Page 154 - Read Online

Sadaf et al. J Transl Genet Genom 2022;6:63-83 https://dx.doi.org/10.20517/jtgg.2021.36 Page 73

[75]
extramedullary phase .

MULTIPLE MYELOMA TREATMENT
ASCT is standard care for MM. However, the foremost decision in MM patient management is ASCT
eligibility. Patients less than 65 years of age with no severe comorbidities are usually eligible for ASCT.
Furthermore, no definitive clinical data is available to support that ASCT is better in the early stage of
[116]
disease than in later/relapsed cases . All transplant-eligible MM patients must receive primary induction
therapy. The induction therapy combination regimens are given in Table 2.

Lenalidomide is a derivative of thalidomide, which is also an immunomodulatory drug (IMiD) but has
more powerful anti-tumor and anti-inflammatory effects. It induces MM cell growth arrest, binding
inhibition to BM-ECM and stromal cells, and downregulation of IL-6 and NF-κB . While lenalidomide
[117]
has a partial response rate of 24%-29% in treatment-refractory MM patients, combinatory lenalidomide and
dexamethasone has peaked partial remission to an additional 29% in the lenalidomide-responsive patient
group .
[118]

Over time, more powerful triplet combinations of lenalidomide/dexamethasone with a monoclonal
antibody (elotuzumab - anti-CD319, daratumumab - anti-CD38) or a PI (bortezomib, carfilzomib,
ixazomib) have evolved with significant improvement in the progression-free survival (PFS) and overall
survival (OS) [119,120] . Combination treatment strategies apply the concept of using therapies with distinct
mechanisms of action . The triple combination therapy trials of proteasome inhibitor and monoclonal
[121]
antibodies are summarized in Tables 3 and 4.

Once remission is achieved, stem cells are harvested via apheresis. Maintenance therapy after
transplantation includes (1) oral lenalidomide - 10 mg/day for the first 3 months; (2) oral Ixazomib - 3 mg
on day 1, 8, and 15 in 28-day cycles in cycles 1 through 4 and increased to 4 mg from cycle 5 if tolerated;
and (3) intravenous bortezomib - 1.3 mg/m on days 1, 4, 8 and 11 every 3 months.
2
Despite these treatment advancements, a considerable number of MM patients have shown resistance to PI,
IMiDs, and monoclonal antibodies. A retrospective study has revealed that refractoriness results in only 5.6
months median OS in MM patients . Hence, there is an urgent need to devise more effective therapeutic
[110]
interventions for this patient population [121,122] .

Conventional chemotherapy
Conventional chemotherapy can serve as salvage therapy in relapsed/refractory MM (RRMM) patients non-
responsive to the triple-drug combination therapies. Due to intense toxicity, these cytoreduction agents are
used for short periods of time and serve best as a bridge to more effective therapies . A study of
[121]
dexamethasone without thalidomide administration with an infusion of cisplatin, doxorubicin,
cyclophosphamide, and etoposide [D(T)PACE] resulted in an overall response rate (ORR) of 49%, median
[123]
PFS of 5.5 months, and OS of 14 months . Among patients that proceeded to ASCT, median PFS was 13.4
months, and OS was 20.5 months. Another study compared the outcome of three chemotherapy regimens
(1) dexamethasone, cyclophosphamide, etoposide, and cisplatin; (2) bortezomib, thalidomide,
dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE); and (3)
cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) in RRMM. The three salvage
[124]
regimens demonstrated similar overall RR (55%), PFS (4.5 months), and OS (8.5 months) .