The last decade has witnessed the identification of several novel druggable targets in multiple myeloma, leading to identification of novel therapies with clinically proven efficacy, both in the newly diagnosed and relapsed setting. More importantly, a common theme of good outcomes was observed among prospective randomized studies that have utilized combinations of agents with different mechanisms of action. The correlation between achieving a deeper response and the improvement in progression-free survival and overall survival has never been so clear. In this article, we elucidate the rationale for use of novel drug combinations in patients with myeloma, and review current evidence-based data supporting the use of specific combinations in various settings. We also attempt to craft a framework to guide clinicians in optimizing the use of combination therapies, to enable patients to derive maximal benefit.
Introduction
Although combination therapies to achieve the best outcomes have been the hallmark of cancer management, this approach was not applicable to patients with myeloma, mainly because of historical data proving that combination chemotherapy with cytotoxic agents had no greater efficacy than the standard of care, the melphalan and prednisone regimen.[1] In addition, the high rates of toxicities associated with combination cytotoxic regimens precluded the use of any combination therapy. In the past decade, however, the availability of newer drugs with different mechanisms of action and favorable toxicity profiles-such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), histone deacetylase inhibitors (HDACIs), and monoclonal antibodies-reignited the concept of combination approaches in myeloma. The use of combination therapies is justified by the depth of response achieved by concurrent treatment with different agents, which ultimately results in durable responses. By combining novel agents, our hypothesis of attaining these deep responses, as measured by minimal residual disease (MRD) negativity, is becoming a reality; these newer approaches are translating into further improvement in the survival of patients with myeloma. The concept of clonal heterogeneity in myeloma and the strategy of adopting combination therapies in the frontline setting, to eradicate both the dominant and minor clones, was supported by deep sequencing studies. Using serial genomic analysis of patient samples tested longitudinally, Keats et al demonstrated clonal competition of subclones with alternating dominance with therapy.[2] Re-emergence of minor clones usually occurs at relapse, and the same concept can be used to support combination approaches in the treatment of relapsed disease.
Obtaining a Better Depth of Response
In the context of the improved novel therapeutic combination regimens, there is an ongoing challenge in measuring the efficacy of these combination therapies, given the increased depth of response observed in recent studies. The current definition for response assessment is limited by the defined thresholds for myeloma detection. The International Myeloma Working Group (IMWG) defines “stringent complete response” (sCR) as the absence of clonality both by immunohistochemistry or immunofixation and by normalization of the free light chain ratio. While immunophenotypic complete response (CR) represents sCR plus absence of phenotypically aberrant clonal plasma cells in bone marrow, with a minimum of 1 × 106 bone marrow cells analyzed by multiparametric flow cytometry (using cytometers capable of detecting four or more colors), molecular CR is defined as CR plus negative ASO-PCR (allele-specific oligonucleotide polymerase chain reaction) results.[3] Although sensitivity varies across these molecular techniques for evaluating MRD negativity, the most sensitive technique by far is next-generation sequencing (NGS), which is able to detect the myeloma clone at concentrations as low as 1 × 10−6. The feasibility of testing frozen samples makes NGS more appealing from a practical standpoint. NGS for MRD assessment seems to be reliable, and, based on the Intergroupe Francophone du Myélome (IFM)/Dana-Farber Cancer Institute (DFCI) 2009 analysis, achieving MRD negativity results in a favorable prognostic impact for myeloma patients. Among the 246 patients analyzed by NGS, evaluation of MRD by NGS was highly predictive of progression-free survival (PFS).[4] Following this analysis, MRD negativity should be evaluated as an endpoint in all future trials.
Clinical Benefits of Novel Combination Therapies
Several novel combination therapies aimed at attaining the deepest response have been under evaluation in patients with myeloma. Combinations based on preclinical synergy and those utilizing combinations of monoclonal antibodies or other immunotherapeutic strategies seem to be the future of antimyeloma therapies.
IMiD and PI–based combination regimens
A theoretical antagonism between the mechanisms of action of IMiDs and PIs was previously described. IMiDs are thought to increase protein ubiquitination, raising the question of the mechanism of synergy between IMiDs and PIs.[5] Despite potentially contradictory preclinical data, early clinical trials support the observation that this combination offers significant clinical benefit.[6] The concept of an alternative protein degradation pathway in IMiD-treated myeloma cells, which was recently described, explains the clinical synergy observed between IMiDs and PIs.[7] It was proven in a phase III trial in relapsed patients that the combination of bortezomib, thalidomide, and dexamethasone (VTD) was superior to thalidomide and dexamethasone (Td) in eliciting deeper responses (CR, 45% vs 21%) and extending the time to progression (TTP; median TTP, 19.5 vs 13.8 months), thereby cementing the idea that combination therapies result in better outcomes.[8] Similar results were observed when the same trial was performed in newly diagnosed patients. The clinical responses and PFS outcomes favored combination therapy; 79% of those treated with VTD vs 58% of those treated with Td had a very good partial response or better (≥ VGPR; P < .0001), and PFS was greater with VTD vs Td (hazard ratio, 0.63 [95% CI, 0.45–0.88]; P = .0061).[9] Similarly, in the United States, the Southwest Oncology Group phase III S0777 trial evaluated the triplet combination lenalidomide, bortezomib, and dexamethasone (RVD) vs the doublet lenalidomide and dexamethasone (Rd) in patients with newly diagnosed myeloma. The study endpoints were PFS, overall survival (OS), and overall response rate (ORR). At a median follow-up of 55 months, the clinical outcomes with RVD vs Rd, respectively (≥ VGPR, 44% vs 32%, P < .0001; PFS, 43 vs 30 months, P = .0018; OS, 75 vs 64 months, P = .025), favored the triplet combination.[10] The IFM/DFCI 2009 analysis, while evaluating the timing of transplant among patients receiving triplet induction therapy with RVD, demonstrated that high-dose therapy plus autologous stem cell transplant (ASCT) achieved deeper responses in a higher proportion of patients.[11] As shown in the Table and in Figure 1, several IMiD and PI combination regimens have shown promising activity.[8,12-17] In evaluating the IMiD and PI combination regimens, a few questions arise. First, does substitution of an IMiD for an alkylating agent result in the same benefits? A prospective phase III trial by Moreau et al demonstrated that the response rates achieved with VTD far outweighed those associated with a regimen of bortezomib, cyclophosphamide, and dexamethasone (VCD).[18] Second, if three drugs are better than two, would four drugs be better than three? Can we add a fourth agent to the RVD backbone? The EVOLUTION study found that combining cyclophosphamide with RVD[19] or adding doxorubicin to RVD[20] resulted in efficacy similar to that achieved by treatment with RVD alone, but with increased toxicity. Quadruplet regimens incorporating a cytotoxic drug as the fourth agent have not shown any benefit in terms of an enhanced antimyeloma effect, and they are associated with greater toxicity. As illustrated in the Table, RVD in combination with an HDACI such as vorinostat[21] or panobinostat[22] deepened the clinical responses seen in patients with myeloma, with acceptable toxicity, but significant dose reductions were needed. Combinations of chemotherapy plus targeted therapy are under investigation, with the goal of attaining MRD negativity. Examples of such studies include a trial of the monoclonal antibody elotuzumab (which is active against SLAMF7 [signaling lymphocytic activation molecule F7], also known as CS1) paired with the active regimen RVD (NCI ClinicalTrials.gov ID: NCT02375555), and addition of the monoclonal antibody daratumumab (which has anti-CD38 activity) to treatment with VTD and to a regimen of carfilzomib administered in combination with lenalidomide and dexamethasone (CRD) (NCI ClinicalTrials.gov ID: NCT01998971). The question of which fourth agent should be added to achieve the maximal treatment benefit is elusive at this point. However, from the preliminary data available, a monoclonal antibody or a well-tolerated HDACI seems to be the perfect choice (see Table).
HDACI-based combination regimens
TO PUT THAT INTO CONTEXT
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Paul Richardson, MD
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MassachusettsHow Have Combination Therapies Advanced the Management of Multiple Myeloma?Over the last 15 years, novel agents have transformed the therapeutic paradigm and improved treatment outcomes in multiple myeloma.[1] Rationally designed novel combination therapies have been intrinsic to this success. Critically, our better understanding of clonal evolution, tumor heterogeneity, and the complexity of resistance has provided a basis for further development of combination approaches. In the setting of newly diagnosed disease, the success of combining a proteasome inhibitor with immunomodulatory therapy and dexamethasone resulted in the landmark experience with a regimen of lenalidomide, bortezomib, and dexamethasone (RVD) in a multicenter phase I/II study: RVD generated a 100% rate of partial response or better, with 52% complete or near-complete responses achieved without autologous stem cell transplantation (ASCT).[2] Importantly, while ASCT further enhances this response benefit, and minimal residual disease negativity may provide an important clue as to who benefits from what treatment and when, the use of continuous therapy has greatly improved patient outcomes over the longer term, regardless of whether ASCT is used or not.What Is the Role of Immunotherapy and Histone Deacetylase Inhibitors? The advent of monoclonal antibodies and histone deacetylase inhibitors (HDACIs) as effective tools in the treatment of multiple myeloma is exciting.[3-6] Indeed, not only do we now have a selection of antibodies from which to choose, but we also have the promise of several active orally bioavailable HDACIs, and it is hoped that use of these agents will lead to further improvements in patient outcome. The impact of immunotherapy in this setting has also been remarkable, with the use of checkpoint inhibitors emerging as another area of promise. Thus, in aggregate, continuous therapy and the use of rational combinations in the management of multiple myeloma is clearly a wave of the future. A current priority is to gain the ability to further adapt these combination strategies to improve efficacy and minimize acute and long-term toxicities. Participation in well-designed prospective clinical trials is essential to this effort to further elucidate the best integration of the various modalities available. Finally, continued development of next-generation novel agents is central to maintaining the momentum we have gained, to ensure an outlook for our patients that is increasingly hopeful.REFERENCES1. Palumbo A, Anderson KC. Multiple myeloma. N Engl J Med. 2011;364:1046-60.2. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-86.3. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-19.4. Dimopoulos MA, Lonial S, White D, et al. Eloquent-2 update: a phase 3, randomized, open-label study of elotuzumab in combination with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma - 3-year safety and efficacy follow-up. Blood. 2015;126:abstr 28.5. Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA-2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013;122:2331-7.6. Niesvizky R, Richardson PG, Gabrail NY, et al. ACY-241, a novel HDAC6 selective inhibitor: synergy with immunomodulatory (IMiD) drugs in multiple myeloma (MM) cells and early clinical results (ACE-MM-200 study). Blood. 2015;126:abstr 3040.Financial Disclosure: Dr. Richardson serves on the advisory committees of Bristol Myers-Squibb, Celgene, Johnson & Johnson, Millennium Takeda, and Novartis.
HDACIs suppress cell growth and induce myeloma cell apoptosis by various effects, including activation of tumor suppressor genes; these processes, in turn, promote toxic accumulation of polyubiquitinated proteins, resulting in increased cellular stress and apoptosis.[23] Synergistic cytotoxic activity between PIs and HDACIs was observed by dual inhibition of the proteasome and aggresome pathways.[24] The synergy of the PI and IMiD was well proven in the PANORAMA-1 trial. In this randomized, placebo-controlled, phase III study, patients received panobinostat or placebo in addition to a bortezomib-plus-dexamethasone (Vd) backbone regimen. Among 768 patients randomized, the 387 patients in the panobinostat combination arm had higher response rates and a 4-month PFS advantage compared with patients randomized to Vd. The major drawback of this regimen is the overlapping toxicity of bortezomib and panobinostat; this was evidenced by an increased incidence of grade 3 adverse events, including diarrhea, asthenia, and thrombocytopenia, compared with patients in the placebo arm.[25] A better schedule, with appropriate dose modifications/reductions or use of an alternate PI or HDACI, may mitigate the toxicities and preserve the efficacy of this combination.
In a similar vein, carfilzomib and panobinostat were evaluated in two phase I trials.[26,27] In a heavily pretreated patient population that was exposed to a median of five lines of therapy, the results with this combination compared favorably to those of the PANORAMA-1 trial. Berdeja et al reported a median PFS of 7.7 months, and median OS was not reached at a median follow-up of 17 months.[26] Panobinostat seems to be well tolerated when given 3 times weekly every other week in a 28-day cycle. With this schedule, the investigators were able to escalate the dosing to 30 mg without dose-limiting toxicities, but ultimately 20 mg seems to be the maximum tolerated dose, since the majority of patients required dose reductions at the higher dose. From our group, Kaufman et al reported similar findings in an equally pretreated patient population (median PFS, 11.4 months, and median OS not reached at median follow-up of 17 months).[27] These results compare similarly to the study of carfilzomib and pomalidomide by Shah et al.[16] The intermittent dosing strategy used in both these trials seems to mitigate the side effect profile, allowing for a longer duration of drug delivery. Panobinostat has been evaluated with other combinations (VTD, Rd, CRD) but the side effect profile remains an issue.[28-30] The alternative strategy was to evaluate newer formulations of HDACIs. The selective HDAC6 inhibitor ACY-1215 (rocilinostat) is a better-tolerated HDACI, with minimal off-target side effects. ACY-1215 has been evaluated in several combinations-with pomalidomide plus dexamethasone (Pd), Vd, and Rd-with promising activity.[31-33] Another HDACI oral formulation, ACY-241, seems to show an almost negligible toxicity profile at the target dosing and exerts maximal activity in combination with Pd.[34]
Antibody-based combination regimens
Daratumumab, a humanized anti-CD38 antibody, is the most active monoclonal antibody in myeloma; it was recently approved in the United States at the active dose of 16 mg/kg, which in an open-label, randomized, phase II trial yielded an ORR of 29%.[35] In combination with Rd, in myeloma patients who had received a median of two lines of therapy, an ORR of 81% and a ≥ VGPR rate of 63% were observed.[36] In combination with Pd, in patients who had received four lines of therapy, the ORR was 71% and the ≥ VGPR rate was 43%. At the 12-month mark in this heavily pretreated population, 53% of patients were disease progression–free.[37] As expected from an immunoglobulin G (IgG) kappa monoclonal antibody, the presence of residual daratumumab can be detected by electrophoresis intended to assess levels of malignant spikes in M-protein levels; this daratumumab interference may result in inconsistent clinical assessment of M-protein responses, which explains the lower rate of CRs seen (Table). Elotuzumab is a humanized anti-SLAMF7 antibody approved for use in combination with Rd. In the setting of early relapse, in combination with Rd, impressive response rates of 79% were observed; this suggests that lenalidomide upregulates the natural killer (NK) cells, which are necessary for NK-mediated cell kill by elotuzumab. In the ELOQUENT-2 trial, results favored combination therapy, with a median PFS time of 19.4 months vs 14.9 months (P < .001), leading to approval of elotuzumab by the US Food and Drug Administration (FDA).[38] Another phase II trial recently reported the results of combination treatment with elotuzumab plus Vd vs Vd (median PFS for patients treated with elotuzumab plus Vd vs Vd: 9.7 months vs 6.9 months; P = .018), demonstrating the power of combination therapies.[39] Another humanized monoclonal antibody, SAR650984 ([isatuximab] which targets CD38), given in combination with Rd, yielded ≥ VGPR in one-third of patients (32%) who had received six prior lines of therapy, demonstrating the potency of the combination.[40] Multiple ongoing trials are investigating various combinations of chemotherapy with antibodies in the treatment of myeloma.
Other combination regimens
Pembrolizumab, a humanized IgG4 anti–programmed death 1 (PD-1) monoclonal antibody designed to block the interaction of PD-1 with programmed death 1 ligands 1 and 2 (PD-L1, PD-L2), was evaluated in combination with IMiDs (Rd and Pd), with the goal of enhancing tumor suppression.[41,42] The ORR for patients treated with Rd was 76% (≥ VGPR, 24%)[41] and the ORR for patients treated with Pd was 60% (≥ VGPR, 19%)[42]; thus, these agents showed impressive activity in both studies, with a tolerable safety profile. Several other combination trials with PD-1 and PD-L1 antibodies are underway. Other exciting combination trials have evaluated carfilzomib in combination with selinexor, a first-in-class selective inhibitor of nuclear export; this combination delivered a ≥ VGPR rate of 22% and a PR rate of 67% in the 9 patients treated at the time of study publication.[43] Another carfilzomib combination trial of interest is investigating ARRY-520 (filanesib), a kinesin spindle protein inhibitor that showed good antimyeloma activity in heavily pretreated multirefractory myeloma patients.[44] Carfilzomib, administered at a dose of 20 mg/m2, also showed promising activity in combination with ibrutinib, a Bruton tyrosine kinase inhibitor, with no dose-limiting toxicities among the 18 patients treated with ibrutinib at 840 mg daily. The preliminary ORR of 67%, with 10% VGPRs, is very encouraging.[45] Agents with novel mechanisms of action potentially may be combined with most other antimyeloma agents, to improve on treatment efficacy via alternate mechanisms that achieve additive or synergistic cell death; in such cases, patients should be monitored for overlapping drug toxicities.
Understanding Frailty
As data with combination therapies encourage us to achieve the best responses and to attain the best survival benefits, we need to accept that not every patient is a candidate for combination therapies. Myeloma is a disease of the elderly; the median age of patients is 70 years, and more than 30% of patients are older than 75 years at the time of diagnosis. Risk-adapted therapies based on the IMWG frailty score enable us to minimize treatment-related toxicities and facilitate the delivery of tolerable therapies. Very few studies have addressed the issue of adapted therapy in elderly patients. Palumbo et al evaluated 869 elderly patients with newly diagnosed myeloma from three randomized phase III trials. One-third of the patients were frail based on the IMWG frailty score, and this frailty score predicted mortality and the risk of treatment toxicity.[46] Performing a geriatric assessment at diagnosis to ascertain the frailty score, then tailoring therapies based on this frailty score, enables patients to attain the maximal benefit from the proposed risk-adapted therapies.
Understanding High-Risk Patient Subsets
Despite major advances in the field of myeloma and approvals of newer classes of drugs, approximately 15% of individuals with myeloma are diagnosed as belonging to a high-risk patient subset. This designation is defined by presentation with primary plasma cell leukemia or extramedullary disease, or by genetic features, including t(4;14), t(14;16), t(14;20), del(17), and del(1p), identified by fluorescence in situ hybridization or cytogenetic analysis, as well as a hypodiploid or complex karyotype, as determined by metaphase cytogenetics.[47] Although high-risk myeloma patients have experienced significantly improved survival outcomes from use of newer regimens incorporating novel agents, their relative survival time is of shorter duration than that of standard-risk patients. The key to achieving long-term survival gains in these patients is to intensify treatment strategies using combination regimens to prevent relapse and subsequently prolong PFS.[48] Frail patients who exhibit high-risk features should be offered modified combination strategies that both improve tolerability and enhance clinical benefit, similar to the experiences of patients in the “RVD lite” trial.[49]
Conclusions
The utilization of combination therapies has certainly revolutionized the myeloma therapeutic arena. The concern over preserving selected antimyeloma agents for a later time in the disease course, thereby favoring use of sequential therapies, is no longer a valid issue; this change in the therapeutic approach results mainly from the abundance of FDA-approved drugs and other antimyeloma agents in the pipeline that are now available to patients participating in clinical trials. The clonal heterogeneity in myeloma and the strategy of eradicating both the dominant clones and the minor clones create a strong rationale for adopting combination therapies. In addition, this approach makes it possible to achieve a greater depth of response, as measured by MRD negativity. Understanding two broad subsets of patients-those with frailty (a host factor) and those at high risk (a disease factor)-and tailoring therapies based on the attributes of these populations allows clinicians to maximize the therapeutic benefit and mitigate regimen-related toxicities. Figure 2 is a simple (but not comprehensive) framework to guide use of the available therapeutic options, based on a given patient’s individual risk factors. Several trials now in progress are employing various combinations of monoclonal antibodies, immunotherapeutic agents, and currently used conventional agents, with the goal of further improving therapeutic options and outcomes for our patients with myeloma.
Financial Disclosure: Dr. Nooka serves as a consultant to Novartis, Onyx Pharmaceuticals, and Spectrum Pharmaceuticals. Dr. Lonial serves as a consultant to Bristol Myers-Squibb, Celgene, Janssen, Millennium, Novartis, and Onyx Pharmaceuticals.
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