Treatment Options for Heavily Pretreated RRMM

EP: 1.72-Year-Old Man with Heavily Pretreated RRMM

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EP: 2.Treatment Options for Heavily Pretreated RRMM

EP: 3.The DREAMM-2 Trial in RRMM

EP: 4.Role of Belantamab Mafodotin In the Treatment of Heavily Pretreated RRMM

EP: 5.Current Status and Future Directions in RRMM

Sagar Lonial, MD, FACP: When we think about treatment options for a patient who has had 4 or more prior lines of therapy, the approved options are limited and speak to the fact that the PFS [progression-free survival] and overall survival rates are quite short for these patients. What often happens is the use of cytotoxic chemotherapy regimens, such as DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin] or VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide] and hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone], that use combinations of alkylating agents and steroids that historically represented early line therapy—given the advance of novel agents in the [treatment] of patients—have moved forward into this situation. Alternatively, one can recycle other novel agents that have been used, particularly retreatment with an anti-CD38, an IMiD [immunomodulatory imide drug], and/or a proteasome inhibitor. Unfortunately, what we know about that is although one may get an initial response, the duration of response ends up being quite short. In this situation, the patient was offered treatment with belantamab mafodotin [belamaf], which is a BCMA [B-cell maturation antigen]-directed antibody drug conjugate that has a very novel and unique mechanism of action.

Functionally, the immunotoxin is different than one that we’ve seen in any other antibody drug conjugate molecules in all of oncology. The immunotoxin is something called MMAF, which is different from MMAE, which is more commonly used in this clinical situation. This allows the direct targeting of chemotherapy agent toward 2 cells that express BCMA. Because BCMA is a little less ubiquitously expressed than other antibody targets in myeloma, such as CD38 or SLAMF7, what this means is that you’re effectively delivering local chemotherapy to the tumor cell itself because BCMA is not expressed on many cells beyond plasma cells. This immunotoxin is somewhat unique and represents the first antibody drug conjugate approved in myeloma and the first BCMA-directed drug in the context of myeloma, as well.

BCMA is a target that has not been used, and this patient has not been exposed to that target to date. This offers a significant benefit, particularly in patients who may have significant comorbidities or difficulty traveling back and forth between the clinic and their home, because belamaf has to be given only once every 3 weeks; this means visits to the office are relatively few. On the other hand, the other approved agent in this context is selinexor, which is an XPO1 inhibitor, an FDA-approved combination with dexamethasone in the context of refractory myeloma—particularly penta-refractory or myeloma. In this context, selinexor given on a twice-weekly dosing schedule is a treatment that could potentially be given at home; however, the twice-weekly dosing schedule that was approved by the FDA in the basis of the STORM trial [NCT02336815] made office visits frequent and required for supportive care—particularly nausea, vomiting, diarrhea, and anorexia. With once-weekly dosing of selinexor—either with dexamethasone or in partnership with bortezomib or carfilzomib, or even combining with pomalidomide—the incidence of the GI [gastrointestinal] toxicity has dropped markedly but remains an issue in supportive care. Hydration, energy, fatigue, and asthenia are all adverse effects that persist and require interventions with additional supportive care measures. It’s clear that both belantamab mafodotin and selinexor have significant activity in the population of patients with refractory myeloma. If patients can tolerate therapy, they may gain significant clinical benefit, but the idea of trying to anticipate and manage the potential adverse events is quite different between these 2 approved agents in the context of refractory myeloma.

Transcript edited for clarity.

A 72-Year-Old Man with Heavily Pretreated, R/R Multiple Myeloma

Initial Presentation

• A 72-year-old man diagnosed with multiple myeloma 4.5 years ago returns for routine follow up
• Treatment history:
  • Initially treated with VRd for 12 months, followed by lenalidomide maintenance 15 mg daily; stable disease lasting 36 months
  • Rechallenged with VRd, stable disease lasting 20 months
  • Subsequently switched to KPd, achieved a partial response lasting 15 months
  • Started DVd; follow up at 12 months showed M protein increase by 0.5 g/dl; patient continues to feel well 
• Currently, 3 months after his last visit, he returns to the clinic complaining of increased muscle weakness, fatigue and bone pain
• PE: new bony tenderness appreciated on ribs, bruising, mild bleeding of the gums

Clinical Workup

• Labs: Hb 8.8 g/dL, calcium 10.2 mg/dL, LDH 160 U/L, creatinine 2.1 mg/dL, albumin 3.0 g/dL, b2 microgloblulin 4.9 mcg/mL, serum M-protein 4.2 g/dL, lambda free light chains 4.1 mg/dL
• HBV negative
• Skeletal survey and MRI revealed stable lytic bone lesions in the left hip, pelvis and L2 vertebrae and new lytic lesions on the ribs 4 and 10 on the left side
• Bone marrow shows 70% plasma cells IgG k
• FISH: t(6;14) (p21;q32) at diagnosis; new del(17p)
• Diagnosis: R-ISS stage II MM
• ECOG 1

Treatment

• Initiated treatment with belantamab mafodotin