Each year at the Annual Meeting of the American Society of He­ma­tol­ogy we hear about dozens of new drugs that are able to annihilate mul­ti­ple myeloma cells in the test tube and in animal models. Unfortunately, at the same meeting, we also sit through pre­sen­ta­tions and walk by posters of drugs that looked hot in the laboratory but then fail to work when given to real patients with myeloma.

This is not new. It has been the story with myeloma for ages. The myeloma cells are smart and are seemingly able to easily over­come any adversity that comes their way in the form of pesky new drugs. For those of us dealing with this dis­ease on a daily basis, we need some good news.

What are the most promising drugs to­day that can outsmart the myeloma cells? Will they work in patients who have failed other ther­a­pies? Will they have a reason­able safety profile?  Will a future filled with many active treat­ments and op­tions hap­pen soon enough?

If I were a patient with myeloma and none of the cur­rent treat­ments were work­ing for me, I would need to have at least some idea which drugs are the most promising, so that I could hunt for the best clin­i­cal trial. However, an Internet search turns up so many possibilities that it is hard for even trained hematologists to de­ter­mine the best op­tions among the array of clin­i­cal trials.

In this column, I will highlight drugs that are unquestionably active in myeloma. These are new treat­ments that are not com­mer­cially avail­able, but in my opinion clearly work in myeloma, even in patients who have failed other treat­ments. I will also discuss other promising drugs where the data sug­gest that there is at least a reason­able probability that they actually work in patients.

Note that by highlighting these drugs, my intention is not to sug­gest that the other agents being studied are unimportant. In fact, deciding the best treat­ment op­tion or a clin­i­cal trial for a given patient is a complex process that re­quires a great deal of thought and de­pends on many variables.

My goal is to simply in­form, and to illustrate the rationale for my hope and enthusiasm.

In the first category are com­­pounds that have shown clearcut ac­­tiv­ity in myeloma in terms of reducing mono­clonal (M)-protein levels by 50 per­cent or more when used on their own (single-agent ac­­tiv­ity). Of countless drugs that have been looked at and not yet approved for com­mer­cial use, only poma­lido­mide and car­filz­o­mib have shown sig­nif­i­cant single-agent ac­­tiv­ity in mul­ti­ple clin­i­cal trials. They seem to work in situations where other myeloma treat­ments have stopped work­ing. They are both in ad­vanced stages of devel­op­ment (i.e., Phase 3 trials are underway).

Pomalidomide: Pomalidomide ^[1] (also called CC-4047) is a new immuno­modu­la­tory analogue of thalidomide ^[2] (Thalomid) and Revlimid ^[3] (lena­lido­mide). It was first studied by Schey and colleagues from the United Kingdom who treated 24 re­lapsed or re­frac­tory patients and found a re­sponse rate of 54 per­cent. Next, Lacy and colleagues at the Mayo Clinic tested the com­bi­na­tion of poma­lido­mide with low dose dexamethasone ^[4] (Decadron) and showed ef­fi­cacy in re­lapsed dis­ease, in patients who had failed Revlimid and in patients who had failed both Revlimid and Velcade ^[5] (bor­tez­o­mib). These re­­sults have since been con­firmed by the Multiple Myeloma Re­search Consortium (MMRC) and by in­ves­ti­ga­tors from the Intergroupe Francophone du Myeloma (IFM). Side effects seem reason­able and similar to Revlimid. Clinical trials are on­go­ing around the world. I hope that poma­lido­mide is approved soon.

Carfilzomib: Carfilzomib ^[6] is a new pro­te­a­some in­hib­i­tor. It has a dif­fer­en­t chemical structure than Velcade, the prototype pro­te­a­some in­hib­i­tor. In a series of clin­i­cal trials con­ducted by the MMRC, car­filz­o­mib pro­duced re­sponses in approx­i­mately 50 per­cent of patients with re­lapsed myeloma, in­clud­ing 15 per­cent who were re­frac­tory to Velcade. Carfilzomib is given in­tra­venously. It appears to be well tol­er­ated and has a lower risk of neu­rop­athy (pain or tingling in the extremities) com­pared with Velcade. As with poma­lido­mide, con­firmatory stud­ies are on­go­ing around the world, and I am hopeful that the drug will be approved soon.

In the second category are agents that have not shown clear single-agent ac­­tiv­ity in myeloma, but are promising nevertheless based on re­sponses seen when they were com­bined with other drugs.

The histone deacetylase in­hib­i­tors, Zolinza ^[7] (vorinostat) and panobinostat ^[8] (Farydak ^[9]), have both shown ac­­tiv­ity when com­bined with Velcade. With these drugs, we have reports of patients with myeloma that was pro­gress­ing while re­ceiv­ing Velcade ther­apy that responded promptly upon the addi­tion or either Zolinza or panobinostat. Clinical trials with these agents also sug­gest that the re­sponse rate when used in com­bi­na­tion with Velcade is more than what we would ordinarily ex­pect to see with Velcade alone. Large trials are on­go­ing with these treat­ments, and we eagerly await the re­­sults of these trials to de­ter­mine the role and fate of these two drugs.

Another treat­ment in this category is the anti CS-1 anti­body, elotuzumab ^[10]. The re­sponse rate with elotuzumab plus Revlimid and dexa­meth­a­sone (Rd) appears to be much higher than what would be ex­pected with Rd alone.

Other po­ten­tial drugs that could join this category are heat shock pro­tein in­hib­i­tors (e.g., KW-2478) and phosphoinositide 3-kinase path­way in­hib­i­tors (e.g., perifosine ^[11]).

There is one other drug that does not fit well into either category listed above, but nevertheless is just as promising: MLN9708, an oral pro­te­a­some in­hib­i­tor. My enthusiasm for this agent stems from the fact that it is avail­able on clin­i­cal trials and that it belongs to a drug class that has already pro­duced two active agents, namely Velcade and car­filz­o­mib.

I raised some questions in the beginning. I think I answered the first three. The fourth (also stated in the title) was not meant to be rhetorical. I know for a fact that the many myeloma in­ves­ti­ga­tors work­ing on these trials under­stand the urgency of the situation. The com­pa­nies that make these com­­pounds recog­nize the need for speed and have been incredibly sup­port­ive. The myeloma field has shown the on­col­ogy world a path to drug devel­op­ment with 4 new drug ap­prov­als in the last 10 years. I am quite hopeful that for most myeloma patients, the future will indeed hap­pen soon enough.

Dr. S. Vincent Rajkumar is a pro­fessor of med­i­cine at the Mayo Clinic in Rochester, Minnesota. His re­search focuses on clin­i­cal, epidemiological, and laboratory re­search for myeloma and re­lated disorders.