Outcomes of VDPACE with an immunomodulatory agent as a salvage therapy in relapsed/refractory multiple myeloma with extramedullary disease

Abstract Extramedullary disease (EMD) is an aggressive form of multiple myeloma (MM). Confirming the presence of plasma cells outside the bone marrow makes the diagnosis of EMD. There is no clear consensus on the management of EMD in MM, and this entity continues to remain an unmet need. Rapidly controlling EMD to prevent end‐organ damage is a priority. Retrospectively, we reviewed our database for patients with EMD that received treatment with bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide (VDPACE) plus an immune modulator (IMiD) regimen. We identified 21 patients with a median age of 61 years. Ten patients received a VDPACE based regimen as a bridge to autologus stem cell transplant (ASCT). After a median follow‐up of 51.4 months, the median overall survival (OS) and progression‐free survival were 14.9 months (95% CI: 7.8‐NA) and 5.5 months (95% CI: 3.9‐NA), respectively. The overall response rate was 76%, with a manageable safety profile. Interestingly, these results were similar regardless of the presence of high‐risk cytogenetics. The safety profile was acceptable. In conclusion, a salvage VDPACE‐based regimen plus an IMiD remains an effective and safe bridging therapy to future ASCT and immunotherapy in relapsed/refractory multiple myeloma patients with EMD.


Inclusion criteria
Patients must meet all of the following criteria to receive VDPACE+ IMiD per the institutional protocol: 1. Written informed consent in accordance with institutional guidelines 2. Confirmed diagnosis of disease progression multiple myeloma 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Adequate hepatic function with total bilirubin < 2× upper limit of normal (except Gilbert's syndrome), AST < 2.5 × ULN and ALT < 2.5 × ULN 5. Adequate renal function with CrCl > 30 mL/min, calculated using the formula of Cockroft 6. Adequate hematopoietic function: total WBC > 1500/mm 3 , ANC > 1000/mm 3 , and platelet count > 50,000/mm 3 (in whom < 50% of bone marrow nucleated cells are plasma cells) or > 20,000/mm 3 (in whom > 50% of bone marrow nucleated cells are plasma cells)

Exclusion Criteria
Patients meeting any of the following exclusion criteria are not eligible to receive VDPACE +IMiD per the protocol: 1. Unstable cardiovascular function: symptomatic ischemia, congestive heart failure of NYH Class III/IV or EF per echocardiogram < 45%, myocardial infarction within 3 months and uncontrolled significant conduction abnormalities 2. Active infection requiring antibiotics, antiviral or antifungals within one week prior to first dose 3. Active hepatitis A, B, or C infection 4. Uncontrolled GI symptoms (diarrhea, nausea or vomiting) 5. Serious psychiatric conditions 6. Lack of social support and caregiver emission tomography-computed tomography (18F-FDG PET), magnetic resonance imaging, or ultrasound], and confirmed by a biopsy [6].
EMD is associated with an adverse prognosis in both NDMM and RRMM patients and tends to be resistant to proteasome inhibitors (PI) and immunomodulatory agents (IMiD) [4,11]. High-risk cytogenetics was reported in RRMM with EMD [12][13][14]. The mechanisms of extramedullary spread in MM are unclear. Some studies suggest decreased expression of adhesion molecules (VLA-4 and CD-44), loss of CD56, downregulation of P-selectin, low expression of chemokine receptors, downregulation of CXCR4, high frequency of RAS mutations, or increase angiogenesis are possible mechanisms in EMD [1,5,15]. Optimal management of EMD is unknown, although several prospective studies reported EMD; however, none of them established a solid approach to treating RRMM with EMD [16][17][18][19][20]. Aggressive RRMM with EMD needs rapid cytoreduction for disease control, which may not be possible with standard novel therapies. This study aimed to analyze the clinical outcomes of the application of salvage VDPACE regimen with an IMiD in patients with aggressive RRMM with EMD.  [22][23][24]. Responses were evaluated using the IMWG criteria [25].

TREATMENT PROTOCOL
The regimen VDPACE + IMiD consisted of high-dose dexametha-

Patients characteristics
We identified 21 patients with extramedullary RRMM treated with VDPACE + IMiD. The median age at the start of VD-PACE + IMiD reg-

Responses
The overall response rate (ORR) was 76%: complete response (CR) in pursue any treatment and received palliative radiation, and one patient had progression prior evaluation for ASCT due to delay to evaluate this patient and was reinduce with a different regimen. Table 4 summarizes the response rates.

Survival
The

DISCUSSION
Relapsed/refractory EMD RRMM is highly aggressive with a dismal MM to both PI and IMiD drugs with an estimated 9-13 months survival [28].  [35]. These data suggest that this regimen is powerful in controlling the disease, albeit for a short time in some cases with EMD. However, it is hard to conclude from this response durability in EMD due to the low sample size.
In our study, ASCT followed VDPACE+IMiD treatment to improve the durability of responses. Those patients who underwent SCT had a median PFS and OS from VDPACE + IMiD of 15.5 and 26.8 months, respectively. Furthermore, the median time to first response was 2 months, but many patients achieved their best response beyond 2 months.
This retrospective single-center study showed that VDAPACE/IMiD treatment strategy is feasible, with favorable tolerability and no TRM.
VDAPACE/IMiD during salvage therapy was associated with predictable hematological toxicities. The absence of any TRM further suggests a favorable benefit-to-risk ratio. The major limitations of our analysis include our single-center retrospective study design with associated limitations in data size, retrieval, interpretation, and absence of any comparator arm.
The safety profile of VDPACE + IMiD primarily consisted of hematologic adverse events (AEs), consistent with previous results. Despite cytopenias being common, the incidence of significant bleeding events or infections was low. Hematologic AEs were generally reversible and clinically manageable with dose delays, growth factor use, platelet transfusions, and appropriate supportive care. Nonhematologic grade 3/4 AEs were infrequent, with infections being the most common.
Moreover, the frequency of infections was generally consistent with the expected infection rates in heavily pretreated patients.
In conclusion, our single-institution experience demonstrates that patients with EMD can achieve a significant response rate using VDPACE+IMiD. Our data demonstrate that VDPACE+IMiD can be utilized as salvage therapy to control EMD MM and serves as a bridge for other treatments.

FUNDING
There was no external funding for this study.

CONFLICTS OF INTEREST
Dr. Ganguly reports the following conflicts: Seattle Genetics: Speak-

AVAILABILITY OF DATA AND MATERIAL
The data sources from which the results of this study were generated can be shared if requested.

AUTHORS' CONTRIBUTIONS
Dr