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In reality, CD38 monoclonal antibody can still benefit RRMM patients in the real world

 Last Update: 2022-10-26
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Multiple myeloma (MM) is a malignant disease with abnormal proliferation of clonal plasma cells, with ^{the second highest} annual incidence among hematological tumors1, and is still incurable, almost all patients with MM will eventually relapse, and the treatment options for relapsed and refractory (RR) MM are limited, and the survival outcome of patients is poor
。 In recent years, the treatment of MM has made rapid progress, and with the clinical application of new drugs and therapies such as immunomodulators (IMiDs), proteasome inhibitors (PIs), CD38 monoclonal antibodies, and CAR-T therapy, the survival of RRMM patients has been significantly improved
in the past two decades.
This article will sort out the treatment status of RRMM patients and the use of a variety of new drugs in the real world, the details are as follows
.

There is still a long way to go, and the recurrence and refractory treatment of MM seriously affects the survival and prognosis of patients

MM is a group of diseases with significant heterogeneity in biological behavior and clinical manifestations, and each patient has a different trajectory of MM, but almost all patients with MM eventually relapse or develop drug resistance, and the depth of remission after each recurrence usually decreases gradually, and the duration of remission is constantly shortened
.
The efficacy of pharmacological therapy for MM diminishes with multiple recurrences of the disease, resulting in greater challenges in the treatment of patients with posterior line recurrence (Figure 1)²
.

Figure 1.
MM disease trajectory characterized by malignant transformation

Recurrence of MM seriously affects patient prognosis and survival, and as the number of MM recurrences increases, the median progression-free survival (PFS) of patients gradually decreases, and a real-world study of 391 RRMM ^patients3 found that the median PFS (mPFS) was 11.
1 months in patients receiving first-line therapy, compared with only 5.
4 months in patients receiving fifth-line therapy (Figure 2A).

In addition, an increase in the number of relapses also leads to a decrease in overall survival (OS), with a Dutch real-world ^study4 of 1922 patients with symptomatic MM showing that median OS (mOS) can reach 37.
5 months in patients receiving first-line therapy, with mOS significantly decreasing as the number of recurrences increases, and patients receiving fourth-line therapy having OS of only 9.
2 months (Figure 2B).

Figure 2.
With the number of relapses increases the patient's mPFS and OS condition

A hundred flowers are blooming, and real-world research on new drugs to treat RRMM is full of surprises

For patients with MM with the first recurrence, the goal of treatment is to achieve maximum remission and prolong PFS, and for patients with multi-line relapsed MM, the main treatment goal should be to improve the quality of life of the patient, on this basis, to obtain the maximum remission
as much as possible.
At present, domestic and foreign guidelines first recommend RRMM patients to enter clinical trials, and those who are suitable can undergo autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation
.
Newer drugs are critical to the treatment of RRMM and are often used
in combination with other types of drugs.
High-risk patients generally choose a three- or four-drug combination regimen containing IMiDs or PIs; Standard-risk or older patients may prioritize a two-drug regimen containing IMiDs or ^PIs5
.

With the emergence of new drugs and therapies, including IMiDs, PIs, CD38 monoclonal antibody and CAR-T therapy, RRMM patients have access to more new treatment options
.
CD38 is the most widely explored target in RRMM therapy so far, and CD38 monoclonal antibody has been recommended for the treatment of RRMM
by many guidelines at home and abroad.
Daratumab (Dara) is currently available in China, and its efficacy in combination with lenalidomide, dexamethasone (D-Rd) and bortezomib and dexamethasone (D-Vd) regimens has been verified
in both POLUX studies and CASTOR studies.
The Dara combination regimen also showed good efficacy in a real-world ^study6 of 34 patients with RRMM, with an overall response rate (ORR) of 88% for all patients, a complete response (CR) rate of 12%, a very good partial response (VGPR) rate of 44%, and a partial response (PR) rate of 32%.

At a median follow-up of 16 months, mPFS and mOS had not yet reached (NR), and the 12-month PFS and OS rates were 78% and 86.
5%, respectively (Figure 3).

Figure 3.
Kaplan-Meier survival curve (A) All patients PFS, (B) All patients OS

In addition to Dara, the new CD38 monoclonal antibody Isatuximab (Isa) combination regimen also has good antimyeloma activity
.
Based on the phase III ICARIA-MM and IKEMA studies, the Isa plus pomalidomide and dexamethasone (Isa-Pd) regimen and the Isa plus carfilzomib and dexamethasone (Isa-Kd) regimen have been approved by the US Food and Drug Administration (FDA) for RRMM patients
, respectively.
The results of the interim analysis of the IMAGE ^study7 were presented at the 19th Annual Meeting of the International Myeloma Society (IMS) in 2022, and the real-world application of the Isa-Pd regimen in France demonstrated good efficacy and controllable safety
.
All patients were followed at a median follow-up of 14.
2 months and mPFS at 12.
4 months (95% CI 9.
0–15.
0), which was consistent with the Isa-Pd subgroup results in the ICARIA-MM study (mPFS 11.
1 months [95% CI 7.
8–13.
8]).

The study also reported for the first time the use of Isa-Pd in patients with first-time relapsed MM, who had not yet achieved mPFS (NR; 95% CI 9.
6–NR), suggesting that Isa-Pd is a potential frontline treatment option
.
The results of the first interim analysis of another non-interventionist, international, observational IONA-MM study of Isa-Pd^/Isa-Kd8 were also presented at the IMS conference, and the IONA-MM study was comparable to the baseline characteristics of patients in the ICARIA-MM and IKEMA studies, with a controlled safety profile in real-world reception of Isa-Pd and Isa-Kd, and more efficacy and safety results are expected in the future
。

Ixazomib is an oral, highly selective PIs, and a multicenter, prospective, observational ^study9 explored the real-world use of ixazomib in combination with lenalidomide and dexamethasone (IRd) in 295 Japanese RRMM populations
.
The median follow-up of the study was 25.
0 months, and the patient had mPFS of 15.
3 months (95% CI 12.
4 to 19.
5), which did not achieve mOS
.
The median time to next treatment (TTNT) and duration of response (DOR) were 13.
2 and 29.
7 months, respectively, and the ORR and ≥VGPR rates were 53.
9% and 31.
5%,
respectively.
The most common adverse events were diarrhoea (27.
1%), low platelet count (26.
4%), low neutrophil count (25.
8%), and low white blood cell count (23.
7%)
.
It can be seen that IRd can be used as an
effective and tolerable treatment option for RRMM patients in the real world.

Belantamab mafodotin (BM) as an antibody conjugate (ADC) targeting B cell maturation antigen (BCMA) has also contributed to the treatment of RRMM, a multicenter retrospective real-world study of ¹⁰ patients with RRMM evaluated efficacy, the results showed an ORR of 45.
5% and a CR rate of 4.
0%, The VGPR rate was 13.
9% and the PR rate was 27.
7%.

At a median follow-up of 11.
9 months, mPFS for the entire patient cohort was 4.
7 months (95% CI 3.
5-5.
9), mDOR was 8.
1 months (95% CI 5.
7-10.
5), and mOS was 14.
5 months (95% CI 9.
5-19.
6) (Figure 4).

This study results show that BM works well in real-world RRMM patients, with ORR, DOR and toxicity comparable to DREAMM-1 trial results, further confirming the value
of BM in the afterline treatment of RRMM.

Figure 4.
BM should be used for survival in patients with RRMM

Idecabtagene vicleucel (ide-cel) is a BCMA-targeted CAR-T immunotherapy that retrospectively analyzed data
from RRMM patients treated with ide-cel at ¹¹ centers in the United States.
By day 90, the 141 patients evaluated had an optimal ORR of 86% and a ≥ CR rate of 42%.

The median follow-up was 5.
3 months, mPFS was 8.
9 months, and mOS was not achieved
.
In terms of safety, IDE-cel toxicity in this study was similar to that of the KarMMa trial, with cytokine release syndrome (CRS) occurring in 82% of patients and neurotoxicity
occurring in 18% of patients.
The above results show that the safety and efficacy of IDE-cel standard therapy in real-world RRMM patients are comparable to the phase II KarMMa trial (Figure 5), and it is the preferred treatment for RRMM patients with good application prospects
.

Figure 5.
IDE-cel is used in clinical trials and PFS and OS in real-world RRMM patients

Summary and outlook

As a highly heterogeneous hematological malignancy, patients with MM will eventually fall into the dilemma of relapse and difficult treatment, and with the increase of the number of treatment lines, the remission and survival of RRMM patients will become more and more poor, and new drugs and new therapies are urgently needed to improve the treatment status and delay survival
.
In the era of new drugs, various new treatment methods have emerged, which has greatly enriched the treatment options
of RRMM patients.
A number of real-world studies have shown that the treatment regimens represented by CD38 monoclonal antibody, ADC and CAR-T have outstanding efficacy and safety in practical application, showing excellent application prospects, and it is expected to bring clinical benefits to more RRMM patients in the future!

*Isatuximab has not yet been approved in Chinese mainland

MAT-CN-2224085

References:

1.
Guidelines for the diagnosis and treatment of multiple myeloma in China (2021 revised edition)

2.
Kurtin SE.
Relapsed or Relapsed/Refractory Multiple Myeloma.
J Adv Pract Oncol 2013; 4(Suppl 1):5-14

3.
Jagannath S, et al.
Expert Rev Hematol.
2016 Jul; 9(7):707-17.

4.
Verelst SGR, et al.
Hemasphere.
2018; 2(4):e45.

5.
2022 CSCO Guidelines for the Diagnosis and Treatment of Hematology Malignant Diseases

6.
Fucci L, et al.
Leuk Res Rep.
2022 May 30; 17:100330.

7.
Xavier Leleu,et al.
2022 IMS.
P-255

8.
Thomas Martin, et al.
2022 IMS.
P-258

9.
Masaki Iino, et al.
2022 IMS.
P-248

10.
Tamir Shragai, et al.
2022 IMS.
P-114

11.
Doris Hansen, et al.
2022 IMS.
OAB-004

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