The phase III ELOQUENT-1 and -2 trials are assessing the use of lenalidomide plus dexamethasone with or without elotuzumab as a treatment for patients with multiple myeloma in the newly diagnosed and relapsed/refractory setting. In the ELOQUENT-2 trial, the elotuzumab triplet demonstrated a higher response rate compared with lenalidomide and dexamethasone alone, which has translated into a 30% reduction in the risk of disease progression for individuals with relapsed/refractory multiple myeloma, says Noopur Raje, MD.

In findings presented at the 2015 ASCO Annual Meeting from the ELOQUENT-2 study, the median progression-free survival (PFS) with the elotuzumab regimen was 19.4 months versus 14.9 months with lenalidomide and dexamethasone alone (HR = 0.70; 

= .0004). The objective response rate (ORR) was 79% with elotuzumab versus 66% in the control arm (

 = .0002). Overall survival (OS) data for the trial are not yet mature.

This is a new milestone in multiple myeloma, comments Raje, noting that monoclonal antibodies can be piggybacked on any combination approach in myeloma once adverse events, such as infusion reactions, are managed. In the study, 10% of patients receiving elotuzumab experienced infusion reactions, the majority of which were grade 1/2 and manageable.

In addition to the ELOQUENT-2 study, the ongoing phase III ELOQUENT-1 trial is examining the elotuzumab plus lenalidomide and dexamethasone regimen in the frontline setting for relapsed/refractory multiple myeloma. Additionally, other monoclonal antibodies are also being explored for patients with multiple myeloma, including daratumumab, an anti-CD38 antibody.

In a phase II trial, single-agent daratumumab showed double-digit response rates in patients with heavily pretreated multiple myeloma, states Jatin J. Shah, MD. In this study, the ORR was 29.2% and the 1-year OS rate was 65%. The duration of response of 7.4 months and PFS of 3.7 months confirms that daratumumab has high single-agent activity, says Heather J. Landau, MD. Patients in this study had received a median of 5 prior therapies over a median of 4.8 years.

With the availability of these very effective agents, the question going forward will be how to fit them into induction, consolidation, and maintenance strategies for patients with multiple myeloma, says Morie A. Gertz, MD. An added benefit is that monoclonal antibodies are not associated with as much toxicity as other options. Given the data presented thus far, it seems likely that monoclonal antibodies will move quickly to the frontline because of their ability to combine well with treatments without adding additional toxicity, suggests Rafael Fonseca, MD.

Introduction: Monoclonal Antibodies in Multiple Myeloma

Immunotherapies and monoclonal antibodies have generated a great deal of excitement as potential treatments for patients with cancer in recent years, states Kenneth Anderson, MD. Monoclonal antibodies have demonstrated efficacy in many other diseases, but, until recently, these therapies had not demonstrated efficacy in multiple myeloma. However, new agents in clinical trials have shown high levels of activity, adds Anderson.

The first agent, elotuzumab, is a monoclonal antibody directed against the signaling lymphocyte activation molecule (SLAMF7) antigen, which is expressed on multiple myeloma and natural killer (NK) cells, Anderson explains. Elotuzumab elicits antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), additionally, by reacting with SLAMF7 expressed on NK cells elotuzumab serves as an activator of NK activity. In essence, explains Anderson, elotuzumab can directly target tumor cells as well as augment the activity of effector cells.

In earlier investigations, combining elotuzumab with lenalidomide and dexamethasone achieved 80% to 90% responses that lasted 33 months, even in high-risk myeloma, says Anderson. This efficacy led to the initiation of the phase III ELOQUENT-1 and -2 trials. These randomized trials are evaluating elotuzumab in the relapsed/refractory and newly diagnosed settings.

In findings reported from the ELOQUENT-2 trial, the combination of elotuzumab, lenalidomide, and dexamethasone extended progression-free survival (PFS) and increased overall response rates (ORR) compared with lenalidomide and dexamethasone alone in patients with multiple myeloma who had one to three prior therapies. The median PFS was improved by 4.5 months with the elotuzumab triplet versus lenalidomide and dexamethasone alone and the ORR was 79% versus 66%, respectively.

A second monoclonal antibody class in development targets the CD38 antigen on multiple myeloma cells. The most advanced antibody in this class, daratumumab, mediates ADCC and CDC. Cross-linking CD38 on the surface of myeloma cells triggers apoptosis and inhibits CD38 enzymatic activity, notes Anderson. Daratumumab possesses high activity in relapsed and relapsed/refractory myeloma, including high-risk disease (such as 17p deletion).

Clinical trials have shown that daratumumab augments response when added to lenalidomide and dexamethasone. Additionally, the agent has been explored as a monotherapy. In a phase II study, monotherapy with daratumumab demonstrated a 65% one-year overall survival rate and a 29.2% ORR in patients with double refractory heavily pretreated multiple myeloma. In combination with lenalidomide and dexamethasone in pretreated patients, the ORR reached as high as 92.3%.

In Anderson’s opinion, combination immune approaches are the future. Combining an antibody with an immunomodulatory agent such as lenalidomide, which targets regulatory T-cells and activates NK cells, results in synergistic cytotoxicity.Other ongoing clinical trials are assessing whether adding a monoclonal antibody to an already active combination of targeted treatments can increase response or extend PFS. Antibodies offer the opportunity to maintain responses in individuals intending to receive transplant as well as those who will not undergo transplant, adds Anderson.

Elotuzumab and Daratumumab in Multiple Myeloma

A good response to frontline therapy, ideally with minimal residual disease (MRD)-negativity, is a marker for better long-term outcomes for patients with newly diagnosed multiple myeloma, says Rafael Fonseca, MD. As a result, when considering front-line therapies, Fonseca evaluates the feasibility of transplant and post-transplant therapy.

Goals of induction therapy are to achieve rapid disease control and reverse end-organ damage, adds Jatin J. Shah, MD. Transplant remains an important part of how to treat patients with multiple myeloma, states Shah, noting that trying to achieve a particular MRD level or complete remission does not affect his decision to pursue a transplant.

A lot of focus falls on achieving the best response in the transplant-eligible patient population, says Noopur Raje, MD, but the majority of myeloma patients are elderly and may not qualify for transplant. Administering lenalidomide and dexamethasone continuously can achieve durable remissions in frail patients, states Heather J. Landau, MD, without exposing these individuals to the neurotoxicity that bortezomib therapy can induce.

Combination therapy is crucial in multiple myeloma management, notes Raje, even in relapsed settings. However, most clinicians do not intend to achieve MRD negativity when administering dose-reduced triplet therapy in the frail, elderly population, comments Morie A. Gertz, MD. This is in contrast with the younger, transplant-eligible population, where the depth of response is being pushed as high as possible.

Treatment Goals in Newly Diagnosed Multiple Myeloma

Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies were all initially evaluated in advanced multiple myeloma and relapsed and refractory disease, but have since moved into the frontline setting for newly diagnosed patients, states Kenneth Anderson, MD. In most cases, triplet therapy is commonly utilized in the frontline setting, which generally consists of a proteasome inhibitor (bortezomib or carfilzomib) in combination with dexamethasone and either lenalidomide or cyclophosphamide.

The oral agent ixazomib is a next-generation proteasome inhibitor currently under investigation, comments Anderson. The agent is given once weekly and is well tolerated. Ixazomib, lenalidomide, and dexamethasone comprise an all-oral regimen, which would be convenient for patients. In the relapsed/refractory setting, ixazomib, lenalidomide, and dexamethasone demonstrated an improvement in progression-free survival (PFS) compared with lenalidomide and dexamethasone alone.

Incorporating proteasome inhibitors into initial management helps achieve high extent and frequency of response, even in high-risk patients, such as in individuals with 17p deletion or p53 non-functioning multiple myeloma. In the older, non-transplant-eligible population, attenuated doses of these same triplets are used as initial treatment, as these individuals are more likely to have comorbid diseases and are more susceptible to adverse events from these medications.

In the FIRST trial, which was the largest randomized clinical trial in newly diagnosed, elderly non-transplant candidates, lenalidomide plus dexamethasone administered continuously until progression extended PFS and overall survival (OS), comments Anderson. Based on an extension in PFS versus MPT of 4.3 months in this trial, the combination of lenalidomide and dexamethasone was approved by the FDA for newly diagnosed patients in February 18, 2015. In the interim analysis, OS was improved by 10.4 months with the doublet versus MPT.

Frontline Treatments for Multiple Myeloma

Randomized clinical trial data currently do not support changing therapy if a younger patient with multiple myeloma has achieved a partial response (PR) with induction therapy, states Jatin J. Shah, MD. Changing therapies in this setting could expose the patient to more toxicity and limit the ability to collect stem cells. If a PR is achieved, it could be ideal to move to transplant, Shah suggests.Â 

Following frontline therapy, patients who do not achieve a deep response with induction therapy and proceed directly to stem cell transplant have similar outcomes to patients who received a second-line non-cross—resistant regimen to drive the response according to a retrospective registry analysis, says Morie A. Gertz, MD. However, data supporting this approach predate induction therapy with novel agents, which makes it difficult to know the optimal way to manage multiple myeloma in this era of newer therapies.

For individuals who achieve a PR with induction therapy, Heather J. Landau, MD, suggestsÂ proceeding to stem cell transplant, with the consideration of stem cell mobilization by chemotherapy in individuals who have not had adequate bone marrow cytoreduction.Â It is important to build clinical trial data to understand what to do now, particularly with a novel agent, says Rafael Fonseca, MD.Â 

Most patients are achieving better than a PR with the newer drugs, states Noopur Raje, MD. For the time being, stem cells can still be collected and stored for later use at least in the younger population, suggests Raje.Â To further explore an optimal sequence for novel agents and transplant, a phase II study is assessing carfilzomib, lenalidomide, and dexamethasone before and after stem cell transplant for patients with newly diagnosed multiple myeloma (NCT01816971). This study will help shed light on a possible sequence, Raje suggests.Â 

Evolving Role of Stem Cell Transplant in Multiple Myeloma

High-risk multiple myeloma is defined by the presence of plasma cell leukemia, elevated levels of lactate dehydrogenase (LDH), or high-risk cytogenetics by FISH analysis, such as 4;14 translocation, 14;16 translocation, 17p deletion, and changes in chromosome 1, explains Morie A. Gertz, MD.

Cells that are sent out for FISH analysis or gene expression profiling are usually from a third aspirate of the bone marrow, which can be very diluted, states Rafael Fonseca, MD. In order to maximize the efficiency of testing, it is important to conduct plasma cell enrichment using cell sorting techniques, notes Fonseca.

Cytogenetic analysis of individuals with rapidly progressing disease and organ damage may not necessarily correlate with other high-risk markers, but these patients still have high-risk disease that requires combination therapy, notes Heather J. Landau, MD. Risk is not only genetic, adds Noopur Raje, MD. Renal failure, bone disease, and other complications need to be treated fairly aggressively, says Raje.

Defining High-Risk Multiple Myeloma

Maintenance therapy in multiple myeloma can be administered short-term, continuously, or for a duration determined by clinical endpoints and risk. However, it is unclear which patients will benefit the most from each of these strategies. For continuous maintenance therapy, Noopur Suresh Raje, MD, recommends utilizing lenalidomide, based on CALGB 100104 data. In this study, maintenance treatment was continued until disease progression or toxicity, says Raje.

At a 65 month follow-up of the CALGB study, lenalidomide maintenance resulted a time to progressive disease of 53 months versus 27 months with placebo in patients with multiple myeloma (HR, 0.54; 

 <.001). At the time of the analysis, median overall survival (OS) had not been reached for the lenalidomide arm and was 76 months for placebo (HR, 0.60; 

 = .001). At this time, this is study provides the only data available on OS for maintenance lenalidomide, notes Heather J. Landau, MD.

In patients with high-risk multiple myeloma, proteasome inhibitors can be utilized as maintenance therapy, says Rafael Fonseca, MD. However, the benefits of these therapies are unclear for patients with low-risk disease. Additionally, some patients do well without maintenance therapy, says Fonseca, and other patients have a long period of disease control with continuous administration of lenalidomide. Rather than immediately initiating maintenance therapy, there should also be a conversation about stem cell transplant.

Even with the advances being made with novel therapies, stem cell transplant still maintains a vital role in the treatment of patients with multiple myeloma, states Jatin J. Shah, MD. Twenty years of experience in multiple randomized trials has shown that transplant improves OS. Clinicians cannot assume that novel agents will replace the need for transplants, states Shah, unless there are data supporting that transplant is no longer necessary. As research evolves, characteristics for selecting which patients should receive transplant should be developed, comments Raje, to avoid the toxicities associated with these procedures.

Maintenance Therapy in Multiple Myeloma

A number of therapies are available in the treatment of multiple myeloma that can prolong both progression-free survival (PFS) and overall survival (OS), states Kenneth Anderson, MD. It is understood now that it is critical not only to achieve a response in multiple myeloma but also to employ maintenance therapy or continuous therapy to prolong PFS and OS. 

In the past, thalidomide was used as maintenance therapy and conferred benefit in terms of prolonging the response, explains Anderson, but even at low doses, thalidomide was associated with the development of neuropathy. Studies have shown that lenalidomide, an immunomodulatory drug, is not associated with neuropathy and confers a PFS and OS advantage in the post-transplant setting and in those who are not eligible for transplant. Lenalidomide is the most common maintenance therapy at the present time, says Anderson.

The modification of maintenance strategies depends on the risk level associated with the multiple myeloma, states Anderson. Standard risk multiple myeloma, defined by genetic testing, can be maintained with lenalidomide alone. However, for patients with high-risk multiple myeloma, such as 17p deletion, a proteasome inhibitor, such as bortezomib, should be incorporated into the maintenance strategy. The HOVON trial in the Netherlands demonstrated that bortezomib prolonged PFS and OS in as a post-transplant induction and maintenance therapy.

The proteasome inhibitor ixazomib offers the opportunity to incorporate proteasome inhibition through an oral formulation. A new drug application has been submitted for ixazomib in combination with lenalidomide and dexamethasone as a treatment for patients with relapsed and/or refractory multiple myeloma. In a phase II study, continuous treatment with ixazomib induced an objective response rate of 90%. 

In general, proteasome inhibitors are generally well tolerated, adds Anderson. Before administering any therapy, the risks and benefits should be weighed, particularly for maintenance therapy, which will be administered for a longer duration. 

Continuous Therapy in Multiple Myeloma

When deciding on the optimal treatment for an individual with relapsed multiple myeloma, it is important to determine whether the relapse was biochemical in nature and whether the patient has standard-risk or high-risk disease, comments Noopur Suresh Raje, MD. An individual with high-risk disease is more likely to encounter poorer outcomes, such as organ dysfunction, and may require earlier treatment. It may not be urgent to initiate treatment for patients on maintenance therapy with lenalidomide who have a modest increase in their M protein levels, says Raje.

Other factors to consider include treatment history, duration and tolerability with previous therapies, current patient status, and renal status, adds Rafael Fonseca, MD. Even once these factors are considered, it remains unclear how to optimally sequence all of the therapies that are available for patients who have relapsed, says Fonseca. Due to the evolution of clones, patients may respond to therapies that have been used previously.

The increased understanding of clonal heterogeneity has led to the use of multi-drug combinations upfront, explains Jatin J. Shah, MD. Evidence suggests that patients have better outcomes when they receive effective combination therapies early in the disease course, says Shah. The type of response seen with a triplet of carfilzomib, lenalidomide, and dexamethasone is equivalent to the progression-free survival (PFS) seen following stem cell transplantation without maintenance therapy, says Heather J. Landau, MD. 

The phase III ASPIRE trial showed that the combination of carfilzomib, lenalidomide, and dexamethasone improved PFS versus lenalidomide and dexamethasone alone in patients with relapsed multiple myeloma. The median PFS with carfilzomib was 26.3 months compared with 17.6 months without the proteasome inhibitor (HR, 0.69; 95% CI, 0.57-0.83; 

 <.0001). While the efficacy can be remarkable with these therapies, the dosing schedule and quality of life remain important considerations, says Landau.

Evidence of disease progression does not necessarily trigger treatment, says Morie A. Gertz, MD. Individuals with high-velocity relapse will need immediate therapy, while patients who are asymptomatic with low-velocity reappearance of the M protein may not require intervention. The immunoglobulin free light chain assay is helpful as a leading indicator of progression in patients who plateau, adds Gertz.

Treating Relapsed and Refractory Multiple Myeloma

Panobinostat is an orally available histone deacetylase (HDAC) inhibitor that was approved the FDA based on results from the PANORAMA-1 study, which showed that panobinostat in combination with the proteasome inhibitor, bortezomib, improved progression-free survival compared with placebo plus bortezomib in pretreated patients with multiple myeloma. 

A predefined subgroup analysis of PANORAMA-1 among patients with multiple myeloma who had received prior bortezomib in addition to an immunomodulatory drug (IMiD)—either lenalidomide or thalidomide&mdash;showed an overall response rate of 58.4% with panobinostat compared with 41.4% for the control, states Morie A. Gertz, MD. A separate analysis that evaluated the depth of response in the trial showed that patients with complete or near-complete responses had a progression-free survival of 16.5 months.

Combination therapy with bortezomib and panobinostat resulted in high incidences of diarrhea and fatigue in PANORAMA-1. These toxicities impact quality of life and pose a challenge to widespread implementation, comments Gertz. Exploratory trials are evaluating the combination of panobinostat with lenalidomide, or panobinostat with carfilzomib, another proteasome inhibitor. Neither regimen has reported significant gastrointestinal toxicity or fatigue, adds Gertz.

Bortezomib was administered intravenously twice weekly in PANORAMA-1. Today, it is commonly administered subcutaneously on a weekly basis, says Jatin J. Shah, MD. Changing the dosing schedule likely improved the tolerability, comments Shah.

Future studies should be evaluating HDAC inhibitors in combination with other drug classes, states Noopur Suresh Raje, MD. Rocilinostat is a more selective HDAC inhibitor that has been studied in combination with proteasome inhibitors and IMiDs. Epigenetic inhibitors may partner better with IMiDs, says Raje.

HDAC Inhibitors in Multiple Myeloma

Carfilzomib is a proteasome inhibitor administered intravenously twice weekly as a treatment for patients with multiple myeloma. Recent studies are evaluating carfilzomib at a once-weekly schedule with dose escalation, states Morie Gertz, MD. 

Three-drug combinations, such as carfilzomib plus lenalidomide and dexamethasone, are providing levels of response in the relapsed setting similar to what has historically been seen among newly diagnosed patients, states Rafael Fonseca, MD. Data from recent combination trials are beginning to challenge the notion that long-term treatment is needed in relapsed/refractory disease, adds Fonseca.

Combining pomalidomide, an immunomodulatory drug, with dexamethasone, and the proteasome inhibitor, bortezomib, is a well-tolerated strategy, says Noopur Suresh Raje, MD. Triplet combination therapies are preferred, even in relapsed settings, says Raje. This is largely due to clonal heterogeneity and the genetics of myeloma. With every relapse, the disease will clonally evolve, and treatment with upfront doublet therapies will be difficult at this point in the disease, comments Raje.

Oncologists have to take into account what therapies their patients may have received prior to referral. Thus, in the community setting, there may be a role for the combination of pomalidomide and dexamethasone in earlier lines of therapy, says Jatin J. Shah, MD.

Triplet Therapy in Multiple Myeloma

Agents used to treat relapsed multiple myeloma include bortezomib, a first generation proteasome inhibitor, and lenalidomide, an early immunomodulatory drug (IMiD), states Kenneth Anderson, MD. The second-generation of agents approved for treatment of relapsed disease include pomalidomide, a new IMiD, and carfilzomib, a new proteasome inhibitor with a greater depth and duration of proteasome inhibition than its predecessor bortezomib, adds Anderson. Additionally, in February 2015, the first-in-class histone deacetylase (HDAC) inhibitor panobinostat was approved as a treatment for relapsed multiple myeloma.

Treatment history, whether the patient has high-risk disease, and the presence of comorbidities should be considered when selecting therapy, says Anderson. Lenalidomide and bortezomib are typically used first-line, while pomalidomide and carfilzomib are second-line treatment options. Panobinostat would likely be reserved for patients whose myeloma returns following several lines of therapy that may include pomalidomide or carfilzomib, explains Anderson. Panobinostat is a broad-acting HDAC that has a high level of activity even in relapsed/refractory disease, but is also associated with certain toxicities.

The phase III ENDEAVOR trial compared bortezomib plus dexamethasone with carfilzomib, dose-escalated up to 56 mg/m

, plus dexamethasone, in relapsed disease. The study demonstrated that progression-free survival was doubled in the carfilzomib arm (18.7 months) versus the bortezomib arm (9.4 months). ENDEAVOR demonstrated that carfilzomib is very active in the relapsed setting and was well-tolerated, says Anderson. More recent data, adds Anderson, has suggested a high level of response with carfilzomib earlier in the disease course.

Second-Generation Agents in Relapsed Multiple Myeloma

The phase III ENDEAVOR trial enrolled 929 patients with relapsed multiple myeloma who had received one to three prior lines of therapy for a head-to-head comparison between proteasome inhibitors, bortezomib and carfilzomib. The carfilzomib dose was escalated to 56 mg/m

, which is higher than the dose on the package insert, and was infused over 30 minutes rather than 10 minutes, potentially improving tolerability.

The primary endpoint of progression-free survival (PFS) was 18.7 months in the carfilzomib arm and 9.4 months in bortezomib arm (HR, 0.53, 95% CI, 0.44—0.65; 

 <.0001). The differences in PFS are clinically important, says Rafael Fonseca, MD. The median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib arm (HR, 0.79; 

 = .066). The objective response rate (ORR) was 77% with carfilzomib versus 29% with bortezomib.

Clinicians should not interpret these results to mean that the higher response rates are due to doubling the carfilzomib dose, notes Jatin J. Shah, MD. As a single agent, carfilzomib 56 mg/m

 is likely the ideal dose; lower doses are appropriate in later-line settings when used in combination with other therapies, says Shah.

The ENDEAVOR results are practice-changing, comments Morie A. Gertz, MD, both in terms of the efficacy and the neurotoxicity findings. In the study, peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% versus 6%; 

The CHAMPION study evaluated the schedule of weekly carfilzomib in patients with relapsed and refractory multiple myeloma who had received one to three prior lines of therapy. Investigators administered carfilzomib at 70 mg/m

 over 30 minutes. The study demonstrated an ORR of 67%. Approximately half of these patients were bortezomib-refractory, notes Shah, commenting that these results cannot be compared with ENDEAVOR data, where most patients were bortezomib-sensitive or -naïve.

Although carfilzomib is associated with an increased risk of cardiac toxicity, treatment with the next-generation proteasome inhibitor was able to salvage many patients, states Heather J. Landau, MD. Other ongoing studies are evaluating carfilzomib dosing schedules will reveal more information concerning cardiac and renal toxicities and its potential incremental benefit in earlier lines of therapy.

Ixazomib is another proteasome inhibitor under investigation. This oral agent has been combined with cyclophosphamide and dexamethasone as well as lenalidomide and dexamethasone. Taking a fixed-dose formulation by mouth has a real impact on the patient’s quality of life, comments Gertz.

Another important targeted agent in myeloma is filanesib, states Shah, which has demonstrated single-agent activity in patients refractory to bortezomib and lenalidomide. Additionally, the recent success of monoclonal antibodies in multiple myeloma has generated a great deal of excitement, adds Shah.

ENDEAVOR and CHAMPION Trials in Multiple Myeloma

Diagnostic criteria and treatment eligibility have been expanded to include patients with multiple myeloma who do not have abnormal levels of calcium, kidney problems, anemia, or bone disease, which were traditional triggers for requiring therapy, states Kenneth Anderson, MD. Patients who do not meet these criteria but have 60% plasma cells in the bone marrow, a kappa/lambda free light chain ratio abnormality, or multiple sites of bone disease, are also now eligible for treatment. This extends benefit of treatment to a broader group of patients, comments Anderson.

Response criteria are also being refined, says Anderson. Advancements in analytical techniques for detecting minimal residual disease (MRD), such as 8-color immunofluorescence and gene sequencing of the myeloma cell, can detect one myeloma cell per one million normal bone marrow cells, notes Anderson. Clinicians are also incorporating positron emission tomography scanning into response criteria. MRD information may also help determine whether individuals can stop maintenance therapy.

These developments in practice have also led to the inclusion of surrogate markers in clinical trial designs so that clinicians do not have to wait 8 to 10 years to define whether a treatment is useful, says Anderson. The leading surrogate endpoint for multiple myeloma trials is currently MRD, although questions still linger and standardization is needed. Findings have shown the MRD can predict progression-free survival and overall survival. 

Diagnostic and Response Criteria in Multiple Myeloma

There are still unmet needs in multiple myeloma, states Morie A. Gertz, MD. Advancements in the understanding of appropriate combinations and the development of new drug classes are imperative for the myeloma community, Gertz notes. Learning the biology and genetics of the disease and clonal heterogeneity of each individual patient is also essential, adds Heather J. Landau, MD.

Sequencing therapies and optimal utilization of existing therapies are other areas of advancement on the horizon, comments Jatin J. Shah, MD. The treatment of myeloma is different than other malignancies, since patients can be retreated with therapies. There is not going to be one standard of care, notes Shah.

Incremental progress is still progress, and it improves the lives of patients with multiple myeloma, says Rafael Fonseca, MD. For example, the toxicity profiles of the immunomodulatory drugs (IMiDs) have improved since thalidomide was introduced; next-generation IMiDs, lenalidomide and pomalidomide, are better tolerated, explains Fonseca.

Emerging Concepts in the Treatment of Multiple Myeloma