How I Treat in Brief: New Agents in Myeloma

This month, Philippe Moreau, MD, discusses the changing landscape of multiple myeloma (MM) therapeutics and options for treatment in frontline and relapsed settings.

This material was repurposed from “How I Treat: New Agents in Myeloma,” published in the July 26, 2017, edition of Blood.

  • Over the past five years, several new agents (including pomalidomide, carfilzomib, ixazomib, panobinostat, elotuzumab, and daratumumab) have been approved and transformed the treatment of patients with MM.
  • Future trials should focus on identifying the most cost-effective regimens and establishing whether limited-duration regimens are as effective as continuous therapy.

The treatment of MM has changed dramatically in the past decade with the introduction of new drugs into therapeutic strategies in both the frontline and relapsed settings, which have led to significant improvements in overall survival (OS).

Over the past five years, several new agents have been approved, incorporated into clinical guidelines, and transformed our approach to the treatment of patients with MM. These include the third-generation immunomodulatory agent (IMiD) pomalidomide, the second-generation proteasome inhibitors (PIs) carfilzomib and ixazomib, the histone deacetylase inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab.

The availability of various classes of agents presents both a great opportunity and a great challenge: On one hand, we can achieve unparalleled results in improving survival, but on the other, questions about the optimal combinations, durations, and dose-modifications of these agents remain unsolved.

This article reviews treatment options both in the frontline and relapsed settings, as illustrated through five patient cases.

Case #1: Frontline Therapy in a 60-Year-Old Patient

A 60-year-old woman was diagnosed with IgG-κ MM in 2014. A bone marrow aspirate confirmed the presence of 33 percent plasma cells, her International Staging System (ISS) score was low, and genetic analysis did not reveal any adverse cytogenetic factors. The first line of therapy consisted of four cycles of bortezomib, cyclophosphamide, dexamethasone (VCD), followed by high-dose melphalan and autologous hematopoietic cell transplantation (AHCT), after which she achieved a complete remission (CR). Lenalidomide maintenance was started two months after AHCT. In 2017, the patient is still receiving lenalidomide maintenance, with a sustained CR.

Comments: Based on response rates, depth of response, and progression-free survival (PFS) as surrogate markers for outcome, three-drug combinations including bortezomib and dexamethasone are the standard-of-care induction prior to AHCT, but only limited data from prospective, phase III trials are available to demonstrate that one combination is superior to the other.

The preferred regimens consist of bortezomib and dexamethasone (Vd) with cyclophosphamide (VCD), thalidomide (VTD), lenalidomide (VRD), or doxorubicin. Carfilzomib plus lenalidomide and dexamethasone (KRd) has also been investigated as induction prior to AHCT and is associated with high response rates and minimal residual disease (MRD) negativity. Other ongoing studies are evaluating the addition of either elotuzumab or daratumumab to a triplet induction combination to further increase the MRD negativity rate prior to AHCT.

Outside of a clinical trial, my approach is a triplet induction therapy, followed by AHCT and lenalidomide maintenance, although the optimal duration of maintenance remains to be defined.

There is an ongoing “cure versus control” debate on whether patients should receive an aggressive multidrug strategy with the aim of achieving CR or a sequential disease-control approach that emphasizes quality of life and OS. However, in 2017, there is no prognostic factor or staging system, such as Revised ISS or gene-expression profiling, that is routinely used to define a risk-adapted strategy.

Case #2: Frontline Therapy in a 75-Year-Old Patient

A 75-year-old man was diagnosed with IgA-κ MM in 2014. Renal function was normal, performance status was good, and no genetic abnormalities were detected. The patient was treated with lenalidomide 25 mg/day for 21 days in 28-day cycles plus low-dose dexamethasone 40 mg per week (Rd). He achieved a very good partial response (VGPR) after six cycles of Rd. However, after six cycles, neutropenia and fatigue led to dose reduction of lenalidomide to 15 mg/day and of dexamethasone to 20 mg/week. Twenty-eight months after therapy initiation, the patient is still in VGPR, and therapy with Rd is ongoing.

Comments: This patient presented with standard-risk MM at diagnosis, and Rd or VRd, VCD, or bortezomib, melphalan, prednisone (VMP) are all reasonable treatment options in this setting. Outside of a clinical trial, I would recommend Rd until progression or unacceptable toxicity.

This patient had an adequate performance status at diagnosis and was able to stay on treatment for a long period of time; for patients considered frail or unfit, dose reductions and/or doublet combinations should be favored. A geriatric assessment is recommended for all older patients at diagnosis and may guide treatment choices, such as when to lower dose intensity.

Several important, ongoing, phase III trials may change the landscape of frontline therapy in older patients in the near future. Rd is being compared with Rd plus elotuzumab, daratumumab, or ixazomib in what may become the first all-oral triplet regimen for transplant-ineligible patients.

Case #3: Relapse After Bortezomib-Based Induction

A 64-year-old man was diagnosed with symptomatic MM in 2014. Genetic analysis showed a t(4;14). He achieved VGPR after four cycles of VCD, followed by melphalan and AHCT. No consolidation or maintenance therapy was given. Twenty months later, the patient presented with disease progression with anemia and bone pain. Renal function and performance status were good at the time of relapse. His was treated with the triplet combination KRd and achieved a VGPR following the first two cycles and a CR at cycle six. He is now receiving cycle 15 with a sustained CR, without the occurrence of significant toxicity.

Comments: The choice of therapy in the relapse setting depends on several parameters such as age; performance status; comorbidities; cytogenetics; the available remaining treatment options; and the type, efficacy, and tolerance of the previous treatment.

When a lenalidomide-naïve patient has progressive disease following bortezomib induction, like this patient, Rd is a feasible option. Rd has been combined with elotuzumab (Rd-Elo), carfilzomib (Krd), ixazomib (IRd), and daratumumab (DRd), and all have shown significant improvements in PFS, compared with Rd alone.

The choice among the combinations is not always straightforward, and cross-trial comparisons are difficult because of substantial differences in patient populations. The toxicity profile of each regimen is different, with more cardiac and vascular issues with KRd, infusion-related reactions with DRd and Rd-Elo, and rash with IRd.

The monoclonal antibodies are attractive partners in combination regimens because of their efficacy and excellent tolerability profile. Therefore, for this patient, outside of a clinical trial, I would recommend DRd.

Case #4: Relapse After Immunomodulatory Agents

A 71-year-old woman presented with anemia and bone pain in 2014 and was diagnosed with MM IgG-λ. Renal function and performance status were adequate, and genetic analysis revealed no adverse cytogenetic abnormalities. She received Rd as frontline therapy and achieved a PR after two cycles, which was associated with clinical improvement. During cycle 22, the M-spike increased from 0.5 to 1.1 g/dL with the reappearance of bone pain. The patient  was then treated with Vd for six cycles and achieved a VGPR. Treatment was discontinued at the end of cycle six because of the onset of grade 2 peripheral neuropathy (PN). The patient did not receive any further therapy. Response is ongoing, and grade 2 neuropathy persists.

Comments: For a patient progressing on Rd as frontline therapy, the logical approach is to switch the class of agent, or to try to increase the doses of lenalidomide and dexamethasone (in case of a previous dose reduction), rather than to add a third agent to Rd. Vd is commonly used in this setting, and adding cyclophosphamide (VCD) may increase the response rate. However, PN remains the most important side effect of Vd combinations.

Kd could also have been a feasible option for this patient, although the schedule of administration is more demanding than that of Vd. The safety profile includes less PN, but higher rates of hypertension, dyspnea, cardiac failure, and acute renal failure.

Outside of a clinical trial, I would propose Vd plus daratumumab (DVd) for this patient. In the CASTOR trial, this triplet combination was associated with improved PFS, compared with Vd alone, across all subgroups of patients, including all characteristics of this patient. Importantly, daratumumab did not increase significant toxicity when added to Vd.

Case #5: Treatment of Refractory Disease

A 67-year-old woman with standard-risk MM was treated with frontline Rd in 2013. The initial response was VGPR, but she progressed on therapy during cycle 26 in 2015. Salvage therapy consisted of Vd. She achieved a PR after two cycles (which was sustained for three cycles), but her disease progressed again with bone pain, anemia, and an M-spike of more than 1.5 g/dL. The patient was then treated with pomalidomide-dexamethasone (pom-dex), but response to pom-dex lasted for only five months before disease progression. At the end of 2016, she started daratumumab therapy, which induced a partial response. The patient is still receiving daratumumab as a single agent, with a sustained response, good tolerance, no bone pain, and normal performance status.

Comments: Pom-dex is an approved combination regimen for the treatment of patients with refractory disease or those whose disease relapses after at least two prior lines of therapy, including lenalidomide and bortezomib. For this patient, who is refractory to both Rd and Vd, I would recommend pom-dex with either cyclophosphamide or daratumumab.

Based on recent trials that have suggested that pom-dex plus cyclophosphamide increases PFS, compared with pom-dex alone, this patient could have benefitted from the addition of cyclophosphamide (PCD), to which she had not been exposed previously. PCD is one of our standard rescue regimens because it is all-oral, effective, and manageable.

Although daratumumab is rarely used as a single agent in the United States, it represents a breakthrough for the treatment of patients with refractory disease. We anticipate that the agent also will be used earlier in the disease course, in combination with PIs and IMiDs, as investigated in the CASTOR and POLLUX trials. The feasibility of retreatment with CD38 monoclonal antibodies remains to be investigated.

The Future of MM Treatment

Many other new drugs and immune therapies are in advanced stages of investigation, including the CD38 monoclonal antibody isatuximab, the nuclear exporter inhibitor selinexor, the oral BCL2 inhibitor venetoclax, and the oral HDAC6 inhibitor ricolinostat, as well as checkpoint inhibitors, bispecific T-cell engager antibodies, and chimeric antigen receptor T-cell therapies that will enrich our therapeutic armamentarium.

Moreover, MM is a heterogeneous disease comprised of different genetic entities that vary from each other in evolution, mode of presentation, response to therapy, and prognosis. Clinical trials seldom target specific genetic subtypes that may benefit most from a new drug. In the future, the use of new agents will probably require the identification of biomarkers to predict response to therapy.

Several questions will need to be answered to further optimize the management of patients with myeloma: Does modifying therapy based on response or MRD detection improve outcome? Can limited-duration combination therapy regimens be developed that are as effective as continuous therapy? What is the best triplet regimen to use in the most cost-effective way at relapse?

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