Multiple myeloma (MM) is a malignant disease with abnormal proliferation of clonal plasma cells. It ranks second among hematologic tumors in 1. It is still incurable. Almost all MM patients will eventually relapse. The treatment plan for relapsed refractory (RR) MM is limited, and the patient's survival outcome is poor. The treatment of MM has progressed rapidly in recent years. With the clinical application of new drugs and therapies such as immunomodulators (IMiDs), proteasome inhibitors (PIs), CD38 monoclonal antibody, and CAR-T therapy, the survival status of RRMM patients has improved significantly in the past two decades. This article will organize the current treatment status of RRMM patients and the use of various new drugs in the real world. The specific content is as follows.
has a long way to go. Relapse of MM is refractory to treat severely affecting the survival and prognosis of patients
MM is a group of diseases with significant heterogeneity in biological behavior and clinical manifestations. The MM disease trajectory of each patient is different, but almost all MM patients will eventually relapse or develop drug resistance, and the depth of remission after each recurrence is usually gradually reduced, and the duration of remission is continuously shortened. The efficacy of MM's drug treatment will gradually weaken with multiple recurrences of the disease, resulting in greater challenges in the treatment of patients with post-line relapses (Figure 1) 2.
Figure 1. MM disease trajectory characterized by malignancy The recurrence of
MM seriously affects the prognosis and survival of patients. With the increase in the number of MM recurrences, the median progression-free survival (PFS) of patients gradually decreased. A real-world study of 391 RRMM patients 3 found that the median PFS (mPFS) in patients receiving first-line treatment was 11.1 months, while the mPFS in patients receiving fifth-line treatment was only 5.4 months (Figure 2A). In addition, the increase in the number of recurrences will also lead to a decrease in the overall survival (OS) of patients with 1922 symptomatic MM. The Dutch real-world study 4 showed that the median OS (mOS) in patients receiving first-line treatment can reach 37.5 months. With the increase in the number of recurrences, the patient's mOS significantly decreased, and the OS in patients receiving fourth-line treatment was only 9.2 months (Figure 2B).
Figure 2. As the number of relapses increases, patients with mPFS and OS are blooming, and new drugs are constantly in real-world research on RRMM is surprisingly constantly
. For patients with first relapse, the treatment goal is to obtain the greatest relief, extend PFS. For patients with multiline relapse MM, improve the quality of life of patients, and achieve the greatest relief as much as possible on this basis. At present, domestic and foreign guidelines first recommend RRMM patients to enter clinical trials. Those with appropriate conditions can undergo autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation. New drugs are very critical for 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; patients with severity or elderly patients can give priority to trying a two-drug combination regimen containing IMiDs or PIs 5.
With the continuous emergence of new drugs and new therapies including IMiDs, PIs, CD38 monoclonal antibody and CAR-T therapy, RRMM patients have obtained more new treatment options. CD38 is the most widely explored target in RRMM treatment so far, and CD38 monoclonal antibody has been recommended by many domestic and foreign guidelines for the treatment of RRMM. Dara is now available in China, and the efficacy of its combination with lenalidomide , dexamethasone (D-Rd), combined with bortezomib and dexamethasone (D-Vd) regimens has been verified in the POLLUX study and CASTOR study. The Dara combined regimen also showed good efficacy in the real-world study of 6 in 34 patients with RRMM. The total response rate (ORR) of all patients was 88%, the complete response (CR) rate was 12%, the very good partial response (VGPR) rate was 44%, and the partial response (PR) rate was 32%. At median follow-up of 16 months, mPFS and mOS have not yet reached (NR), with 12-month PFS and OS rates of 78% and 86.5%, respectively (Figure 3).
Figure 3. Kaplan-Meier survival curve (A) PFS in all patients, (B) OS
in all patients, except Dara, the novel CD38 monoclonal antibody Isatuximab (Isa) combination therapy regimen also has good anti-myeloma activity.Based on the Phase III ICARIA-MM and IKEMA study, the Isa combined with pomalidomide and dexamethasone (Isa-Pd) regimen and Isa combined with kafezomib and dexamethasone (Isa-Kd) regimens have been approved by the U.S. Food and Drug Administration (FDA) for RRMM patients, respectively. The results of the IMAGE interim analysis of 7 have been announced at the 19th International Society of Myeloma (IMS) Annual Meeting in 2022. The application of the Isa-Pd program in the real world in France has demonstrated good efficacy and controllable safety. The median follow-up was 14.2 months for all patients and 12.4 months for mPFS (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]). This study also reported for the first time the use of Isa-Pd in patients with first relapsed MM, who had not achieved mPFS (NR; 95% CI 9.6–NR) in patients who had received only 1-line treatment, indicating that Isa-Pd is a potential frontline treatment option. Another interim analysis of the non-intervention, international, observational IONA-MM study of Isa-Pd/Isa-Kd was also announced at the IMS conference. The IONA-MM study was comparable to the baseline characteristics of patients in the ICARIA-MM and IKEMA study. It has controllable safety in the real world. We look forward to more announcements of efficacy and safety results in the future.
Isazomir is an oral, highly selective PIs. A multicenter, prospective, observational study 9 explores the real application of the isazomib combined with lenalidomide and dexamethasone (IRd) protocol in 295 Japanese RRMM population. The median follow-up of this study was 25.0 months, with the patient's mPFS of 15.3 months (95% CI 12.4-19.5), and did not achieve mOS. The median to next treatment time (TTNT) and duration of remission (DOR) were 13.2 months and 29.7 months, respectively, with ORR and ≥VGPR rates of 53.9% and 31.5%, respectively. The most common adverse events of were diarrhea (27.1%), decreased platelet count (26.4%), decreased neutrophil count (25.8%) and decreased leukocyte count (23.7%). It can be seen that in the real world IRd can be one of the effective and tolerant treatment options for RRMM patients.
Belantamab mafodotin (BM) as an antibody-conjugated drug (ADC) targeting B-cell mature antigen (BCMA) also contributed to the treatment of RRMM. A multi-center retrospective real-world study 10 evaluated the efficacy of 101 RRMM patients. The results showed that the patient's ORR was 45.5%, the CR rate was 4.0%, the VGPR rate was 13.9%, and the PR rate was 27.7%. Median follow-up was 11.9 months, with mPFS of the entire patient cohort of 4.7 months (95%CI 3.5-5.9), mDOR of 8.1 months (95%CI 5.7-10.5), and mOS of 14.5 months (95%CI 9.5-19.6) (Figure 4). This study results show that BM is effective in the treatment of real-world RRMM patients, and the ORR, DOR and toxicity are comparable to the results of the DREAMM-1 trial, further confirming the value of BM in post-line treatment of RRMM.
Figure 4. Survival of BM in RRMM patients
Idecabtagene vicleucel (ide-cel) is a CAR-T immunotherapy targeting BCMA. A real-world study 11 retrospectively analyzed data on RRMM patients who received ide-cel treatment in 11 centers in the United States. By day 90, the optimal ORR of 141 patients evaluated was 86%, and the ≥CR rate was 42%. The median follow-up was 5.3 months, mPFS was 8.9 months, and mOS was not achieved. In terms of safety, the toxicity of ide-cel in this study is similar to that of the KarMMa trial, with cytokine release syndrome (CRS) present in 82% of patients and neurotoxicity present in 18% of patients. The above results show that the safety and efficacy of IDE-cel standard treatment in real-world RRMM patients is comparable to that of the Phase II KarMMa trial (Figure 5). It is the preferred treatment plan for RRMM patients and has good application prospects.
Figure 5. IDE-cel application in clinical trials and real-world PFS and OS
summary and prospects
MM As a highly heterogeneous hematologic tumor, patients will eventually fall into a dilemma of recurrence and refractory. As the number of treatment lines increases, the remission and survival of RRMM patients becomes increasingly poor, and new drugs and new therapies are urgently needed to improve the current treatment status and delay survival. In the era of new drugs, various new treatment methods are coming one after another, greatly enriching the treatment options for RRMM patients.Several real-world studies have shown that treatment plans represented by CD38 monoclonal antibody, ADC and CAR-T are highly effective and safe in actual applications, showing excellent application prospects, and we look forward to bringing clinical benefits to more RRMM patients in the future!
*Isatuximab has not been approved in mainland China
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 Guidelines for diagnosis and treatment of CSCO hematologic 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
Editing: Hui-Y
Review: Irena
Typesetting: moly
Execution: moly
