A Practical Guide to Relapsed/Refractory Multiple Myeloma

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Managing Multiple Myeloma in First Relapse and Beyond

Multiple myeloma (MM) is a plasma cell malignancy that is characterized by the presence of a monoclonal plasma cell population in the bone marrow producing a monoclonal immunoglobulin, along with evidence of end organ damage that usually includes renal failure, anemia, bone lesions, and immune dysfunction. The outcomes and management of MM in the US have changed dramatically over the last 15 years, during which time the survival of an average MM patient has tripled.1 The majority of MM patients do relapse,2,3 requiring subsequent lines of therapy to manage their disease like a chronic condition. We recognize that MM is not one disease, that the MGUS (monoclonal gammopathy of undetermined significance) to MM transition may be more indolent for some patients, while it may be very rapid for others. Recognizing the heterogeneity in the biology and clinical presentation of newly diagnosed MM patients,4 current clinical investigations are attempting to move away from a “one-size fits all” method for both risk- and response-adaptive strategies.

Management becomes more challenging for relapsed/refractory MM (RRMM) patients where the clinician is choosing therapy based on disease biology (cytogenetics, depth, duration of response to previous therapy, etc.), disease burden (presence/absence of renal failure, bone fractures, pattern of plasma cell leukemia at relapse, presence of extra-medullary disease, etc.), host factors (age, comorbidities, performance status, etc.), access to clinical trials and financial limitations (cost of therapy, insurance, etc.). As of now, there are 10 drugs that have been FDA-approved for use in MM: thalidomide, lenalidomide, bortezomib, liposomal doxorubicin hydrochloride, carfilzomib, pomalidomide, panobinostat, daratumumab, elotuzumab, ixazomib; the last four approvals occurred in 2015 alone. There are, however, several new novel drug classes and immunotherapy approaches making their way through clinical development, and, as such, it is still important to refer RRMM patients to appropriate clinical trials (Figure 1). The present review will highlight some of the novel drug combinations in clinical trials with recently approved agents, and will address how best to incorporate them into clinical practice. Specifically, data from the recent phase III trials in patients with RRMM and 1-3 prior lines of therapy will be discussed in the context of the practical management of these patients.

Lenalidomide-based Combinations for First Relapse
Lenalidomide (Len)-based combinations may be considered for patients in their first relapse, if they have:

  • Clinical or biochemical relapse: Received Len-based induction regimen at the time of diagnosis with good tolerance and progression-free survival (PFS) of at least 12-18 months.
  • Clinical or biochemical relapse: Received bortezomib-based induction regimen at the time of diagnosis with poor tolerance and PFS of less than 12 months.
  • Biochemical relapse: Received Len-based induction regimen at the time of diagnosis, followed by low-dose Len maintenance with good tolerance and PFS of at least 24 months.

There are four large randomized trials (Table 1) that are investigating potential treatment options for patients eligible for Len-based combinations.5-8

  • The ASPIRE5 trial data showed better overall response rates (ORR) and median PFS in favor of carfilzomib-lenalidomide-dexamethasone (KRd) compared with lenalidomide-dexamethasone (Rd) in first relapse patients, perhaps demonstrating the most robust proteasome inhibitor (PI)/immunomodulatory agent (IMiD) combination activity in this setting.
  • The ELOQUENT-26 trial compared Rd with Rd plus elotuzumab (EloRd), showing statistically significant ORR and median PFS benefit. EloRd demonstrated an excellent safety profile, with an apparent duration of response similar in high-risk and standard-risk patients.
  • The TOURMALINE-MM17 trial compared ixazomib-lenalidomide-dexamethasone (IxaRd) to Rd validating the superiority of an all-oral PI/IMiD combination based on ORR and median PFS.
  • The POLLUX8 trial is the most recent data in this setting, and was presented at the European Hematology Association 2016 Annual Meeting, where daratumumab-Rd (DRd) was compared with Rd. This study showed perhaps the best depth of response, durability of response, and median PFS benefit.

It is extremely important to appreciate that the patient populations in the four studies were different (prior therapies received, cytogenetics/risk categories). The ELOQUENT-2, ASPIRE, and POLLUX trials primarily had patients with bortezomib exposed/refractory patients, and lenalidomide refractory patients were excluded from all studies. The ELOQUENT-2 trial appeared to have a higher proportion of high-risk cytogenetics compared with the other two trials. The first three studies (ELOQUENT-2, ASPIRE, TOURNMALINE-MM1) led to drug approvals for their respective drug combinations, whereas POLLUX may lead to a label change for daratumumab later this year. Table 1 summarizes practical considerations for optimal use of these four regimens.

Bortezomib-based Combinations for First Relapse
Bortezomib (Bor)-based combinations may be considered for patients in their first relapse if they have:

  • Clinical or biochemical relapse: Received Bor-based induction regimen at the time of diagnosis with good tolerance and PFS of at least 12-18 months, especially for translocation (4;14) patients.
  • Clinical or biochemical relapse: Received Len-based induction regimen at the time of diagnosis with poor tolerance and PFS of less than 12 months.
  • Biochemical relapse: Received Bor-based induction regimen at the time of diagnosis, followed by low-dose Bor maintenance with good tolerance and PFS of at least 24 months, especially for translocation (4;14) patients.

For patients who are Bor-based regimen-eligible, there are two relevant phase III studies (Table 2), PANORAMA-19 and CASTOR.10 In PANORAMA-1, panobinostat-bortezomib-dexamethasone (Pano-Vd) was compared to bortezomib-dexamethasone (Vd), administered intravenously twice weekly on a 21-day schedule. Although achieving its primary endpoint and proof-of-principle for a PI-HDAC inhibitor-based platform, the experimental arm was critiqued for its high incidence of side effects, including fatigue and GI toxicities. It was thought that perhaps the use of intravenous Bor and a more intensive Pano schedule attributed to the safety issues. The Pano-Vd benefit, however, was even observed in the double-refractory (PI/IMiD) patients. The CASTOR study, presented at the ASCO 2016 plenary session, compared daratumumab-Vd (Dara-Vd) with Vd, administered subcutaneously twice weekly on a 21-day schedule. The study demonstrated that Dara appears to work in combination with both a PI and an IMiD in the early relapse setting. The time-to-response was fairly short and all subgroups appeared to benefit. Long-term Dara administration was not associated with any new safety signals. Although there was concern that both arms only had Vd for 8 cycles and only the Dara-Vd arm had a maintenance strategy, about half of the patients on each arm developed peripheral neuropathy during induction. Table 2 summarizes practical considerations for the optimal use of these two regimens.

Carfilzomib-based Combinations for First Relapse
Carfilzomib (K)-based combination may be considered for patients in their first relapse if they have:

  • Clinical relapse: Received combined Bor/Len-based induction regimen at the time of diagnosis and PFS of ≤12 months.
  • Clinical or biochemical relapse: Received Bor-based induction regimen at the time of diagnosis with poor tolerance (significant peripheral neuropathy or GI toxicity) but PFS of >12 months, especially for translocation (4;14) patients.

The ENDEAVOR11 trial compared carfilzomib-dexamethasone (Kd) with Vd and demonstrated a superior overall response rate (76.9% vs 62.6%; P<.0001) along with near doubling of median PFS in the former (18.7 mo vs 9.4 mo; hazard ratio = 0.53; P<.0001). The ENDEAVOR trial had patients with prior lenalidomide exposure or refractoriness but no bortezomib-refractory patients. Table 2 summarizes practical considerations for optimizing the use of this regimen compared to a Bor-based regimen.

Future Directions
The management of early relapse MM is becoming increasingly complex with the investigation of new drug classes and combinations. There are several pomalidomide-based (Pom) regimens (Table 3) in development. For patients who are relapsing on Len-based combination therapy, replacement of Len with Pom to recapture response may be an emerging strategy, but data is currently lacking. The other potential strategy in development is using genomic mutation-targeted compounds in combination with available regimens. It may not be feasible (time, resources, etc.) to conduct the necessary clinical trials to identify which regimens are most suitable for particular subgroups of RRMM patients, but gaining insights from subgroup analyses may help guide clinicians in the treatment of patients with RRMM.