**4.6 Triplet therapy**

For many years, monotherapy or doublet regimens were commonly used in the treatment of NDMM. However, with the progressive development of the previously discussed treatment options over the past decades, numerous clinical trials have investigated their use in combination in two-, three-, and four-drug regimens in an attempt to achieve deeper reductions in clonal disease burden. Generally, threedrug combinations (i.e., VCD, VRD, VTD) have been shown to derive the highest ORR and VGPR compared with two-drug regimens and remain the standard of care for fit patients prior to autologous stem cell transplantation (SCT). A Southwest Oncology Group trial randomized 525 patients to either RVD or RD and maintained on RD until progression, with the three-drug combination displaying a better median PFS of 43 months vs. 30 months and median OS 75 vs. 64 months (HR 0.7, p = 0.025). As part of triplet therapy, lenalidomide, bortezomib, and dexamethasone (RVD) currently remain standard of care for induction. Though the addition of a fourth drug has not yet shown clear benefit to date, its use likely marks the future, with daratumumab-containing regimens appearing promising. Recently, the GRIFFIN trial compared daratumumab with RVD vs. RVD in NDMM and demonstrated that D-RVD significantly improved strict CR rates and MRD-negativity in transplant-eligible patients [67].

### **4.7 Autologous stem cell transplant**

In the early 1980's, high dose therapy (HDT) with melphalan followed by autologous stem cell transplant (SCT) was performed by McElwain on a patient with plasma cell leukemia. This demonstrated some benefit, but initial adoption was limited due to toxicity of the transplantation process. In the late 1980's, Barlogie further investigated the use of SCT and developed the framework for

**17**

diagnosis [68].

**4.9 Performance status**

**4.10 Renal function**

commonly select for fit patients (typically.

less fit patients are encountered with greater frequency.

*Prognostic and Predictive Factors in Newly Diagnosed Multiple Myeloma Patients with Early…*

SCT in the 1980's and 1990's as part of the standard of care for eligible patients following induction. This led to several prospective, randomized clinical trials in the 1990's which demonstrated superior ORR, PFS, and OS in individuals up to age 65, whereas others demonstrated no survival advantage. Today, SCT following induction therapy in eligible patients remains standard of care. Steady advances in SCT outcomes have occurred over the past 30 years, with patients treated in 2014 or later having superior OS and reduced excess risk for MM death. Second stem cell transplantation may be considered in those with progression-free survival (PFS) or more than three years. Similarly models have supported the potential for cure, estimated at 6.3% to 31.3% depending on the year of treatment [55]. Whether novel agents will supplant HDT followed by SCT backed by minimal residual disease (MRD) continues to be explored. Consideration of myeloablative regimens beyond high-dose melphalan is another venue to be explored for increasing and deepening

Solitary plasmacytomas are uncommon and account for only 6% of all plasma cell neoplasms. They are defined as the presence of a single osseous lesion (medullary) or in the soft tissue outside of the bone (extramedullary) without evidence of bone marrow, clonal plasmacytosis, or CRAB criteria. The incidence of solitary plasmacytomas has increased with increased radiographic imaging use over the past thirty years; incidence increased by 10% from 1999 to 2004 as compared to 1992–1998. Patients with less than 10% plasma cells by bone marrow biopsy can be managed with therapies against the solitary lesion alone, typically 40–50 cGy of radiation or surgical excision alone depending on the location. These patients will eventually progress to MM over the subsequent years but have a generally favorable prognosis, with PFS 63% at 10 years. Extramedullary plasmacytoma has an even more favorable prognosis with myeloma-specific death seen in less than one-third of patients. Progression to MM typically occurs within 5 years from initial diagnosis. Features suggestive of high risk for progression include persistent monoclonal protein after treatment of the solitary lesion, detectable clonal plasma cells in the bone marrow, age 40–60 years old, and individuals of African-American descent. Despite the marked difference in long-term prognosis to NDMM, previous staging systems have not accounted for the presence or absence of solitary plasmacytoma at

Baseline performance status has long been understood to play a prominent role in prognosis in NDMM, with unfit patients often remaining ineligible for SCT, the use of triplet therapy, and certain novel therapies. Without these therapies, disease control is less common, and outcomes are worsened. Furthermore, clinical trials

ECOG 0–1), reducing the generalization of data to community setting, where

Baseline renal function in NDMM patients is an essential part of long-term prognosis. Impaired renal function at baseline limits the usage of novel agents that can be administered, as many are renally cleared. Persistent renal dysfunction limits what therapeutic options are available and thus long-term outcomes

*DOI: http://dx.doi.org/10.5772/intechopen.95819*

the CR and MRD negative status.

**4.8 Solitary plasmacytoma**

*Prognostic and Predictive Factors in Newly Diagnosed Multiple Myeloma Patients with Early… DOI: http://dx.doi.org/10.5772/intechopen.95819*

SCT in the 1980's and 1990's as part of the standard of care for eligible patients following induction. This led to several prospective, randomized clinical trials in the 1990's which demonstrated superior ORR, PFS, and OS in individuals up to age 65, whereas others demonstrated no survival advantage. Today, SCT following induction therapy in eligible patients remains standard of care. Steady advances in SCT outcomes have occurred over the past 30 years, with patients treated in 2014 or later having superior OS and reduced excess risk for MM death. Second stem cell transplantation may be considered in those with progression-free survival (PFS) or more than three years. Similarly models have supported the potential for cure, estimated at 6.3% to 31.3% depending on the year of treatment [55]. Whether novel agents will supplant HDT followed by SCT backed by minimal residual disease (MRD) continues to be explored. Consideration of myeloablative regimens beyond high-dose melphalan is another venue to be explored for increasing and deepening the CR and MRD negative status.

#### **4.8 Solitary plasmacytoma**

*Multiple Myeloma*

refractory setting.

patients.

**4.6 Triplet therapy**

mortality in the disease [53, 66].

transplant-eligible patients [67].

**4.7 Autologous stem cell transplant**

Emerging novel agents and therapies

the treatment of multiple-myeloma. Monotherapy bortezomib FDA approval in 2003 demonstrated an ORR of 27% and a 10% CR rate. In combination with dexamethasone, ORR improved to 88% and CR + VGPR rate of 19%, with a 1-year OS of 87% [65]. Other proteasome inhibitors, including carfilzomib and ixazomib, have been developed and are FDA approved in the relapsed-

e.Within the past 5 years, several agents have become available in the treatment of multiple myeloma. Notable agents, Dartumumab, a monoclonal antibody against CD-38, has displayed promising efficacy. Belantamab mafadotin, an antibodydrug conjugate between the B-cell maturation antigen (BCMA) and MMAF (a chemotherapy payload) was recently FDA approved for relapsed/refractory disease. BCMA CAR-T cell therapy also shows promise in the relapsed/refractory setting. Though not yet approved in NDMM, these agents, along with others, show promise in the treatment of newly-diagnosed and relapsed-refractory

In 2005, OS in NDMM was 4.6 years, increasing to 6.1 years by 2010. Over the past decade, the adoption of immunomodulatory agents and proteasome inhibitors in triplet therapy extended median OS to greater than 7 years. These gains were predominantly driven by triplet therapy in the elderly and by reducing early

For many years, monotherapy or doublet regimens were commonly used in the treatment of NDMM. However, with the progressive development of the previously discussed treatment options over the past decades, numerous clinical trials have investigated their use in combination in two-, three-, and four-drug regimens in an attempt to achieve deeper reductions in clonal disease burden. Generally, threedrug combinations (i.e., VCD, VRD, VTD) have been shown to derive the highest ORR and VGPR compared with two-drug regimens and remain the standard of care for fit patients prior to autologous stem cell transplantation (SCT). A Southwest Oncology Group trial randomized 525 patients to either RVD or RD and maintained on RD until progression, with the three-drug combination displaying a better median PFS of 43 months vs. 30 months and median OS 75 vs. 64 months (HR 0.7, p = 0.025). As part of triplet therapy, lenalidomide, bortezomib, and dexamethasone (RVD) currently remain standard of care for induction. Though the addition of a fourth drug has not yet shown clear benefit to date, its use likely marks the future, with daratumumab-containing regimens appearing promising. Recently, the GRIFFIN trial compared daratumumab with RVD vs. RVD in NDMM and demonstrated that D-RVD significantly improved strict CR rates and MRD-negativity in

In the early 1980's, high dose therapy (HDT) with melphalan followed by autologous stem cell transplant (SCT) was performed by McElwain on a patient with plasma cell leukemia. This demonstrated some benefit, but initial adoption was limited due to toxicity of the transplantation process. In the late 1980's, Barlogie further investigated the use of SCT and developed the framework for

**16**

Solitary plasmacytomas are uncommon and account for only 6% of all plasma cell neoplasms. They are defined as the presence of a single osseous lesion (medullary) or in the soft tissue outside of the bone (extramedullary) without evidence of bone marrow, clonal plasmacytosis, or CRAB criteria. The incidence of solitary plasmacytomas has increased with increased radiographic imaging use over the past thirty years; incidence increased by 10% from 1999 to 2004 as compared to 1992–1998. Patients with less than 10% plasma cells by bone marrow biopsy can be managed with therapies against the solitary lesion alone, typically 40–50 cGy of radiation or surgical excision alone depending on the location. These patients will eventually progress to MM over the subsequent years but have a generally favorable prognosis, with PFS 63% at 10 years. Extramedullary plasmacytoma has an even more favorable prognosis with myeloma-specific death seen in less than one-third of patients. Progression to MM typically occurs within 5 years from initial diagnosis. Features suggestive of high risk for progression include persistent monoclonal protein after treatment of the solitary lesion, detectable clonal plasma cells in the bone marrow, age 40–60 years old, and individuals of African-American descent. Despite the marked difference in long-term prognosis to NDMM, previous staging systems have not accounted for the presence or absence of solitary plasmacytoma at diagnosis [68].

#### **4.9 Performance status**

Baseline performance status has long been understood to play a prominent role in prognosis in NDMM, with unfit patients often remaining ineligible for SCT, the use of triplet therapy, and certain novel therapies. Without these therapies, disease control is less common, and outcomes are worsened. Furthermore, clinical trials commonly select for fit patients (typically.

ECOG 0–1), reducing the generalization of data to community setting, where less fit patients are encountered with greater frequency.

#### **4.10 Renal function**

Baseline renal function in NDMM patients is an essential part of long-term prognosis. Impaired renal function at baseline limits the usage of novel agents that can be administered, as many are renally cleared. Persistent renal dysfunction limits what therapeutic options are available and thus long-term outcomes are worse [69]. As cyclophosphamide is hepatically cleared, cyclophosphamide, bortezomib, and dexamethasone remains standard induction regimen in individuals with compromised renal function. Melphalan, which is cleared through spontaneous hydrolysis, is another renal-independent therapeutic option. Previous risk-stratification systems have not addressed this conundrum with renal dysfunction.
