Frontline treatment of multiple myeloma

Abstract

The treatment of myeloma has been revolutionized by the availability of new drugs. Combination therapy followed by stem cell transplant holds the promise of ultimately curing a fraction of patients. Objective responses are the norm for induction therapy and up to 50% of patients achieve a complete remission. Ongoing clinical trials continue to address the role of long term maintenance therapy. Understanding the proper management of these agents is paramount to providing patients disease control and yet minimizing side effects from treatment.

Keywords:

• Lenalidomide
• Bortezomib
• Transplant
• Myeloma
• Induction

Introduction

The treatment of multiple myeloma (MM) has been revolutionized over the past 10 years by the introduction of more effective treatment regimens that are able to produce disease response in larger proportions of patients, and these responses are of increasing quality (i.e. deeper and more durable). The combination of optimal induction regimens, with proper application of stem cell transplant (SCT) in suitable candidates holds the promise of curing patients with this disease. In fact, a small fraction of patients can now enjoy durable complete remissions that often extend well beyond 10 years, a clear sign of permanent disease control. Despite this enthusiasm, various challenges remain. First, for most patients, cure is not possible and the optimal sequence of treatments is not yet defined. Second, most patients are not currently considered candidates for SCT and in the absence of that treatment modality cure is not considered feasible. Third, the road to optimal treatment is still fraught with significant risks for side effects of the medications and disease complications that can have a very serious effect on the quality of life for patients. Fourth, these advances have been particularly impressive for patients without markers of high-risk disease. For patients with high-risk MM, we cannot say that they have a ‘chronic disease.’ And last, the availability of these treatments for medical and economic reasons remains beyond the reach of a large portion of the world population. Despite these limitations, the future for MM treatment remains bright with an increasing likelihood of making cure a reality for more patients.

Lenalidomide-based Regimens

The use of thalidomide and lenalidomide became commonplace in MM treatment after they were shown in the late 1990s to possess antitumor activity.1 After corticosteroids and alkylators these groups of drugs, collectively called immunomodulatory drugs (IMIDs), were the first new class of drugs to be effective against MM. IMIDs have been used in various clinical trials, mostly in combination with dexamethasone as induction regimens for the disease. Two notable studies include E1A002 (which demonstrated the superiority of the combination of thalidomide and dexamethasone versus dexamethasone alone as induction therapy) and E4A03, which showed a high degree of activity of the combination of lenalidomide and dexamethasone as frontline therapy for the disease.3

Worldwide the use of thalidomide and dexamethasone has become one of the main options for the treatment of MM. In the USA and in our institution, we have migrated to the use of lenalidomide due to the more favorable toxicity profile [2% grade 3 or 4 peripheral neuropathy (PN)], and higher efficacy. While this drug is not currently approved as frontline therapy for the disease, it is a very convenient option with current results similar to that of other induction regimens. One of the lessons learned in developing IMIDs as treatments for MM was that lower doses of dexamethasone could result in similar level of disease control, but with less toxicity and greater compliance with the prescribed treatments. This better adherence is thought to explain the better overall survival reported in E4A03-treated patients with lower doses of dexamethasone, despite a lower rate of overall response.3 The high activity of IMIDs has been proposed by some to use lenalidomide-based regimens as sole and primary therapy for the disease.

Lenalidomide-based induction regimens are overall well tolerated. Most patients will respond (>85%). One caution is that the use of these agents carries a risk of deep venous thrombosis. All patients receiving an IMID and dexamethasone should receive thromboprophylaxis according to the international proposed consensus guidelines. Other notable toxicities can include myelosuppression, fatigue, and rash.

Proteasome Inhibitor-based Regimens

The advent of bortezomib in the early 2000s added a completely new class of drugs for the treatment of MM.4 Bortezomib is the prototype proteasome inhibitor that as a single agent has activity against the disease of about 40%. When combined with dexamethasone this activity is increased to nearly 90%, and when used in triple combination, the rate of complete responses (CRs) can be as high as 50%.5 Bortezomib in combination with dexamethasone (VD) then has become one of the standard treatment options for newly diagnosed MM patients. The drug has FDA approval in the USA and other countries to be used as first line of treatment. Bortezomib has the advantage of creating rapid and profound responses, and can be safely used even in the setting of renal insufficiency.

Proteasome inhibitors are well tolerated but carry some specific toxicity. The most important one is development of PN. This PN can be seen in up to 40% of patients, but in up to 10% of patients, it can be disabling, painful, or otherwise incapacitating. Susceptibility to bortezomib-induced PN is thought to be genetic, but no accurate predictive markers exist yet. Recent studies show that bortezomib administered on a weekly basis (as opposed to the classic days 1, 4, 8, and 11 schedule) can result in similar rates of response with much lower rates of PN and discontinuation of treatment due to this side effect.6 Another study showed that subcutaneous administration of bortezomib reduces the rate of PN, even among patients treated with the traditional schedule of administration. With these developments in our clinical practice, we now routinely use bortezomib on a weekly basis, sometimes subcutaneously, and almost always in combination with dexamethasone and another agent such as cyclophosphamide. Other toxicities include Herpes zoster for which all patients are placed on acyclovir prophylaxis, gastrointestinal disturbances, and thrombocytopenia.

There are other proteasome inhibitors being developed in various pre-clinical and clinical stages. Some of these proteasomes hold the promise of a lower rate of PN due to diminished off-target effects. Other variations include orally administered proteasome inhibitors. One such drug, carfilzomib, is far advanced in clinical development and has been used in combination with dexamethasone and other drugs as well. One study looking at the medication in the frontline setting in combination with lenalidomide has shown an unprecedented rate of CR of ∼60%.

Goals of Therapy and Role of SCT

A debate remains as to whether the goal of MM should be cure versus chronic disease control. The authors’ opinion is that for most patients who are suitable SCT candidates, cure should be sought, or at least offered to patients as part of the goal of a given treatment strategy. To improve on the activity of bortezomib, various investigators have used other drugs in combination with VD. Notable among these are those that use cyclophosphamide or lenalidomide.6,7 These three drug combinations can achieve a rate of CR in the vicinity of 50%. Several recent studies, some published in abstract form only, show that the quality of responses before transplant is maintained in the post-transplant period. Groups of patients with higher rates of CR have higher rates of CR in the post-transplant period and hence achieving this level of response in the transplant candidate seems a good goal. This seems a reasonable option at the time of treatment initiation. It is less clear whether someone who achieves ‘only’ a partial response or a very good partial response should be treated with an alternative regimen in search for a deeper response. It may be all related to underlying biology.

SCT remains one of the mainstays of treatment for MM. The hope remains that the level of disease control that is attained with induction therapy is enhanced with timely application of SCT. MM has been classically considered incurable and only a minority of patients is believed to enjoy durable and permanent control of their disease with SCT. However, one recent study from Spain has shown that the level of response in the post-SCT setting has a major predictive value regarding the likelihood of patients remaining with durable remissions.8 In this particular study, about 10% of patients remained without detectable disease after more than a decade, a clear sign of disease cure. An additional 10% of patients remained with measurable disease but without need for further treatment. That 10% in durable CRs was approximately one-third of all patients achieving such deep responses. It follows that for durable disease control, CR is a laudable goal. These data are with precedent, although not all previous clinical studies have shown such correlation.

Non-stem Cell Transplant Candidates

The reality remains that most patients, by virtue of their age and co-morbid conditions, are still not considered candidates for SCT. Whether the data regarding recent developments with SCT will sway more patients into this treatment modality remains unclear. Despite this, however, it is likely that most patients will still not go through the process of high-dose chemotherapy. Several treatment options exist and include melphalan and prednisone (MP)-based regimens (such as MP in combination with bortezomib,9 MP in combination with thalidomide,10 and MP in combination with lenalidomide). The largest studies so far have compared the first two combinations and shown overall survival as compared to MP alone. The last combination is still being studied. Thus most patients can be treated with the combination with bortezomib (MPV) or thalidomide (MPT). The choice for one versus the other remains largely medical (e.g. presence of renal failure, risk for PN, etc.) and logistical (ability to travel to the treatment center, etc.). This author does not recommend the use of MP and lenalidomide, and its use should be deferred until further information becomes available from the various clinical trials. The reason for such caution is that myelosuppression produced by this combination is high. We recommend instead the use of lenalidomide and low-dose dexamethasone as an option for elderly patients avoiding the use of melphalan and the potential leukemogenic late effects.

Role of Maintenance and Disease Evaluation

Because of the availability of active drugs and the high rates of responses, post-transplant maintenance has been proposed as an adjunct to prolong and enhance responses. Several clinical trials addressed the role of corticosteroids (i.e. prednisone), interferon, and thalidomide as maintenance after SCT. Most recent studies concentrated on the use of thalidomide. Most if not all studies showed an improvement in progression-free survival. Some studies did show an improvement in overall survival, with some of the negative ones potentially being underpowered with a high risk of type 2 error. Despite these overall positive results, the use of thalidomide did not become mainstream, certainly not among MM specialists, due to the high toxicity of thalidomide used long-term and causing irreversible sensory PN. The availability of lenalidomide rekindled the interest in IMID-based maintenance and two clinical studies have been completed with a randomization to placebo. In both cases, the trials were stopped prematurely due to the fact they reached significance for the analysis of the primary endpoint, progression-free survival. With additional follow-up, the CALGB trial is now showing an improved overall survival. While the other study is likely to show similar results, the MM community still debates the net gains in disease control and overall survival provided by maintenance with lenalidomide. This author believes that most patients will ultimately be placed in an intensification or maintenance strategy (see below). Other maintenance strategies using bortezomib are also being studied, but not mature yet for reporting.

Given the higher rate of disease response and CRs after SCT, better tools will be needed to better gauge the effectiveness of induction and consolidation (i.e. SCT). More and more patients present now for the ‘day 100’ evaluation without evidence of MM in the bone marrow examination and without measurable disease markers in the peripheral blood such as a negative immunofixation text and normal serum-free light chain assays (so-called stringent CR). We know that many of these patients are at risk of relapse due to low burden disease that is below the threshold for clinical detection. It seems logical that better, more sensitive methods of detecting minimal residual disease are necessary. These methods have included use of multicolor flow cytometry bone marrow analysis and molecular methods detecting immunoglobulin gene rearrangements. Other methods could also be developed such as more sensitive detection of even lower serum concentrations of the monoclonal protein markers. It stands to reason that clinical decisions could be guided by this knowledge, avoiding any further treatment in patients in ‘very stringent sCR’ versus consideration of additional therapy for those with measurable residual disease. A skeptic could throw a word of caution and request clinical trial evidence of such an approach. I would counter that it is likely that the results of ongoing maintenance trials may ultimately dictate all patients be placed in maintenance and that the aforementioned approach is more rational.

I believe in time those with ‘very stringent sCR’ will not need maintenance, those with residual disease but low-risk lenalidomide maintenance may be in order, and for those with high-risk disease, regardless, maintenance with a combination that incorporates a proteasome inhibitor will be used.

Conclusion

The treatment of MM continues to improve. As we move forward in our clinical trials, regimens and strategies that improve the rate of ‘very stringent sCR’ need to be developed. These will likely include an optimal induction regimen, consolidation with SCT, and intensification/maintenance post-SCT. These strategies will need to be guided by proper risk stratification of patients. Because of the longer life expectancy and the possibility of disease cures, the road to optimal treatment needs to be extremely mindful of treatment-associated toxicities. There is as of yet a paucity of data regarding the effects of treatments and their effect on the disease and the quality of life of patients. Prolonging life at the detriment of quality does not seem appropriate. However, we currently have unprecedented ability to maintain disease control and offer patients life expectancies hereto unknown.