Gathering in the Cloud, Peak Dialogue-Professor Usmani talks about optimizing treatment for relapsed MM

On October 16, 2021, the 3rd Great Wall Blood Forum of the Hematology Professional Committee of the Chinese Medical Education Association was held in 2021.
The conference invited Professor Saad Z.
Usmani from the Levin Cancer Institute in the United States, Chinese and foreign experts gathered in the cloud, peak dialogue, focus International frontier hot spots of multiple myeloma (MM), listen to Chinese and foreign academic strong voices, and share academic feasts
.

Optimal selection of patients with relapsed MM for the first time Under the auspices of Professor Hu Yu from Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, Professor Saad Z.
Usmani gave a special lecture on the optimal treatment of early relapse of MM based on actual clinical cases, and elaborated on the latest clinical practice.
The treatment recommendations for the first relapse of MM in the practice guidelines focus on sharing the treatment considerations for relapsed and refractory multiple myeloma (RRMM) and how to formulate an individualized treatment plan based on patient characteristics and clinical evidence-based medicine evidence
.

Professor Saad Z.
Usmani first introduced a 75-year-old female patient with mild eucellular anemia and mild renal insufficiency.
The patient was diagnosed with R-ISS II IgGκ type t(11;14) MM.
After 4 cycles of RVd (lenalidomide + bortezomib + dexamethasone) induction therapy, a very good partial remission was achieved.
After receiving lenalidomide maintenance therapy for about 1 year, the treatment was stopped, and 1 year later There was an increase in M ​​protein and a decrease in hemoglobin level but no clinical symptoms.
FISH results of myeloma after re-staging showed del(17p) and t(11;14)
.

Professor Saad Z.
Usmani pointed out that the treatment of RRMM needs to consider the patient, disease and previous treatment factors to choose a plan: patients who are not refractory to first-line bortezomib can still choose treatment based on proteasome inhibitors after the first relapse
.

The current large-scale phase III clinical studies of ENDEAVOR (Kd vs Vd), PANORAMA (PanoVd vs Vd), CASTOR (DVd vs Vd), OPTIMISSMP (PomVd vs Vd) have all explored the application of new drugs combined with proteasome inhibitors in RRMM
.

Among them, the ENDEAVOR study of a head-to-head comparison between a new generation of proteasome inhibitors and bortezomib in RRMM showed that the Kd (carfilzomib + dexamethasone) regimen was significantly improved compared to the Vd (bortezomib + dexamethasone) regimen.
Progressive survival (PFS) (18.
7 months vs 9.
4 months, P<0.
0001), especially in patients with first relapse, the Kd regimen compared with the Vd regimen significantly improved PFS (22.
2 months vs 10.
1 months, P<0.
0001) and OS (51.
3 months vs 43.
7 months, P=0.
0330)
.

For patients whose first-line lenalidomide is not difficult to treat, the combination of new drugs and Rd is still an option to consider
.

The current large-sample phase III clinical studies ASPIRE (KRd vs Rd), TOURMALINE (IRd vs Rd), ELOQUENT-2 (Elo-Rd vs Rd), POLLUX (Dara-Rd vs Rd) have all explored the combination of new drugs and Rd in RRMM In the ASPIRE study, KRd (carfilzomib + lenalidomide + dexamethasone) can bring a median PFS of 26.
3 months, which is significantly better than the Rd (lenalidomide + dexamethasone) regimen (17.
6 months, P=0.
0001).
For patients who relapsed for the first time, 12 months of PFS (29.
6 months vs 17.
6 months) were not refractory to first-line bortezomib and lenalidomide, the original For treatment, you can also choose a three-drug combination of new drugs
.

First-line bortezomib and lenalidomide refractory patients, although most phase III studies did not enroll a large number of lenalidomide refractory patients, based on the current research data, pomalidomide or Carfilzomib-based treatment programs have shown effectiveness for patients refractory to lenalidomide
.

The study evaluating pomalidomide combined with low-dose dexamethasone and carfilzomib regimen (NCT01464034) enrolled bortezomib refractory (97%) and lenalidomide refractory (100%) patients, showing Good anti-tumor activity (objective response rate [ORR] up to 50%, median PFS up to 7.
2 months); the CANDOR study also included refractory to first-line proteasome inhibitors (30%) and refractory to lenalidomide ( 33%) of patients, the results showed that the ORR of the DKd (daratumomab + carfilzomib + dexamethasone) group was 84%; the median PFS was 28.
6 months
.

In addition, based on the recommendations of the latest IMWG guidelines, the treatment plan chosen by patients with first relapse is also used as the treatment plan for patients with lenalidomide resistance
.

DRd (daratumomab + lenalidomide + dexamethasone) or KRd treatment can be used as the first-line treatment for patients with lenalidomide resistance, PVd (pomalidomide + bortezomib + dexamethasone) , DKd and lsa-Kd (Ixazomib+lenalidomide+dexamethasone) can be used as alternative treatment options
.

Professor Saad Z.
Usmani said that the patient's initial response, physical condition, age, and comorbidities are all factors that need to be considered when selecting and optimizing treatment options for patients with early relapse
.

Randomized trials have shown that switching to next-generation drugs or a new class of drugs can achieve the best efficacy
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For patients who have relapsed for the first time, if the disease progresses rapidly or the symptoms are obvious at the time of relapse, it is recommended to give VD-PACE or KD-PACE regimen for salvage treatment before using the new treatment regimen
.

For the above patients, first chose to continue KRd treatment, and chose DPd (daratumomab + pomalidomide + dexamethasone) combination therapy when there was a second relapse after 27 cycles
.

Finally, Professor Saad Z.
Usmani also introduced the exploration of new small-molecule targeted drugs in RRMM, including XPO-1 inhibitor Selinexor and BCl-2 inhibitor Venetoclax.
Among them, Venetoclax combined with bortezomib and dexamethasone regimens for the treatment of RRMM The ORR of RRMM combined with carfilzomib and dexamethasone was 79%.
In a phase I exploration, carfilzomib refractory (95%) and pomalidomide were included.
Refractory (81%) and double-drug refractory/quadruple exposure (81%) relapsed patients, explore the efficacy of Selinexor combined with carfilzomib and dexamethasone, ≥minimal remission (MR) rate, ≥partial remission The (PR) rate and the very good partial remission (VGPR) rate were 71%, 48%, and 14%, respectively
.

Wonderful discussion review.
Under the auspices of Professor Qiu Lugui from the Hospital of Hematology of the Chinese Academy of Medical Sciences, experts at the meeting discussed with Saad Z.
Professor Usmani exchanged in-depth views.
The main contents are as follows: 1.
How to judge which drugs are refractory to first-line MM patients? Professor Saad Z.
Usmani proposed that if a patient progresses after 2 or 2.
5 years of first-line treatment, it cannot be judged that the patient is refractory to the first-line treatment.
According to the definition of IMWG, "refractory" refers to disease progression within 60 days of the last treatment
.

If the patient cannot continue to take the drug for three or four months or the disease progresses, the patient is highly likely to be refractory to the drug.
If the patient uses the three-drug combination therapy and the disease progresses, it indicates that the patient It is refractory to the three drugs
.

Clinically, we should pay attention to the quality of bone marrow specimen sampling, because it is very important to predict the patient's condition.
In order to reduce the error in diagnosis, it is usually recommended to perform multiple bone marrow biopsy or FISH tests
.

2.
Can CAR-T cell therapy be recommended as a second-line treatment? Professor Saad Z.
Usmani said: Judging from the current clinical data, CAR-T treatment cannot completely cure patients, and the timing of treatment should be selected reasonably
.

Under normal circumstances, CAR-T therapy can be used as a four-line option
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For high-risk, MM patients who relapse six months after the first treatment or undergo autologous transplantation, CAR-T treatment can be performed as soon as possible
.

Early CAR-T treatment is not recommended for patients with standard risk or who can obtain longer PFS after first-line treatment
.

Concluding Remarks Sino-foreign Cloud Dialogue focuses on MM in-depth discussion of individualized plans for early relapse treatment.
The content of keynote speeches is rich, the discussion sessions are wonderful, and the dialogue and exchanges have profound meanings, allowing academics to cross national boundaries
.

It is hoped that through the successful convening of this meeting, more patients with hematological tumors can receive more standardized diagnosis and treatment
.

Saad Z.
UsmaniClinical Professor of Medicine, UNC-Chapel Hill School of Medicine Chief, Plasma Cell Disorders Division, Levine Cancer Institute, Charlotte, NCDirector, Clinical Research in Hematologic MalignanciesLevine Cancer Institute, Charlotte, NC