Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.


Introduction
Multiple myeloma (MM) is a plasma cell neoplasm that accounts for 1% of all cancers and approximately 10% of all hematologic malignancies [1]. MM is defined by the presence of ≥10% of clonal plasma cells in the bone marrow (or a biopsy proven extramedullary plasmacytoma) and by endorgan damage attributable to the MM such as anemia, lytic bone lesions, renal failure, and hypercalcemia [1]. Approximately, 1% to 2% of patients have extramedullary disease (EMD) upon initial diagnosis and 8% develop EMD later on in the disease course, typically after multiple relapses [2]. EMD is defined by the presence of soft-tissue plasmacytomas or plasma cell infiltration outside of the bone marrow [3]. e presence of high-risk cytogenetics (particularly del(17p) and amp [1q21]) is associated with development of EMD [4]. EMD is associated with an adverse prognosis in newly diagnosed and in relapsed MM patients and tends to be resistant to proteasome inhibitors, immunomodulatory agents, and even novel agents such as daratumumab [5][6][7]. As such, infusional "traditional" chemotherapy agents are used in the treatment of patients with relapsed/refractory MM (RRMM) as a means of rapid tumor debulking or as a bridge to high-dose therapy and stem cell transplant. Several such intensive infusional chemotherapy regimens are currently used.
In a population of patients with RRMM, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) has been reported to produce an overall response rate (ORR) of 40% and a median overall survival (OS) of 15 months [8]. Dexamethasone with continuous-infusion cyclophosphamide, etoposide, and cisplatin (DCEP) demonstrated an ORR of 58% and a median response duration of 9 months in a population of RRMM patients [9]. In patients with RRMM, DT-PACE (thalidomide, dexamethasone, and 4-d continuous infusions of cisplatin, doxorubicin, cyclophosphamide, and etoposide) produced an ORR of 61% [10]. Bortezomib (V) is frequently administered with DT-PACE [11]. In RRMM, the proteasome inhibitor carfilzomib (K) has proven to produce superior response rates, progression-free survival (PFS), and OS compared to V [12]. Likewise, the addition of K to lenalidomide (R) and D produces superior response rates and PFS compared to RD in RRMM [13]. Furthermore, the overlapping toxicity of peripheral neuropathy by bortezomib and thalidomide makes them less desirable to combine in a regimen [14].
As a majority of patients may be heavily pretreated and refractory to V by the time they are considered for salvage infusional chemotherapy, we wanted to examine the efficacy of KRD-PACE as the salvage therapy for RRMM. Herein, we describe the efficacy and clinical course of two patients with aggressive, V-refractory, extramedullary, RRMM with highrisk cytogenetics who were treated with KRD-PACE and provide a succinct review of the literature.  Table 1. e patient was not a candidate for additional RT or surgery to the spine, and thus was started on V-cyclophosphamide-D (CyBorD) for relapsed, extramedullary multiple myeloma. After receiving one cycle of CyBorD, the patient continued to complain of back pain and developed worsening paresthesias of the thighs bilaterally and lower extremity weakness. An MRI of the thoracic spine revealed an increase in the size of the lateral aspect of the left-sided paraspinal mass with severe cord compression from T3 through T5, and 18F FDG PET-CT images are shown in Figure 1(a). Given the patient's poor response to CyBorD and urgency of cord compression, it was decided to start the patient on salvage carfilzomib (K), lenalidomide (R), dexamethasone (D), cisplatin (P), doxorubicin (A), cyclophosphamide (C), and etoposide (E); KRD-PACE. KRD-PACE was dosed at K (20 mg/m 2 on days 1 and 2 followed by 56 mg/m 2 on days 8,9,15, and 16), R (25 mg daily on days 1-21), D (40 mg orally on days 1-4) with P (10 mg/m 2 /day), A (10 mg/m 2 /day), C (400 mg/m 2 /day), and E (40 mg/m 2 / day) given as a continuous intravenous infusion over 24 hours on days 1-4 ( Table 2). e patient tolerated two cycles of KRD-PACE well without the need for extended hospitalization, dose reductions, transfusion, or growth factor support. He did not develop febrile neutropenia. e patient had a very good partial response (VGPR) to therapy (Table 1) with near resolution of the paraspinal plasmacytoma (Figure 1(b)). He subsequently went on to stem cell mobilization and collection followed by a melphalan 200 mg/m 2 salvage autologous stem cell transplant (ASCT) after which he obtained a complete response. He is currently on maintenance therapy with lenalidomide 10 mg on days 1-21 and ixazomib 2 mg weekly, 13 months after KRD-PACE.

Patient 2.
A 56-year-old male developed temporal-occipital headaches in the April of 2017. In the November of 2017, an MRI brain was done which revealed an enlarging enhancing skull base lesion involving the clivus, right temporal bone, right petrous apex, and bilateral occipital condyles with the involvement of the right hypoglossal canal. e MRI brain also picked up bilateral upper cervical lymphadenopathy. A subsequent skeletal survey revealed multiple poorly defined lytic lesions throughout the axial and appendicular skeleton. A CT of the chest, abdomen, and pelvis revealed left axillary, right retrocrural, and left pericardial lymphadenopathy. e patient had a multiple myeloma workup (Table 1) which revealed a high-risk, revised international scoring system (R-ISS) III IgA kappa myeloma. A biopsy of one of the aforementioned cervical lymph nodes revealed sheets of kappa-restricted plasma cells, and FISH revealed a duplication 1q consistent with extramedullary disease at diagnosis. Bone marrow cytogenetics revealed a 1q duplication as well as trisomy 6, 11, and 15 and monosomy 13.   Figure 2(a)). Restaging studies are given in Table 1. Peripheral flow cytometry did not real evidence of plasma cell leukemia. e patient was subsequently started on KRD-PACE salvage therapy with the following dosing schedule: K (20 mg/m 2 on day 1 followed by 27 mg/m 2 on day 2 of each cycle), R (15 mg daily on days 1-21), D (40 mg orally on days 1-4) with P (10 mg/m 2 /day), A (10 mg/m 2 /day), C (400 mg/m 2 /day), and E(40 mg/m 2 /day) given as a continuous intravenous infusion over 24 hours on days 1-4 ( Table 2). He ultimately received 2 cycles of KRD-PACE. e patient developed grade 3 mucositis and anemia, grade 4 thrombocytopenia and neutropenia requiring transfusion (a total of 8 units of packed red cells and 10 units of platelets), and growth factor support (three 6 mg filgrastim injections), as well as a right upper extremity deep venous thrombosis (Table 1). He did not develop neutropenic fever. e patient was only hospitalized for 4 days during each cycle of KRD-PACE and was never rehospitalized. Transfusional and growth factor support was managed in the outpatient setting. e patient had a complete response (CR) to therapy (Table 1) with a resolution of lymphadenopathy (Figure 2(b)). He went on to stem cell mobilization but was unable to collect an adequate number of stem cells on two occasions. He remained in CR of therapy but developed an extramedullary relapse 6 months after completion of KRD-PACE and is now being considered for enrollment in an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy trial.

Conclusion
We describe two cases of aggressive, relapsed, bortezomibrefractory extramedullary MM with high-risk cytogenetics who achieved deep responses with KRD-PACE salvage therapy. One of the patients, a 32-year-old male with minimal MM bone marrow involvement and less prior treatment, tolerated 2 cycles of KRD-PACE without any complications or need for transfusional support. He achieved a VGPR and proceeded to high-dose therapy and ASCT to which he achieved a CR. e 56-year-old patient had extensive bone marrow involvement and 2 prior lines of treatment. He tolerated 2 cycles of KRD-PACE without the need for extended hospitalization, but developed profound cytopenias which required 34-48 days to recover and multiple red cell and platelet transfusions as well as granulocyte colony stimulating factor support. He achieved a complete response which lasted for 6 months without additional therapy.