Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity

Abstract

The use of modern therapies such as thalidomide, bortezomib and lenalidomide coupled with upfront high-dose therapy and autologous stem cell transplant (ASCT) has resulted in improved survival in patients with newly diagnosed multiple myeloma (MM). However, patients with relapsed/refractory multiple myeloma (RRMM) often have poorer clinical outcomes and might benefit from novel therapeutic strategies. Emerging therapies, such as deacetylase inhibitors, monoclonal antibodies and new proteasome inhibitors, appear promising and may change the therapeutic landscape in RRMM. A limited number of studies has shown a benefit with salvage ASCT in patients with RRMM, although there remains ongoing debate about its timing and effectiveness. Improvement in transplant outcomes has re-ignited a debate on the timing and possible role for salvage ASCT and allogeneic stem cell transplant in RRMM. As the treatment options for management of patients with RRMM become increasingly complex, physicians must consider both disease- and patient-related factors in choosing the appropriate therapeutic approach, with the goal of improving efficacy while minimizing toxicity.

Figure 1

Hypothetical example of clonal evolution and heterogeneity in patients with multiple myeloma (MM) over the disease course. MM is characterized by clonal heterogeneity. As the disease progresses and patients receive various therapies, different clones may emerge and become dominant, thus contributing to treatment resistance typical of patients with relapsed/refractory MM. (a) The clonal distribution at diagnosis, prior to treatment with lenalidomide plus dexamethasone. (b) An emergence of clone 2 at relapse, prior to re-treatment with lenalidomide plus dexamethasone. (c) Emergence of a lenalidomide-resistant clone 3. BMSC=bone marrow stromal cells.

Figure 2

MOA of agents approved or under development for MM. Agents approved or under development for MM target key biological pathways that drive MM cell proliferation and survival. (a) Approved agents include proteasome inhibitors (proteasome inhibitors target the proteasome, which plays a role in the normal degradation and clearance of intracellular misfolded and unfolded proteins. This inhibition leads to protein accumulation and eventual apoptosis), IMiDs (the CRBN E3 ubiquitin ligase complex marks protein with ubiquitin for degradation. The binding of an IMiD to this complex leads to the degradation of two key proteins, Aiolos (IKZF3) and Ikaros (IKZF1), ultimately killing MM cells) and DAC inhibitors (DAC inhibitors target proteins in the nucleus and cytoplasm. HDACs deacetylate target nuclear proteins implicated in gene regulation, including histones and tumor suppressor genes. DACs, which target cytoplasmic proteins, namely HDAC6, play a role in protein metabolism through the formation of aggresomes that transport proteins to be degraded by lysosomes. DAC inhibitors target HDAC6, blocking aggresome formation and subsequent protein degradation, thus leading to protein accumulation and apoptosis). (b) Agents under development: CAR-T cells (CAR-T cells are engineered to recognize target tumor cells and induce cell death), mAbs (mAbs utilize antibody-dependent cellular toxicity (targeting of cell surface proteins such as CS1 and CD38) to induce apoptosis; antibody drug conjugates (e.g., indatuximab ravtansine) target cells expressing the recognized receptor, leading to receptor internalization and release of cytotoxic chemotherapy and cell death), oncolytic virotherapy (viruses stimulate MM apoptosis through many complex mechanisms, including direct virus-mediated cytotoxicity and indirect enhancement of immune responses) and KSP inhibitors (KSPs facilitate early mitosis by separating microtubules. KSP inhibitors block this process, thereby serving as antimitotic agents in rapidly dividing MM cells). Adapted with permission from Novartis Pharmaceuticals Corporation. A=antigen; ADCC=antibody-dependent cell-mediated cytotoxicity; CAR=chimeric antigen receptor; CRBN=cereblon; HDAC=histone deacetylase; HSP90=heat-shock protein 90; i=inhibitor; IMiD=immunomodulatory drug; KSP=kinesin spindle protein; mAb=monoclonal antibody; MM=multiple myeloma; MOA=mechanism of action; NK=natural killer; TCR=T-cell receptor.

Figure 2

MOA of agents approved or under development for MM. Agents approved or under development for MM target key biological pathways that drive MM cell proliferation and survival. (a) Approved agents include proteasome inhibitors (proteasome inhibitors target the proteasome, which plays a role in the normal degradation and clearance of intracellular misfolded and unfolded proteins. This inhibition leads to protein accumulation and eventual apoptosis), IMiDs (the CRBN E3 ubiquitin ligase complex marks protein with ubiquitin for degradation. The binding of an IMiD to this complex leads to the degradation of two key proteins, Aiolos (IKZF3) and Ikaros (IKZF1), ultimately killing MM cells) and DAC inhibitors (DAC inhibitors target proteins in the nucleus and cytoplasm. HDACs deacetylate target nuclear proteins implicated in gene regulation, including histones and tumor suppressor genes. DACs, which target cytoplasmic proteins, namely HDAC6, play a role in protein metabolism through the formation of aggresomes that transport proteins to be degraded by lysosomes. DAC inhibitors target HDAC6, blocking aggresome formation and subsequent protein degradation, thus leading to protein accumulation and apoptosis). (b) Agents under development: CAR-T cells (CAR-T cells are engineered to recognize target tumor cells and induce cell death), mAbs (mAbs utilize antibody-dependent cellular toxicity (targeting of cell surface proteins such as CS1 and CD38) to induce apoptosis; antibody drug conjugates (e.g., indatuximab ravtansine) target cells expressing the recognized receptor, leading to receptor internalization and release of cytotoxic chemotherapy and cell death), oncolytic virotherapy (viruses stimulate MM apoptosis through many complex mechanisms, including direct virus-mediated cytotoxicity and indirect enhancement of immune responses) and KSP inhibitors (KSPs facilitate early mitosis by separating microtubules. KSP inhibitors block this process, thereby serving as antimitotic agents in rapidly dividing MM cells). Adapted with permission from Novartis Pharmaceuticals Corporation. A=antigen; ADCC=antibody-dependent cell-mediated cytotoxicity; CAR=chimeric antigen receptor; CRBN=cereblon; HDAC=histone deacetylase; HSP90=heat-shock protein 90; i=inhibitor; IMiD=immunomodulatory drug; KSP=kinesin spindle protein; mAb=monoclonal antibody; MM=multiple myeloma; MOA=mechanism of action; NK=natural killer; TCR=T-cell receptor.

Figure 3

Proposed treatment guidelines for management of relapsed/refractory multiple myeloma (RRMM). Treatment decisions are guided by previous therapeutic exposure, comorbidities, risk assessment and disease- and/or treatment-related symptoms. The availability of new therapies has increased the complexity of the treatment algorithm for RRMM. BTZ=bortezomib; C=cyclophosphamide; CFZ=carfilzomib; CTD=cyclophosphamide, thalidomide and dexamethasone; D=dexamethasone; GEP=gene expression profiling; Len=lenalidomide; PLD=pegylated liposomal doxorubicin; PAN=panobinostat; POM=pomalidomide; RIC=reduced-intensity or nonmyeloablative conditioning; T=thalidomide; TD=thalidomide and dexamethasone.