Late Line Therapy in Multiple Myeloma
Presentation by Dr Jason Chandler, West Cancer Center
Written By Bailey Mars, NP | Saint Luke's Health System
At the 2023 West Oncology conference, Dr. Jason Chandler of West Cancer Center in Memphis, Tennessee, discussed the management of what he calls “penta-refractory” multiple myeloma (MM) patients and the available treatment options. He began by noting studies from the late 1960’s utilizing melphalan and prednisone, with the median overall survival (OS) at that time being approximately 26 months from diagnosis, or 21 months from treatment initiation.
A case study of a patient in Dr Chandler’s practice explored the experience of a 64 year old female, presenting with monoclonal gammopathy of undetermined significance (MGUS) and mild anemia. She was, importantly, noted to not have positron emission tomography scan (PET)-avid disease or any notable lytic lesions. The patient was also noted to have an increased IgA kappa M protein of 0.45, an IgA level of 535, a kappa free light chain (FLC) of 18.6, a hemoglobin of 9.5, and multiple trisomies, including deletion 13q (del13q). At her diagnosis in 2011, the patient was treated with Revlimid, Velcade, and dexamethasone (RVD) followed by an autologous stem cell transplant (ACST), which kept her in a state of remission until 2016.
In 2016 the patient began showing signs of relapse, and was treated with Kyprolis, Revlimid, dexamethasone (KRD), followed by Darzalex, Pomalyst, dexamethasone in 2021, Kyprolis, Cytoxan, dexamethasone in January of 2022 and elotuzumab, Velcade, dexamethasone in Decemeber of 2022. In early 2023, the patient presented again with increasing light chains, IgA 627, M protein 0.34 and back pain, which correlated with PET-avid lesions. At the time she also presents with a new trisomy 8 and 11. Given this scenario of progressive, relapsed, refractory MM, Dr. Chandler discussed three treatment options/combinations available to this patient population. Of note, the prognosis for this subset of patients becomes close to 7 months when they have reached the ‘penta-refractory’ state.
Selinexor
Dr. Chandler reviewed data showing that with newer treatments, such as those mentioned in the patient case study, patients with relapsed/refractory (R/R) MM have shown an increase in median OS. He then introduced the topic of the drug Selinexor in the treatment of MM. Dr. Chandler explained that exportin1 (XPO1) is overexpressed in MM and levels of XPO1 correlate with poor prognosis and drug resistance. This is due to the fact that XPO1 overexpression causes tumor suppressor proteins (i.e., p53, FOXO) and glucocorticoid receptor inactivation as well as enhanced oncoprotein (c-myc, BCL-XL) translation. Selinexor is an oral selective XPO1 inhibitor that reactivates multiple tumor suppressor proteins and inhibits oncoprotein translation. An interesting note about Selinexor mentioned by Dr. Chandler is that it was shown to be much better tolerated in smaller doses. He noted that, for patients on Selinexor and dexamethasone, progression free survival (PFS) was 3.7 months and median OS was 8.6 months. Significant toxicities, however, are associated with the full dose treatment, including nausea and thrombocytopenia. In this regard, Dr. Chandler recommended starting at a lower dose and combining treatment with antiemetics both prophylactically and as needed for at least three days of the first two cycles. He referenced both the BOSTON trial and the STOMP trial in which it was shown that patients with R/R MM receiving Selinexor, dexamethasone and another “backbone” therapy (Velcade, Cytoxan, etc) had an increase in PFS and median OS.
Chimeric Antigen Receptor- T Cells (CAR-T Cells)
Another treatment option that is now available in late-line treatment of R/R MM patients is CAR-T cells. Two options are currently available, Idecabtagene (Ida-Cel) and Ciltacabtagene (Cilta-Cel). Dr. Chandler described CAR-T as a treatment that harnesses the innate immune system and uses it to fight disease. CAR-T cells are constructed T cells that have been engineered to fight the individual patient’s disease. This is done through a process which Dr. Chandler breaks down as simply using a B-cell antibody receptor on a T-cell, which results in the T-cell being turned “on” to attack the cancerous cells. In the study KarMMa with Ida-Cel, patients underwent leukapheresis to obtain cells that were then engineered into CAR-T cells. They were then given cytoreductive chemotherapy with fludarabine and Cytoxan and lastly, re-infused with the engineered CAR-T cells. Of note, in two-year follow-up data, the overall response rate (ORR) was noted to be 81% with an OS rate of 70% (median levels have not been reached yet). At 27 months, PFS was 54.9% and OS was 70.4%. CARTITUDE, another CAR-T trial featuring Cilta-Cel followed a similar treatment course including leukapheresis, bridging chemotherapy, cytoreductive chemotherapy and then finally reinfusion of CAR-T cells showed a similar positive outcome, with an ORR of 97% and 12-month PFS of 77% and OS of 89%.
Teclistamab, BiTE therapy
Dr. Chandler also noted the recently approved teclisatamab, a Bi-specific T-Cell Engager (BiTE) as another treatment option available for R/R MM patients. Teclistamab and other BiTEs use T cells and negative signals to “pull” the T cell closer to the target cell (cancer cell) and force the T cell to kill the target cell. One difference in this treatment option is that it does not require bridging or cytoreductive chemotherapy prior, nor does it require pheresis and manufacturing of T cells. MajesTEC-1 was a trial of BiTE therapy, with teclistamab being used in ramp up doses, and the study showed promising results, with an ORR of 63% and OS of 18.3 months observed thus far. Although less time and chemotherapy is needed with this treatment option, one significant possible side effect is cytokine release syndrome (CRS). CRS can be severe and even life threatening and it is therefore critical that providers are aware of, and can recognize this adverse event. Symptoms of CRS can include nausea, vomiting, anorexia, diarrhea, tachypnea, pulmonary edema, hypofibrinogenemia, bleeding, rash, tachycardia, hypotension, capillary leak syndrome, fever, rigors, malaise, mylagias, headache, increased pulse pressure, initial increase in cardiac output followed by late decrease in cardiac output. Because of this, patients are typically observed in the hospital initially.
Quick Summary
Late line therapy for R/R MM can include Selinexor, CAR-T Cells, and BiTE therapy.
Selinexor
Readily available
ORR 74%
Major toxicities at high doses, start lower and give with prophylactic and PRN antiemetics
Watch for nausea and thrombocytopenia
CAR-T
Difficult to arrange
ORR 81-97%
Intense treatment that often requires hospitalizations
BiTE
Moderately difficult
ORR 63%
Hospitalization required initially
Providers need to be aware of and able to recognize CRS symptoms and manage before they become life-threatening
Overall, even in elderly patients with R/R MM there are worthwhile treatment options available as they are shown to have significant improvements in OS, PFS, and ORR
See more from the 2023 West Oncology Conference here.
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