Navigating the Labyrinth of Multiple Myeloma Treatment

04/24/18
Thomas Marsland, MD

I often today find myself telling patients with multiple myeloma I have good news and bad news. The good news is I have 1000 ways to treat you; the bad news is also that I have 1000 ways to treat you. Do we use "A" before "B" or "B" before "C," or "A" and "B" together? This is true for many cancers: breast cancer, lymphoma, prostate cancer, and even lung cancer, but it is especially true in multiple myeloma. The explosion of new therapies has taken average survival from a few years to close to 10 years or more.

So with the multitude of choices, there are many accompanying problems. What are the options for initial therapy? How are patients chosen? Who gets transplantation or who needs maintenance? How does one decide on salvage therapy?

All patients with a good performance status and good organ function should be evaluated for stem cell transplantation. There is now strong data to suggest that when transplant is possible, it should be done. Progression-free survival and even overall survival is improved after transplantation. But once transplant is planned, the question remains what induction therapy should be considered? Multiple studies have shown that triple drug therapy is better than doublet in this scenario.

To digress for a moment, there are basically three classes of drugs with a number of other agents that do not fit into any of the three categories. The three categories include immune modulator drugs (IMiDs), proteosome inhibitor (PI), and steroids. Assorted other agents include traditional cytotoxins, especially alkylating agents; anti-neoplastic antibodies; histone deacetylase (HDAC); and venetoclax. Risk factors that one looks at include organ function, protein levels, mutational status, and cytopenias.

As mentioned, triple drug induction therapies tend to be superior to doublet. These normally include IMiDs, PIs, and steroids. These induction treatments are normally older drug combinations and do not include many of the newer agents. Lenalidomide, bortezomib, and dexamethasone (RVD) and bortezomib, cyclophosphamide, and dexamethasone (CyBorD) are the two most common and both are preferred, category I National Comprehensive Cancer Network recommendations. There are no head-to-head comparisons, but in transplant candidates, CyBorD may have less effect on bone marrow and stem cells.

In the non-transplant population, data show superior outcomes with triplet vs doublet treatment. Classically, these include IMiDs, PIs, and steroids. The data are most mature for the older first-generation IMiDs and PIs, like lenalidomide and bortezomib. Second-generation PI’s—such as carfilzomib and Second generation IMiDs like pomalidomide—are working their way into earlier treatment, but again there are no data showing superiority over the earlier triplet. The older combination is more useful are used more due to familiarity and ease of administration. The newer oral PI ixazomib may potentially change that.

Today, maintenance therapy is the standard of care for most patients with multiple myeloma. The options with the most data include lenalidomide and bortezomib in the higher-risk patients. Maintenance therapy has at least somewhat complicated how to treat the relapsed, recurring patient. One question to consider is how long has it been since the primary treatment? Are these patients truly refractory, or can they be successfully retreated with the same combination? Patients with recurring disease greater than 6 months or more after primary treatment can often be retreated successfully with the same combination, whereas patients recurring in less than 6 months often need alternative programs.

Second- and third-generation IMiDs and PIs have shown high response rates with durable responses. Monoclonal antibodies often produce excellent results in this setting. With so many drugs available the number of three drug combinations can be challenging. Further complicating these clinical decisions if the fact that many of these combinations mix new drugs with older agents to which many of the patients have already been exposed and often progressed.  Trials clearly show effectiveness, yet it is puzzling why patients respond when combinations include already failed compounds. There are few studies comparing these triplets against each other—most of which have been approved in studies compared with doublets—so it is difficult to determine whether one triplet is clearly superior to another.

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Toxicities and ease of administration also play a role in treatment choice. Third and even fourth lines of treatment are possible and effective due to all the drug options available. How to sequence these is one of the most difficult questions we face. Clinical trials with current and newer agents are critical to try and answer many of these questions.

Guidelines are helpful in these settings; they provide evidence-based options, but they still leave many decisions to be made by the clinicians and patients. Pathways can be helpful.  Pathways need to be evidence-based, balancing efficacy, toxicity, and the best treatments. The American Society of Clinical Oncology recently published standards by which pathways should be developed and judged.

In conclusion, there is good news accompanying many new effective therapies that have enhanced survival, along with bad news accompanying ongoing questions as to how to best utilize the therapies for optimal outcomes.