies PFS in each weak subgroup

Figure 3 ALCYONE studies PFS in each weak subgroup

In addition to being used to treat NDMM, the CD38 monoclonal antibody combination regimen has also shown positive effects
in elderly patients with frail relapse/refractory MM (RRMM).
The results of the CANDOR Study ⁶ Frailty Subgroup analysis (Figure 4) published at the 2022 EHA Annual Meeting showed that the combination of carfezomib and dexamethasone (Kd) in combination with Dara (DKd) resulted in a therapeutic benefit for patients with varying degrees of debilitation in RRMM patients (debilitating subgroup: median PFS 18.
5 vs 9.
3 months; Overall response rate [ORR] 75% vs 54%) with no increase in
toxicity.

Figure 4 Mitigation data for each subgroup of the CANDOR study

Another ICARIA-MM ^study7 of patients with RRMM evaluated the efficacy and safety of pomadomide combined with dexamethasone (Pd) and Isa in combination with Pd (Isa-Pd) (Figure 5).

In frail patients, ORR (52.
1% vs 34.
2%) and very good partial or better remission (≥VGPR) rates (29.
2% vs 2.
6%) were higher in the Isa-Pd group, median PFS was longer (9.
0 vs 4.
5 months), and more patients achieved MRD-negative
.
Clinical outcomes tend to improve in patients who receive the Isa-Pd regimen who are frail compared to the Pd regimen, possibly helping patients achieve deep remission
.

Figure 5 Mitigation data for each subgroup of the ICARIA-MM study

In terms of safety, the toxicity observed in frail patients receiving Isa-Pd is manageable, similar to that observed in non-frail patients, with treatment discontinuation rates and duration of treatment commensurate
.
The findings further support the benefits
of the Isa-Pd regimen for elderly patients with frail RRMM.

At present, the emergence of some drugs with new mechanisms of action, such as the nuclear output protein inhibitor Selinizol, has also provided new ideas
for the treatment of elderly patients with frail MM.
A retrospective subgroup analysis of BOSTON Study ⁸ showed that Selinizol plus Vd (XVd) was safe and effective
in elderly patients with frail MM who had previously been treated.
In the frail subgroup (Figure 6), the XVd group had longer PFS (median PFS 13.
93 vs 9.
46 months) and OS (median OS NR vs 23.
49 months) than the Vd group, and there was a tendency
to improve in the duration of median remission and the time to next treatment.
In terms of safety, the incidence of any grade of peripheral neuropathy in frail patients treated with XVd was significantly lower than in the Vd group (27.
3% vs 50.
0%)
.

Figure 6 BOSTON studies PFS and OS trends in each subgroup

Elderly patients with frail MM have a poor prognosis and need to develop or optimize more effective frailty assessment tools to accurately identify and treat
them on the premise that toxic side effects are tolerated.
A number of research results have shown that the combination therapy based on new drugs such as CD38 monoclonal antibody and Selinizol can significantly improve the clinical efficacy and controllable safety of elderly patients with frail MM, and it is expected that more clinical studies will be carried out in the future to bring safer and more effective treatment options for elderly patients with frail MM and help improve their clinical outcomes
.

*Isatuximab has not been approved in Chinese mainland

MAT- CN-2222106

References

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