JHO: Dara-DCEP treatment with extramedullary lesions RRMM, ORR 67.7%, PFS 5 months

Extramedullary multiple myeloma (EMD) is an aggressive manifestation of multiple myeloma (MM) and has long been a difficult and painful point
in the treatment of MM.
Although survival for most patients with MM has improved in recent decades with the development of novel immunomodulatory drugs (IMiD), proteasome inhibitors (PI), CD38 monoclonal antibodies, etc.
, treatment outcomes for EMD remain unsatisfactory
.

Interestingly, this is an area where
traditional cytotoxic chemotherapy is still effective.
Although the data are not robust, the lymphoma-like regimen of stem cell transplantation after multiple chemotherapy regimens remains the current first-line regimen
based on available data.
Therefore, VD-PACE (bortezomib, dexamethasone-cisplatin, doxorubicin, cyclophosphamide, and etoposide) plus IMiD remain the recommended mainstay of treatment for EMD
, even as the treatment options for MM continue to increase.

Unfortunately, there is currently no standard treatment for patients with bortezomib refractory EMD, and daratumumab (DARA) has shown some promising efficacy in patients with EMD, with previous studies of daratumumab monotherapy in patients with EMD MM with approximately 20%
ORR.

To further explore the treatment of RRMM with EMD, Professor Youngil Koh et al.
of Seoul National University Hospital conducted a phase II study of DARA combined with chemotherapy DCEP (dexamethasone, cyclophosphamide, etoposide and cisplatin), which was recently published in the Journal of Hematology & Oncology
.

Study design

This is an open-label, multicenter, non-randomized phase II study that included > 19 years of age with multiple myeloma with EMD and relapsed/refractory to bortezomib, with other conditions including ECOG score 0-2, good bone marrow function, and exclusion of plasma cell leukemia
.
The definition of "EMD" includes (1) soft tissue masses in extraosseous locations; (2) Bone-associated plasma cell tumor
extending to continuous soft tissues through cortical bone destruction.

The study flow is shown in Figure 1A, where patients receive 3 cycles of DARA-DCEP induction therapy, followed by 5 cycles of DARA maintenance therapy
.
Induction period: 28 days/cycle; Days 1-4 dexamethasone 40 mg (oral or intravenous), cyclophosphamide 400 mg/m2, etoposide 40 mg/m2, cisplatin 10 mg/^m2; The allowable dose reduction of < 30%
for DCEP cycle 1.
Daratumab is given 16 mg/kg weekly for weeks 1 to 8 and 16 mg/kg
every two weeks for weeks 9 to 12.
In addition, to mitigate hematological adverse events of cytotoxic chemotherapy, prophylactic granulocyte colony-stimulating factor (G-CSF) was used: during the induction phase, patients are admitted to hospital and given prophylactic peltegrastim 6 mg 24 h after completion of each cycle of chemotherapy (day 6
).
In addition, ciprofloxacin 500 mg twice daily or trimethoprim-sulfamethoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) are used twice daily as prophylactic antibiotics
.

After 3 cycles of induction, bone marrow examination and imaging were performed to evaluate
the efficacy.
If ≥ PR is achieved according to IMWG criteria, the patient can receive an autologous stem cell transplant (ASCT) followed by DARA maintenance therapy, or DARA maintenance therapy without transplantation
, as appropriate.
For patients undergoing ASCT, DARA maintenance therapy
must be given within 12 weeks of ASCT.
During maintenance therapy, daratumumab is given 6 times every two weeks at a dose of 16 mg/kg, followed by an outpatient dose of 16 mg/kg twice a month
.

The primary endpoint of the study was complete remission (CR) rate
.
Secondary endpoints included ORR, progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

Research results

Baseline characteristics of the patient

A total of 33 patients were enrolled, but 1 case withdrew informed after screening (Figure 1B), and the baseline characteristics of 32 patients who received at least one dose of study drug are shown in Table 1
.

Twenty-three patients (71.
9%) had extraosseous soft-tissue masses with or without bone lesions, and 9 patients (28.
1%) had only parabone plasmacytoma
.
The most common site of extramedullary lesions is the chest
.
Risk stratification was available for 23 patients, of which 16 (69.
6%) were high-risk
.
Four patients (17.
4%) carried Del(17p) and six patients (26.
1%) carried T(4;14) and T(14;16).

The median number of prior treatment lines was 3, and the median time from MM diagnosis to study selection was 26 months
.
All patients were exposed to bortezomib prior to study enrollment, 78.
1% to carfilzomib, and 90.
6% to lenalidomide
.
Twenty-seven (84.
4%) were doubly refractory
.
Of the 19 patients who had previously received ASCT, all but four received mephalan 200 mg/^m2
.

Treatment outcomes

Twenty-five patients (78.
1%) were able to complete 3 cycles of DARA-DCEP and 7 patients (21.
9%) completed all 8 cycles (3 cycles of DARA-DCEP + 5 cycles of DARA maintenance therapy).

。 Three patients withdrew from the study due to other treatments: one patient underwent radiotherapy after completing 3 cycles of DARA-DCEP, one patient underwent allogeneic hematopoietic stem cell transplantation after completing 3 cycles of DARA-DCEP, and one patient received delayed autologous stem cell transplantation
after completing 3 cycles of DARA maintenance therapy.

One patient withdrew informed consent after day 1 of cycle 1, so treatment outcomes and toxicity profiles
were assessed in 31 patients.
Based on optimal response during the study period, the CR rate was 35.
5% (11/31) and the ORR was 67.
7% (Table 2).

There was no difference in CR rate between patients with soft tissue plasmacytoma (39.
1%) and paraosteoplasmacytoma alone (25.
0%) (p= 0.
472).

Two patients with persistent EMD were classified as VGPR
.

At a median follow-up of 11 months, a median PFS of 5 months (Figure 2A) and a median OS of 10 months (Figure 2B), PFS (median vs 3 months, p< 0.
001) were significantly better in PFS (Figure 2C) compared those who achieved ≥ PR remission (i.
e.
, 'remitters')
and those who did not achieve ≥ PR (i.
e.
, 'non-remitters').
。 In addition, early exposure to DARA-DCEP showed a trend towards better survival, but the difference was not statistically significant (DARA-DCEP as second-line ≥versus third-line treatment, median PFS of 6 versus 5 months, p=0.
233).

Six of the 7 patients who completed the study maintained remission before the data cut-off date (1 progression, PFS 10 months).

Hematologic adverse events

In cycle 1, 9/32 (28.
1%) patients received a full dose of DCEP, and 23/32 (71.
9%) patients received a 30% reduced dose as specified in the protocol (Table 2).

Two patients reduced the dose during cycle 2 and the final dose was 50%
of the full dose of DCEP.
On the other hand, 2 patients received a full dose of DCEP in cycle 2
after receiving a 30% reduction in the dose in cycle 1.
DCEP dose
adjustment is not required for cycle 3.

DARA-DCEP had four cases of delayed administration in cycle 2, all caused by cytopenias (Table 2).

There were 3 cases of delayed administration of DARA-DCEP in cycle 3, 2 due to cytopenias, and 1 due to general condition
.

Hematologic adverse events are shown in Table 3
.
Thrombocytopenia was the most significant adverse event, and its incidence increased with increasing cumulative chemotherapy cycles; Grade 3 thrombocytopenia
≥ occurred in 36% of patients on DARA-DCEP cycle 3.
In DARA-DCEP cycle 1, one patient was treated for bacterial pneumonia and one patient was treated
for Klebsiella pneumoniae.
In DARA-DCEP cycle 2, 6 patients developed infection: 1 pneumonia, 2 Staphylococcus aureus bacteremia, 2 disseminated herpes zoster infection, and 1 local herpes zoster infection
.
During cycle 1 of DARA maintenance therapy, one patient developed localized herpes zoster infection
.

DARA-DCEP Cycle 1, 5 patients (16.
1%) admitted for AE management: 2 for infection, 2 for febrile neutropenia with no documented infection, and 1 for gastrointestinal (GI) bleeding
.
DARA-DCEP Cycle 2, 3 patients (10.
3%) hospitalized for AE management: 2 due to infection and 1 with GI bleeding (same as Cycle 1).

DARA-DCEP cycle 3, no patient admission for AE management
.

Non-haematological adverse events

During cycle 1 of DARA-DCEP therapy, 48.
4% of patients developed a daratumab fluid-related reaction (IRR), of which 3 had grade 3 IRR (9.
7%) with symptomatic bronchospasm, but recovered without sequelae, and these 3 patients subsequently received prophylactic acetaminophen, H2 blockers, and steroids; Subsequently, one patient developed a grade 1 IRR at cycle 2, while the other two patients did not develop IRR
again.

As shown in Table 4, the most common non-hematological adverse events were nausea (22.
6%), followed by dyspepsia (12.
9%), diarrhea (12.
9%), and stomatitis (12.
9%)
.
One patient developed axillary deep vein thrombosis during DARA-DCEP cycle 2 and was treated
with rivaroxaban.

There were two deaths during the study period (Table 2), one patient from underlying MM progression, and one patient from bacterial and cytomegalovirus pneumonia
.
The latter patient was classified as a treatment-related death because the patient had PR at the time of the event (Table 4).

conclusion

In this study of daratumumab combined with conventional chemotherapy DCEP for RRMM with EMD, the median ORR of 100% bortezomib exposure was 67.
7% (21/31) of the patients treated with 3rd line, of which CR was 35.
5% (11/31), and 19.
4% (6/31) of treated patients experienced sustained remission; Median PFS of 5 months and median OS 10 months, demonstrating DARA-DCEP as an effective regimen for the treatment of patients with EMD RRMM after bortezomib treatment failure.

The importance of this study is that 1) it is one of the very few prospective trials focusing on EMD, and 2) it has successfully laid the groundwork
for immunochemotherapy in the treatment of MM.

In addition, adequate dose adjustment and prophylactic use of G-CSF ensure maximum
efficacy while minimizing toxicity.

References

Ja Min Byun, Chang-Ki Min, Kihyun Kim ,et al.
Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease.
J Hematol Oncol .
2022 Oct 23; 15(1):150.
doi: 10.
1186/s13045-022-01374-5.

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