A major source of op­ti­mism in the myeloma com­munity these days is the large num­ber of poten­tially very ef­fec­tive treat­ments under devel­op­ment for the dis­ease.

Increasing the num­ber of ef­fec­tive treat­ment op­tions for the dis­ease could lead to a sizable jump in sur­vival for both newly diag­nosed and re­lapsed mul­ti­ple myeloma patients.

There is, how­ever, a common theme among many of the promising inves­ti­ga­tional ther­a­pies for mul­ti­ple myeloma that could limit their ability to make as large an im­pact on myeloma sur­vival as many hope. The common theme can be summarized in four letters: BCMA.

BCMA, or B-cell maturation an­ti­gen, is a pro­tein found on the surface of myeloma cells. Many of the poten­tial new treat­ments for myeloma that have been in the news the past few years use BCMA to target myeloma cells.

The CAR T-cell ther­apy bb2121, the anti­body-drug con­ju­gate be­lan­ta­mab mafo­dotin (GSK2857916), and the bispecific anti­body AMG 420 all have shown promising ef­fi­cacy in early stage clin­i­cal trials for mul­ti­ple myeloma, and all use BCMA to target myeloma cells.

Indeed, among the many drugs in var­i­ous stages of devel­op­ment as poten­tial new treat­ments for mul­ti­ple myeloma, roughly half are BCMA-directed ther­a­pies.

This raises an im­por­tant set of ques­tions: Will patients be able to ben­e­fit from each and every one of these new BCMA-directed treat­ments, assuming many of them even­tu­ally are approved by regu­la­tory author­i­ties? Or will patients who relapse after being treated with one BCMA-directed ther­apy be unlikely to respond when treated with any of the other BCMA-based treat­ments?

Researchers have to con­sider ques­tions like these because myeloma patients de­vel­op re­sis­tance not just to in­di­vid­ual treat­ments, but to classes of ther­a­pies.

A patient who relapses after a long period of treat­ment with, for example, a pro­te­a­some in­hib­i­tor such as Velcade (bor­tez­o­mib) is not as likely to respond to treat­ment with another pro­te­a­some in­hib­i­tor, such as Ninlaro (ix­az­o­mib) or Kyprolis (car­filz­o­mib), com­pared to a re­lapsed patient with no prior exposure to a pro­te­a­some in­hib­i­tor.

Will there be a similar “class effect” with BCMA-directed ther­a­pies?

This is the ques­tion that re­searchers at the Uni­ver­sity of Pennsylvania in Philadelphia and Memorial Sloan Kettering Cancer Center in New York City sought to address when they re­viewed records from clin­i­cal trials at their in­sti­tu­tions, looking for patients who had re­ceived more than one BCMA-targeted ther­apy.

Their task was not an easy one because many trials for BCMA-directed ther­a­pies exclude patients who pre­vi­ously have been treated with a BCMA-directed ther­a­pies.

The re­searchers were able to find, how­ever, two patients who re­ceived treat­ment at dif­fer­en­t times with two dif­fer­en­t BCMA-targeted ther­a­pies and who responded to both treat­ments.

These two patient cases are initial evi­dence sug­gesting myeloma patients may be able to respond to more than one BCMA-targeted ther­apy. This is good news for myeloma patients and their physicians, as it in­creases the extent to which patients can ex­pec­t to ben­e­fit from the many BCMA-directed ther­a­pies under devel­op­ment.

Case Details – P-BCMA-101 After Be­lan­ta­mab Mafodotin

The most en­cour­ag­ing of the two cases discussed by the Penn and Sloan Kettering re­searchers is that of a 49-year-old male myeloma patient who had re­ceived 5 prior lines of myeloma ther­apy. The patient’s dis­ease had be­come re­sis­tant to Revlimid (lena­lido­mide), Dar­za­lex (dara­tu­mu­mab), Empliciti (elo­tuzu­mab), Pomalyst (poma­lido­mide), and Kyprolis.

In August of 2016, the patient had a 70 per­cent bone plasma cell per­cent­age and decided to start treat­ment with the BCMA-targeted anti­body-drug con­ju­gate be­lan­ta­mab mafo­dotin (GSK2857916) as part of a clin­i­cal trial.

Unfortunately, the drug did not halt the patient’s dis­ease pro­gres­sion, and he and his doctors decided to switch treat­ment in Octo­ber 2016 to Keytruda (pem­bro­lizu­mab), Revlimid, and dexa­meth­a­sone.

Treatment with this three-drug regi­men led to a minor – but durable – minimal re­sponse. Because the re­sponse was not very sig­nif­i­cant, how­ever, a de­ci­sion was made about a year and a half later to switch treat­ment to a sec­ond BCMA-targeted ther­apy, the CAR T-cell treat­ment P-BCMA-101, again as part of a clin­i­cal trial.

The in­fusion of P-BCMA-101 T-cells took place in April 2018 fol­low­ing con­di­tioning with cyclo­phos­pha­mide (Cytoxan) and flu­dar­abine (Fludara).

This sec­ond BCMA-targeted treat­ment led to a partial re­sponse that has persisted until the time the re­searchers’ recent article was pub­lished. The patient’s bone mar­row plasma cell per­cent­age dropped from 65 per­cent prior to in­fusion of the P-BCMA-101 CAR T-cell ther­apy to 15 per­cent 79 days there­after.

Case Details – Belan­ta­mab Mafodotin After MTV273 

The other case discussed by the re­searchers was that of a 59-year-old female myeloma patient who had re­ceived 10 prior lines of ther­apy, in­clud­ing Velcade, Revlimid, Kyprolis, Pomalyst, and Dar­za­lex. She started treat­ment in June 2016 with a BCMA-directed CAR T-cell ther­apy MTV273, which has been under devel­op­ment by the Uni­ver­sity of Pennsylvania and the pharma­ceu­tical com­pany Novartis.

The patient’s bone mar­row plasma cell per­cent­age was 90 per­cent prior to start­ing treat­ment with MTV273, and it dropped to 20 per­cent a month after the CAR T-cell in­fusion. However, the patient’s dis­ease began to progress again in the next couple of months, and a de­ci­sion was made to try an alter­na­tive ther­apy.

The next treat­ment the patient tried was be­lan­ta­mab mafo­dotin (GSK2857916), which reduced her bone mar­row plasma cell per­cent­age from 38 per­cent to 5 per­cent over the course of four months. The patient’s dis­ease did begin to progress again, how­ever, late in 2016, and a de­ci­sion was made in Jan­u­ary­ 2017 to switch to a dif­fer­en­t treat­ment.

The patient even­tu­ally went through sev­er­al addi­tional ther­a­pies, in­clud­ing a salvage au­tol­o­gous stem cell trans­plant, which did keep her dis­ease at bay for another year and a half. However, she did even­tu­ally pass away in Sep­tem­ber 2018.

Additional Perspectives

The Penn and Sloan-Kettering re­searchers note that it may not be a coincidence that, among the two cases they summarize, the patient who appeared to ben­e­fit more from sequential BCMA-targeted ther­a­pies was the one who had be­lan­ta­mab mafo­dotin (GSK2857916) first, then a Keytruda-based regi­men, and then the P-BCMA-101 CAR T-cell ther­apy.

More spe­cif­i­cally, it is be­lieved that myeloma cells dying as a re­­sult of treat­ment with be­lan­ta­mab mafo­dotin may trigger an addi­tional anti-myeloma re­sponse by the im­mune sys­tem. This im­mune sys­tem re­sponse could have been heighted by sub­se­quent treat­ment with a Keytruda-based regi­men, because Keytruda also uses the im­mune sys­tem to fight mul­ti­ple myeloma.

In addi­tion, the tendency for Keytruda to re­main in a patient’s body for a long time (it’s “long half life”, in tech­ni­cal jargon) may have augmented the im­pact of the P-BCMA-101 CAR T-cell ther­apy the patient re­ceived after stopping treat­ment with the Keytruda, Revlimid, and dexa­meth­a­sone regi­men.

The authors of the new study also note that ex­peri­ence with other blood can­cers sug­gests retreatment of myeloma with dif­fer­en­t BCMA-targeted ther­a­pies could be pos­si­ble. In par­tic­u­lar, people with acute lympho­blastic leukemia who relapse after treat­ment with a bispecific anti­body targeting the cell surface pro­tein CD19 can respond to CAR T-cell ther­a­pies that also target CD19.

For more in­for­ma­tion, please see the article by Cohen, AD, et al., “Serial treat­ment of re­lapsed / re­frac­tory mul­ti­ple myeloma with dif­fer­en­t BCMA-targeting ther­a­pies,” in Blood Advances, August 27, 2019 (full text).