What strategies should be used when managing patients after they suffer a first relapse?

When initiating therapy for patients with multiple myeloma (MM), the primary goal of treatment is to achieve a deep response for the longest duration possible. Relapse among MM patients is relatively common, but advances with new drugs and treatment combinations are likely to decrease the incidence of these cases. Despite these advances, cases of relapsed/refractory MM (RRMM) are particularly challenging to manage, regardless of whether they occur earlier or later in the disease course. Clinical trials are seeking to optimize approaches to managing patients after a first relapse.

When managing a first relapse, the goals of treatment are similar to those for newly diagnosed MM patients. Ultimately, we want to consider the patient’s age and fitness status, and then find a therapeutic approach that achieves a very deep response so that patients can achieve long-term benefits. Recent studies are shedding light on emerging approaches to managing MM after a first relapse. For example, the POLLUX trial compared daratumumab, lenalidomide, and dexamethasone with lenalidomide plus dexamethasone in RRMM. This trial found that the duration of remission for the three-drug combination of daratumumab, lenalidomide, and dexamethasone was nearly 4 years.1 This duration is similar to what has been reported in newly diagnosed MM patients in the context of stem cell transplant, consolidation, and maintenance therapy.

Several randomized phase 3 clinical trials have been conducted to determine if three-drug therapy is better than two-drug regimens as a first salvage treatment approach in MM. Some trials have compared new drugs in combination with lenalidomide plus dexamethasone,2-4 while others have compared new agents with a combination of bortezomib plus dexamethasone.5-7 In most but not all of these investigations, three-drug combinations have been more effective that two-drug regimens in terms of duration of remission and overall survival (OS), but more research is needed to establish the safest and most effective triple therapy combinations to improve RRMM outcomes. Findings from these trials support the importance of hitting MM as hard as possible in newly diagnosed patients so that they can avoid suffering a relapse.

Figure 1. EXAMPLE OF SEQUENCING THERAPY
Emory's Approach to Early Relapse

Clinical Trial
Check if Patient is t(11;14)

*Increase len dose

What current and emerging therapies are commonly used to treat MM after patients suffer a second or third relapse, and are these treatment strategies effective?

Several relatively new drugs are now being used for the treatment of second and third relapses in MM, including monoclonal antibodies (mAb; eg, daratumumab and elotuzumab) and second- and third generation proteasome inhibitors (PI; eg, carfilzomib and ixazomib). Many patients receive lenalidomide monotherapy or a combination of lenalidomide and dexamethasone as maintenance therapy, but those who have suffered a relapse are likely to be resistant to lenalidomide. At this point, our attention should shift toward using bortezomib- (a first generation PI) or pomalidomide (immunomodulatory agent/IMiD) based combinations in patients who have received lenalidomide as maintenance therapy.

Clinical trials have supported using three-drug combination therapy for second and third relapses of MM. For example, the CASTOR trial found that combining daratumumab with bortezomib and dexamethasone resulted in significantly longer progression-free survival (PFS) than bortezomib and dexamethasone alone.6 The ENDEAVOR trial showed that PFS in relapsed MM patients was significantly longer when carfilzomib was added to dexamethasone than for those receiving a combination of bortezomib and dexamethasone. A follow-up analysis of ENDEAVOR found that carfilzomib plus dexamethasone provided a significant and clinically meaningful increase in OS when compared with combination bortezomib/dexamethasone.5 The CASTOR and ENDEAVOR trials are among the largest datasets using proteasome inhibitors as part of the control group.

When considering pomalidomide-based approaches in patients experiencing second or third relapses, fewer data are available. A phase 2 study released in 2017 revealed that daratumumab plus pomalidomide and dexamethasone induced rapid, deep, and durable responses in heavily treated MM patients.8 At ASCO 2018, results of the phase 3 OPTIMISMM study on the combination of pomalidomide, bortezomib, and dexamethasone were released. This trial showed that RRMM patients receiving the triplet therapy combination had significantly improved PFS and an earlier, deeper, and more durable response than those receiving a two-drug regimen with bortezomib and dexamethasone.9

When managing MM patients who are progressing on lenalidomide maintenance therapy, it’s important to distill the available information and consider adding a monoclonal antibody during early relapses. The default approach has been to use pomalidomide or daratumumab as part of a three-drug regimen, but clinical trials are needed to establish the most appropriate approach to partnering a monoclonal antibody with two-drug regimens.

What safety issues should community oncologists keep in mind when using current and emerging therapies for relapsed MM?

The new drugs available to treat relapsed MM, including monoclonal antibodies and proteasome inhibitors, are associated with potential safety concerns. As such, it’s critical for community oncologists to determine the severity of these issues and whether they limit the utility of a particular drug.

The most common side effects of two monoclonal antibodies, elotuzumab and daratumumab, are infusion-related reactions. These typically occur with the first or second dose but become less of an issue thereafter. In most cases, infusion-related side effects can be easily mitigated. A study found that giving elotuzumab and daratumumab in 90-minute infusions is safe for patients beyond their second dose of therapy.10 It’s also important to monitor absolute neutrophil count (ANC) levels and be vigilant about infection risks. Monoclonal antibodies are associated with higher infection risks, but the cause of this increased risk is currently unknown. Decreases in ANC levels can be managed with dose modifications or adjustments, but ANC should still be monitored during the first cycle to minimize long-term infectious complications.

Proteasome inhibitors are also associated with safety concerns, but many of these issues are manageable. For example, ixazomib is commonly associated with gastrointestinal toxicity, nausea, vomiting, and diarrhea, but these side effects are typically dose-related. Adjusting the dosing and scheduling of ixazomib can reduce these toxicities over time. The PI carfilzomib has different properties than bortezomib and ixazomib. It’s associated with subjective shortness of breath, hypertension, and renal insufficiency that is typically self-limited and often resolves on its own. In 2-3% of cases, congestive heart failure occurs with carfilzomib. Depending on the underlying cause, congestive heart failure is reversible in most patients. However, it can be an issue for individuals with underlying cardiac dysfunction.

How can community oncologists overcome challenges with integrating evidence-based recommendations for treating and monitoring RRMM into their daily clinical practice?

With RRMM, there is no one-size-fits-all approach or simple treatment algorithm to follow, and evidence is lacking because many of the available drugs are so new. The National Comprehensive Cancer Network guidelines allow clinicians to choose therapies, but do not provide specific guidance on what to use when patients have already received some treatments.11 Two- and three-drug combinations are routinely used when managing relapsing MM. Community oncologists should partner with experts from myeloma centers and select regimens that they’re most comfortable using. Doing so will increase preparedness for identifying and managing potential adverse events and reactions.

Clinicians should develop their own algorithmic approach to treating RRMM that integrates strategies to optimize care and minimize long-term side effects. Ideally, the goal is to get the most mileage from the available treatments at our disposal by rationalizing drug exposure and developing risk-based approaches. There are several factors to consider, including previous treatments, side effects and resistance with other agents, genetic information, and plans for salvage therapy. Community oncologists should be prepared to determine strategies that optimize therapies for standard- and high-risk patients who may or may not have received lenalidomide maintenance therapy. By being prepared with this information, community oncologists can sort through the available treatment options and tailor therapy with an approach that they’re most comfortable using.

What key takeaways should community oncologists remember when MM patients have suffered a relapse after their initial treatment?

For patients with MM who suffer a relapse, we’re fortunate to have a wealth of new drugs and combination regimens that are either FDA approved or currently in clinical trials. Community oncologists should determine if participation in a clinical trial is an option because it enables patients to be treated in a safe environment with the added benefit of increasing our knowledge and understanding on how best to use newer drugs and/or regimens to treat RRMM.

As a practice, community oncologists should develop plans to establish approaches to a first relapse as well as second and third relapses. They should identify drugs and regimens they’re most comfortable using and be prepared with strategies to handle possible adverse events and reactions associated with these agents. Partnering with myeloma centers and experts can ensure that contingency plans are in place. In busy community oncology practices, clinicians may see 15 to 20 different types of cancers in a day. For these clinicians, it can be difficult to be prepared for such a wide variety of cases, but being armed with contact information for experts and consulting partners can help when managing more complicated patients.