In particular, the re­searchers found that the older a patient is at diag­nosis, the more their sur­vival is affected by their general health and by how ad­vanced their multiple myeloma is at diag­nosis.

In contrast, the impact of high-risk chromosomal ab­nor­mal­i­ties on sur­vival de­creases with patient age.

The study findings are based on an analysis of data for almost 4,000 newly diag­nosed multiple myeloma patients who par­tic­i­pated in the Myeloma XI ran­dom­ized clin­i­cal trial in the United Kingdom, which began in 2010.

The study authors believe their findings are im­por­tant for the treat­ment of multiple myeloma because they sug­gest dif­fer­en­t treat­ment ap­proaches may need to be con­sidered for dif­fer­en­t age groups. For younger patients, the re­searchers sug­gest focusing on whether or not the patient has high-risk chromosomal ab­nor­mal­i­ties, while for older patients, they rec­om­mend focusing on the patient’s general health, treat­ment type, and treat­ment intensity.

Background

Substantial progress has been made in the past decade in the treat­ment of multiple myeloma. Patients are experiencing longer times in remission after starting treat­ment and longer over­all sur­vival.

There con­tinues to be, how­ever, a group of patients with high-risk dis­ease that has rel­a­tive­ly poor out­comes com­pared to the rest of multiple myeloma patients.

In addi­tion, time in remission and over­all sur­vival con­tinue to be strongly tied to a patient’s age at diag­nosis. Older myeloma patients generally spend less time in remission after the start of their initial treat­ment, and their over­all sur­vival is not as long as ex­peri­enced by younger myeloma patients.

Factors that con­trib­ute to poor treat­ment out­comes in multiple myeloma are both patient-related, such as a patient’s over­all health, and dis­ease-related, such as whether or not a patient’s dis­ease in­volve­s high-risk chromosomal ab­nor­mal­i­ties.

According to the British re­searchers, a lot of re­search has been conducted to assess the effect of chromosomal ab­nor­mal­i­ties on sur­vival, and it is well estab­lish­ed that age has a sizable impact on sur­vival out­comes (see, for example, Figure 2 in this Beacon article about sur­vival in U.S. myeloma patients.)

What has not been clear, how­ever, is whether the importance of patient and dis­ease char­ac­ter­istics varies with patient age. The British re­searchers there­fore sought to de­ter­mine how dif­fer­en­t factors affect sur­vival in multiple myeloma of dif­fer­en­t ages who re­ceived the same treat­ment.

Study Design

The analysis the British re­searchers conducted was based on data from the Myeloma XI trial, a large, multi-center Phase 3 trial conducted in the UK. The trial in­cluded 3,894 newly diag­nosed multiple myeloma patients who were recruited from academic and district general hos­pi­tals around the UK be­tween 2010 and 2016.

The median patient age was 68 years old.

Patients re­ceived initial treat­ment with either cyclo­phos­pha­mide (Cytoxan), Revlimid (lena­lido­mide), and dexa­meth­a­sone (CRD), or cyclo­phos­pha­mide, thalido­mide, and dexa­meth­a­sone (CTD). Patients who achieved less than a very good partial re­sponse­ were ran­dom­ized to re­ceive either cyclo­phos­pha­mide, Velcade (bor­tez­o­mib), and dexa­meth­a­sone, or no further initial ther­apy.

Transplant eli­gible patients underwent stem cell trans­plan­ta­tion with mel­phalan.

After initial treat­ment and, when relevant, stem cell trans­plan­ta­tion, patients were ran­domly assigned to re­ceive Revlimid main­te­nance ther­apy or observation.

For their analysis, the re­searchers categorized patients into four dif­fer­en­t age groups: 60 years old and younger; 61 to 70 years old; 71 to 80 years old; and older than 80 years.

Similarly, they categorized patients’ myeloma into standard risk, high risk, and ultra-high risk based on the presence of chromosomal ab­nor­mal­i­ties t(4;16), t(14;16), t(14;20), del(17p) and gain(1q). The absence of these chromosomal ab­nor­mal­i­ties was defined as standard risk, the presence of one as high risk, and the presence of more than one as ultra high risk.

For their analysis, the re­searchers also con­sidered the patients’ over­all health, which they measured using data about each patient’s “performance status,” a variable that reflects a patient's ability to per­form cer­tain activ­i­ties of daily living without the help of others.

The measure of per­for­mance status used in the Myeloma XI trial is from the World Health Organi­za­tion (WHO). In the WHO per­for­mance status scale, a score of 0 in­di­cates a patient is fully able to carry out daily activ­i­ties on their own, while a score of 4 in­di­cates a patient is unable to carry out any activ­i­ties on their own.

The re­searchers used pro­gres­sion-free sur­vival to measure each patient’s time in remission after the start of treat­ment, and each patient’s Inter­na­tional Staging System (ISS) dis­ease stage was used as a measure of how ad­vanced a patient’s dis­ease was at diag­nosis.

(For results such as those from the Myeloma XI trial, pro­gres­sion-free sur­vival usually is defined as the time from trial enrollment until a patient ex­peri­ences either dis­ease pro­gres­sion or death prior to dis­ease pro­gres­sion. For a trial enrolling newly diag­nosed myeloma patients, this means median pro­gres­sion-free sur­vival is very close to median time to pro­gres­sion, or median time in remission, because only a small minority of newly diag­nosed myeloma patients die prior to dis­ease pro­gres­sion. Overall sur­vival for a study such as this one typically is defined as the time from trial enrollment until death.)

Study Results

The study authors found that patient age was strongly asso­ci­ated with both pro­gres­sion-free and over­all sur­vival. Younger patients under the age of 60 had sig­nif­i­cantly longer pro­gres­sion-free and over­all sur­vival than patients over the age of 80: 38.3 months vs. 13.6 months for pro­gres­sion-free sur­vival, and 65.6 months vs. 28.9 months for over­all sur­vival.

Chromosomal Abnormalities And Risk Status

Data on chromosomal ab­nor­mal­i­ties were avail­able for 1,567 patients. The re­searchers found that the share of patients with t(4;14) and del(17p) de­creased sig­nif­i­cantly with age while that of patients with gain(1q) in­creased. Overall, the share of patients with high-risk or ultra-high-risk chromosomal ab­nor­mal­i­ties was con­stant across the first three age groups, whereas it was slightly higher in patients older than 80 years.

The impact of chromosomal ab­nor­mal­i­ties on sur­vival varied, how­ever, across the age groups. Whether or not a patient was standard risk, high risk, or ultra high risk mattered in a con­sis­tent way in patients 60 years of age or younger and for patients 61 to 70 years of age, with sur­vival being the longest for standard-risk patients, shorter for intermediate-risk patients, and shortest for ultra-high-risk patients.

In older patients, on the other hand, risk status had less of an effect on sur­vival. In patients over 80 years of age, for example, there was essentially no dif­fer­ence in sur­vival be­tween those with standard risk and high risk dis­ease. In patients 71 to 80 years of age, standard risk patients clearly had better sur­vival, but there was not much dif­fer­ence in over­all sur­vival be­tween high-risk and ultra-high-risk patients.

Disease Stage And Overall Health

When the re­searchers looked at dis­ease stage, which like risk status is a dis­ease rather than patient char­ac­ter­istic, they found that it varied sub­stan­tially with age. More ad­vanced dis­ease, reflected in a higher dis­ease staging, became more common at higher patient ages. Less than a quarter of patients under the age of 60 had Stage 3 dis­ease at diag­nosis, whereas almost half of patients over the age of 80 were Stage 3.

As for over­all health at diag­nosis, it too varied with age, in the ex­pec­ted way. The share of patients with an excellent over­all health status de­creased from 82 per­cent in patients 60 years and younger to 67 per­cent in those over the age of 80.

Relative Importance Of The Factors

The re­searchers then assessed the rel­a­tive­ impact on sur­vival of risk status, dis­ease stage at diag­nosis, and over­all health in each of the four age groups.

To do this, they used a statistical model to esti­mate for each age group how much each of one of the three variables affected pro­gres­sion-free and over­all sur­vival in the group.

Then, re­searchers used the results from their statistical models, com­bined with the variability of each factor in each age group, to assess how much each factor accounts for dif­fer­ences in sur­vival in each age group.

The results of this modeling exercise for over­all sur­vival are shown in Figure 1 below.

The results in­di­cate that variation in dis­ease stage has little impact on sur­vival among patients under the age of 60, but then be­comes im­por­tant in a rather con­stant way across the three remaining older age groups.

The impact of over­all health on sur­vival declines as one goes from the group with the youngest myeloma patients to those 61 years of age to 70 years of age, but then be­comes in­creas­ingly im­por­tant as age grows.

Finally, the presence or absence of high risk chromosomal ab­nor­mal­i­ties has the greatest impact on sur­vival among young myeloma patients, and be­comes less im­por­tant with greater patient age.

For more in­for­ma­tion, please see the study by Pawlyn, C. et al., “The rel­a­tive­ importance of factors predicting out­come for myeloma patients at dif­fer­en­t ages: results from 3894 patients in the Myeloma XI trial,” in Leukemia, Octo­ber 14, 2019 (full text).

In their study, the researchers focus in particular on how the levels of a patient’s un­in­volve­d immuno­glob­u­lins are affected by treat­ment with Darzalex.

Uninvolved immuno­glob­u­lins in myeloma patients are immuno­glob­u­lins that have a type dif­fer­en­t from any mono­clonal immuno­glob­u­lin made by a patient’s myeloma cells.

Someone with IgG multiple myeloma, for example, has myeloma plasma cells that produce mono­clonal immuno­glob­u­lin G (IgG). For this myeloma patient, the un­in­volve­d immuno­glob­u­lins are IgA, IgM, IgD, and IgE – that is, every type of immuno­glob­u­lin other than IgG, which is the patient’s in­volve­d immuno­glob­u­lin.

Similarly, for someone with IgA multiple myeloma, the un­in­volve­d immuno­glob­u­lins are IgG, IgM, IgD, and IgE, and IgA is the in­volve­d immuno­glob­u­lin.

Uninvolved immuno­glob­u­lins in myeloma patients are polyclonal as opposed to mono­clonal. They are basically the same as the immuno­glob­u­lins of the same type found in people without multiple myeloma.

The Dutch researchers found that Darzalex affects the levels of IgG, IgA, and IgM dif­fer­en­tly when they are a patient’s un­in­volve­d immuno­glob­u­lins.

The drug seems to have little effect on IgG when it is an un­in­volve­d immuno­glob­u­lin. On the other hand, when IgA is one of a patient’s un­in­volve­d immuno­glob­u­lins, its level drops quickly after the patient’s first Darzalex in­fusion, reaching levels that are well below nor­mal, and then con­tinues to remain low, even a year after the start of treat­ment.

When IgM is one of a patient’s un­in­volve­d immuno­glob­u­lins, on the other hand, its level drops after a patient’s first Darzalex in­fusion, but then recovers over the course of the next 6-9 months of treat­ment.

Significance Of The Study Findings

These Dutch research team’s findings are im­por­tant for at least two reasons.

First, the findings highlight the need for patients being treated with Darzalex to be vigilant about pro­tecting themselves against in­fec­tion due to the impact the drug can have on IgA levels. People with lower-than-normal levels of IgA do not automatically develop lung or gastro­in­tes­ti­nal in­fec­tions, but they tend to be more sus­cep­tible to them. Thus, patients being treated with Darzalex who develop lower-than-normal levels of IgA should discuss with their doctors what precautions they should take to pro­tect themselves against poten­tial in­fec­tions.

Second, the findings can help physicians and patients better under­stand the implications of immuno­glob­u­lin level results from regular blood tests. The study results sug­gest, for example, that patients with IgG multiple myeloma need not be alarmed if their IgA level drops drastically after starting treat­ment with Darzalex.

Similarly, patients with IgA multiple myeloma who ex­peri­ence sig­nif­i­cant changes in their IgG level – either up or down – during treat­ment with Darzalex may want to work with their doctors to better under­stand the implications of those results.

Study Design

The results the Dutch researchers published re­gard­ing Darzalex and its impact on the levels of un­in­volve­d immuno­glob­u­lins were part of a broader study investigating the link be­tween Darzalex treat­ment and the risk of in­fec­tion.

Other parts of the Dutch study looked at how Darzalex affects plasma cell frequency in the bone marrow of myeloma patients and how the drug affects the efficacy of flu vaccines.

For their research related to Darzalex and un­in­volve­d immuno­glob­u­lin levels, the study authors analyzed blood samples from 30 re­lapsed and re­frac­tory multiple myeloma patients who par­tic­i­pated in a Phase 1/2 trial in the Netherlands investigating Darzalex as a single agent and in com­bi­na­tion with all-trans retinoic acid in re­lapsed and re­frac­tory multiple myeloma.

Patients in the trial re­ceived 16 mg/kg of Darzalex weekly for 8 weeks, bi-weekly for 16 weeks, and monthly there­after. During the first part of the trial, which is the source of un­in­volve­d immuno­glob­u­lin level data the researchers analyzed, patients re­ceive only Darzalex as a single agent (that is, without all-trans retinoic acid or any other myeloma treat­ment).

Patients who par­tic­i­pated in the first part of the trial a median of five prior ther­a­pies, in­clud­ing Revlimid Revlimid (lena­lido­mide) (100 per­cent of patients), Velcade (bor­tez­o­mib) (97 per­cent), Pomylast (poma­lido­mide, Imnovid) (50 per­cent), and Kyprolis (car­filz­o­mib) (10 per­cent).

The majority of patients (70 per­cent) had IgG myeloma. Another 27 per­cent had light-chain myeloma, and 3 per­cent had IgA myeloma.

The median patient age was 70 years old.

The levels of patients’ un­in­volve­d immuno­glob­u­lin levels were assessed at the start of the trial, at the start of each Darzalex treat­ment cycle, and at the time of dis­ease pro­gres­sion. Blood samples were drawn directly before the start of Darzalex treat­ment.

Patients who re­ceived in­tra­venous immuno­glob­u­lins (IVIG) transfusions as prophylaxis against in­fec­tions were excluded from the analysis.

Study Results

The results of the Dutch researchers’ analysis show that patients on average had below-normal levels of un­in­volve­d immuno­glob­u­lins even before they started treat­ment with Darzalex.

After 4 weeks of treat­ment with Darzalex, the researchers observed a sig­nif­i­cant de­crease in un­in­volve­d IgA, IgM, and IgE levels. IgG levels, on the other hand, remained stable. This devel­op­ment occurred in all patients independent of treat­ment re­sponse­. Figure 1 below in­cludes graphs of the average levels of un­in­volve­d IgG (Panel 1), IgA (Panel 2), and IgM (Panel 3) measured by the Dutch researchers during their study.

Uninvolved IgG levels remained stable, albeit below the lower limit of nor­mal, with successive treat­ment. The researchers point out that un­in­volve­d IgG levels may have been slightly overestimated because Darzalex is an IgG kappa anti­body. However, un­in­volve­d IgG remained stable after they made ad­just­ments to reflect Darzalex’s poten­tial influence on un­in­volve­d IgG levels.

The levels of un­in­volve­d IgE and IgM levels returned to the same level as at the start of the trial after 24 and 36 weeks of treat­ment, re­spec­tive­ly.

Uninvolved IgA levels, on the other hand, did not recover sub­stan­tially with successive treat­ment.

A Potential Explanation For The Results

The authors of the Dutch study note that plasma cells that produce nor­mal (non-monoclonal) IgG are found mainly in the bone marrow, whereas other parts of the body, such as mucous linings, lymph nodes, and the spleen play im­por­tant roles in the pro­duc­tion of non-monoclonal IgA, IgM, and IgE.

The Dutch researchers speculate that the dif­fer­en­t locations of these healthy plasma cells in the body may ex­plain why levels of un­in­volve­d IgG, IgA, and IgM change in dif­fer­en­t ways when myeloma patients are treated with Darzalex.

For more in­for­ma­tion, please see the study by Frerichs, K. A. et al., “Effect of dara­tu­mu­mab on nor­mal plasma cells, polyclonal immuno­glob­u­lin levels, and vaccination re­sponse­s in extensively pre-treated multiple myeloma patients,” in Haematologica, Sep­tem­ber 26, 2019 (full-text).

One of the reasons Darzalex (dara­tu­mu­mab), for example, has been such an im­por­tant new treat­ment for multiple myeloma is because it rep­re­sents a new way of treating the dis­ease. Darzalex was not just another immuno­modu­la­tory agent, like Revlimid (lena­lido­mide) or thalido­mide, and not just another pro­te­a­some in­hib­i­tor, like Velcade (bor­tez­o­mib), Ninlaro (ixazomib), or Kyprolis (car­filz­o­mib). As a mono­clonal anti­body targeted at the CD38 protein found on myeloma cells, Darzalex is the first in an entirely new class of treat­ments for the dis­ease.

This is why tiragolumab, the focus of this edition of the Beacon’s “Getting To Know” series of articles about poten­tial new myeloma ther­a­pies, is so intriguing.

A Monoclonal Antibody Anti-TIGIT Therapy

Tiragolumab cur­rently is being in­ves­ti­gated as a poten­tial treat­ment for multiple myeloma and several other cancers in three dif­fer­en­t clin­i­cal trials. The drug pre­vi­ously has had code names such as RG6058, RO7092284, and MTIG7192A,

Tiragolumab is what is known as an “anti-TIGIT” ther­apy. More specifically, it is a mono­clonal anti­body aimed at a re­cep­tor known as “TIGIT” (rhymes with “digit”), which is found on T-cells and natural killer (NK) cells.

There are no anti-TIGIT ther­a­pies cur­rently approved for the treat­ment of multiple myeloma or, for that matter, any other form of cancer. There are, how­ever, several anti-TIGIT ther­a­pies in the early stages of clin­i­cal trial testing for dif­fer­en­t kinds of cancer, and the anti-TIGIT ap­proach is con­sidered by many researchers to be a promising anti-cancer strat­e­gy.

How Anti-TIGIT Therapies Work

Normally, T cells and NK cells play an im­por­tant role in protecting the body against cancer by attack­ing and helping to kill off cancer cells. The cancer cells that man­age to survive in the body usually do so by finding ways to defend themselves against the immune response mounted by T cells and NK cells.

One way some cancer cells defend themselves against T cells and NK cells is by emitting two types of protein molecules, known as CD112 and CD155, which can attach themselves to the TIGIT re­cep­tors on T cells and NK cells.  When the protein molecules bind to a TIGIT re­cep­tor, it starts a sequence of events that can sig­nif­i­cantly dampen or even shut down the anti-cancer activity of the T cells and NK cells.

Anti-TIGIT ther­a­pies are designed to stop CD112 and CD155 proteins from “putting the brakes” on T cells and NK cells. The ther­a­pies do this by getting to the TIGIT re­cep­tors first, attaching themselves to the re­cep­tors, and preventing CD112 and CD155 from binding to the re­cep­tors.

Importantly, when the anti-TIGIT ther­a­pies attach themselves to the TIGIT re­cep­tors, they do not have the anti-cancer dampening effect that the CD112 and CD155 molecules do.

Anti-TIGIT Therapy Is A Form Of Checkpoint Inhibition

If the way anti-TIGIT ther­a­pies are designed to work sounds familiar, it’s because they belong to a broader group of ther­a­pies known as “checkpoint in­hib­i­tors.” These types of anti-cancer treat­ments work by preventing cancer cells from exploiting immune sys­tem “checkpoints” such as TIGIT to dampen the activity of T cells and NK cells.

Probably the best known checkpoint in­hib­i­tors are ther­a­pies that block cancer cells from targeting a re­cep­tor on T cells and NK cells known as PD-1. Like anti-TIGIT ther­a­pies, PD-1 checkpoint in­hib­i­tors block proteins emitted by cancer cells – in this case, proteins known as PD-L1 and PD-L2 – from binding to the PD-1 re­cep­tor and reducing the anti-tumor response of T cells and NK cells.

PD-1 checkpoint in­hib­i­tors have be­come im­por­tant in the treat­ment of a number of cancers. Myeloma researchers were there­fore op­ti­mis­tic when clin­i­cal trials were started to test whether PD-1 checkpoint in­hib­i­tors such as Keytruda (pem­bro­lizu­mab) or Opdivo (nivolumab) could be used either as single-agents, or together with existing myeloma ther­a­pies, to treat multiple myeloma.

PD-1 Safety Concerns Heighten Interest In Anti-TIGIT Therapies

Unfortunately, safety issues arose in some of the trials testing PD-1-related ther­a­pies in myeloma patients, and many of those trials have been halted. This is one of the reasons, ex­plains Fotis Asimakopoulos, a myeloma specialist at the University of California, San Diego, that researchers are “excited about TIGIT in the case of myeloma." Targeting TIGIT is an alter­na­tive checkpoint-related ap­proach with the poten­tial to im­prove treat­ment out­comes in the dis­ease.

In an interview with The Myeloma Beacon, Dr. Asimakopoulos, who has published a commentary on research related to TIGIT’s role in multiple myeloma, noted that interest in TIGIT as a thera­peutic target is driven by more than just a desire to find a substitute checkpoint in­hib­i­tor for PD-1. “TIGIT,” he ex­plained, “seems to be a major path­way that controls the crosstalk and the rela­tion­ship be­tween immune sys­tem cells [such as T cells and NK cells] and myeloma plasma cells.”

The Phase 1 Trial Of Tiragolumab In Multiple Myeloma

A Phase 1 trial of tiragolumab in multiple myeloma cur­rently is recruiting patients at three locations in the U.S.: Denver, Colorado; St. Louis, Missouri; and Nashville, Tennessee. Additional trial sites are planned for Atlanta, Georgia and Philadelphia, Pennsylvania and four dif­fer­en­t hos­pi­tals in Seoul, Korea.

The Phase 1 trial is recruiting patients with either re­lapsed myeloma or re­lapsed non-Hodgkin lym­phoma. Patients who take part in the first part of the trial will receive treat­ment with just tiragolumab, in­fused once every 21 days. Multiple myeloma patients who start the trial during its second part will receive treat­ment with both tiragolumab and Darzalex.

More in­for­ma­tion about the trial, in­clud­ing eligibility and exclusion criteria, can be found at the trial’s page at clin­i­caltrials.gov.

The Com­panies Developing Tiragolumab

Tiragolumab is being devel­oped by Genentech, a sub­sid­i­ary of the pharma­ceu­tical com­pany Roche. Neither Genentech nor Roche has provided financial or any other form of compensation to The Myeloma Beacon or its employees. To ensure the objectivity of the in­for­ma­tion it provides the myeloma com­munity, The Beacon neither seeks nor accepts financial sup­port from pharma­ceu­tical com­pa­nies or or­ga­ni­za­tions sup­ported by them.

For The Really Curious: Some Additional Odds And Ends

“TIGIT” stands for “T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based in­hib­i­tory motif domains.” “PD-1” stands for “programmed cell death protein - 1.”

Although the discussion in this article mentions both CD112 and CD155 as the molecules that bind to the TIGIT re­cep­tor and dampen T-cell and NK-cell anti-tumor activity, it is believed the CD155 plays the most im­por­tant role.

Anti-TIGIT ther­a­pies may not just stop cancer cells from dampening the anti-tumor activity of T cells and NK cells; they may actually stim­u­late such activity. This is because the protein molecules CD112 and CD155 that dampen immune cell activity by latching on to the TIGIT re­cep­tor also can stim­u­late T cell and NK cell activity if they bind to CD226, a dif­fer­en­t re­cep­tor also found on those immune sys­tem cells.

Thus, anti-TIGIT ther­a­pies, by preventing CD112 and CD155 molecules from binding to TIGIT re­cep­tors, in­crease the likelihood that those molecules end up binding to CD226 re­cep­tors, thereby stim­u­lating the anti-tumor response of the T cell or NK cell.

In short, anti-TIGIT ther­a­pies may do more than release the brake on the immune cells that fight myeloma; they also may step on the gas pedal.

The trial was motivated by pre­vi­ous research showing that nelfinavir can overcome resistance to Velcade, for a period of time, in many re­lapsed myeloma patients.

Unfortunately, the results of the more recent nelfinavir trial are not as en­cour­ag­ing as the pre­vi­ous research involving nelfinavir and Velcade. Less than a third of the patients in the more recent trial responded to the three-drug regi­men of nelfinavir, Revlimid, and dexa­meth­a­sone that they were given during the study. In addi­tion, among the patients who responded to the treat­ment, the median duration of response was just four months.

It might seem en­cour­ag­ing that nearly a third of the trial par­tic­i­pants responded to the treat­ment, given that all patients in the trial pre­vi­ously had been treated with Revlimid and ex­peri­enced dis­ease pro­gres­sion either while they were being treated with the drug, or shortly there­after.

However, the par­tic­i­pants in the trial had a median of just two prior lines of ther­apy, meaning in most cases that their dis­ease was still sensitive to a number of addi­tional treat­ment options.

In addi­tion, the dexa­meth­a­sone dose used in the trial was not incidental. Patients got either 40 mg or 20 mg of dexa­meth­a­sone once a week for every week of the trial, depending on whether they were younger than 75 (40 mg) or not (20 mg). In patients with a median of just two prior lines of ther­apy, the dexa­meth­a­sone alone could account for many of the responses seen in the trial par­tic­i­pants.

Still, the researchers who carried out the trial believe the nelfinavir-Revlimid-dexamethasone regi­men is “active” in patients with Revlimid-resistant dis­ease, noting that, in addi­tion to the 31 per­cent of trial par­tic­i­pants who had at least a partial response to the regi­men, another 38 per­cent had either a minimal response or stable dis­ease for a period of time.

The researchers also point out that, to reduce the cost of conducting the trial, patients received at most four months of treat­ment with the trial regi­men. Given that patients’ deepest responses to Revlimid-based treat­ment can occur after 6, 12, or even 18 months of treat­ment, more responses to the trial regi­men might be observed in real life than were seen during the trial.

Despite these caveats, it seems likely that the inno­va­tive myeloma specialists who use nelfinavir to im­prove treat­ment out­comes for their patients will do so mainly by using the drug in com­bi­na­tion with Velcade or, perhaps, other pro­te­a­some in­hib­i­tors such as Ninlaro (ixazomib). It is in com­bi­na­tion with such treat­ments that nelfinavir seems to have the greatest ability to overcome drug resistance, poten­tially im­prov­ing over­all survival by im­prov­ing the treat­ments physicians have to treat the dis­ease.

(See this recent Beacon column for insight into why im­prov­ing current treat­ments and adding addi­tional effective treat­ments are key to im­prov­ing the survival of myeloma patients.)

Background To The Nelfinavir-Revlimid Trial

Nelfinavir (Viracept) is an orally admin­istered drug that belongs to a class of ther­a­pies called protease in­hib­i­tors. Nelfinavir was approved by the U.S. Food and Drug Admin­istra­tion in 1997 for the treat­ment of human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syn­drome (AIDS).

The original patent for nelfinavir has expired in most countries, so generic versions of the drug are now avail­able (but not yet in the United States). Generic versions of pre­vi­ously patent-protected drugs have the same active ingredient as the original brand name drug, but they usually cost much less.

After laboratory research suggested that nelfinavir might be able to overcome resistance to pro­te­a­some in­hib­i­tors such as Velcade (bor­tez­o­mib) in re­lapsed multiple myeloma patients, trials were carried out to explore whether nelfinavir in com­bi­na­tion with Velcade and dexa­meth­a­sone could im­prove treat­ment out­comes in Velcade-resistant patients.

The results of these trials were very en­cour­ag­ing. In a Phase 2 trial with Velcade-resistant patients who had received a median of five prior lines of ther­apy, 65 per­cent of the patients had at least a partial response to treat­ment with nelfinavir, Velcade, and dexa­meth­a­sone (see related Beacon news article and myeloma specialist interview).

These results en­cour­aged researchers to organize a trial to explore whether nelfinavir also could overcome Revlimid (lena­lido­mide) resistance in multiple myeloma patients.

Design Of The Nelfinavir-Revlimid Trial

Between May 2012 and De­cem­ber 2016, researchers at seven treat­ment centers in Switzerland recruited 29 re­lapsed / refractory multiple myeloma patients for par­tic­i­pa­tion in the trial.

To par­tic­i­pate in the trial, patients had to be refractory to Revlimid, which was defined as having progressed during or within 60 days of termination of Revlimid-containing ther­apy of two or more months duration.

The median patient age was 64 years old. Approximately one third of the patients (31 per­cent) presented with high-risk chromosomal ab­nor­mal­i­ties (t(4;16), t(14;16), or del(17p)).

Patients had received a median of two prior ther­a­pies. All patients had pre­vi­ously received Revlimid and 83 per­cent had prior Velcade exposure. All were refractory to Revlimid, and 34 per­cent were double refractory to Revlimid and Velcade. More than half of the patients (62 per­cent) had pre­vi­ously received a stem cell trans­plant.

The Phase 1 part of the trial was designed to estab­lish­ the target dose to be used in the Phase 2 part of the trial.  Thus, during Phase 1, patients received be­tween 1,250 mg and 1,875 mg of oral nelfinavir twice daily on days 1 through 21, 25 mg of Revlimid on days 1 through 21 plus 20 mg / 40 mg of oral dexa­meth­a­sone on days 1, 8, 15, and 22 for up to four 28-day treat­ment cycles. Treatment was limited to a maximum of four cycles due to cost constraints.

A total of 10 patients par­tic­i­pated in the Phase 1 part of the trial. The researchers observed two incidents of dose-limiting side effects at 1,850 mg of nelfinavir twice daily. As a result, in the Phase 2 part of the trial, all patients received 1,250 mg of oral nelfinavir twice daily plus Revlimid and dexa­meth­a­sone at the same doses as in the Phase part of the trial.

A little more than half of the patients (52 per­cent) com­pleted all four treat­ment cycles. The remaining patients dis­con­tinued treat­ment due to progressive dis­ease (28 per­cent), unacceptable side effects (14 per­cent), or patient refusal (7 per­cent).

Results Of The Nelfinavir-Revlimid Trial

Overall, 31 per­cent of patients responded to treat­ment, with 10 per­cent achieving a very good partial response and 21 per­cent achieving a partial response. An addi­tional 24 per­cent of patients achieved a minor response and 14 per­cent had stable dis­ease.

Of the patients who were refractory to both Velcade and Revlimid, 40 per­cent achieved a minor response or better. Among patients who had high-risk chromosomal ab­nor­mal­i­ties, 78 per­cent achieved a minor response or better.

The median duration of response was 4 months.

The median pro­gres­sion-free survival was 3.4 month, and the median over­all survival was 21.6 months.

According to the researchers, the treat­ment was well tolerated. They note that they did not observe any unexpected side effects, and that the side effects were similar to those observed with the in­di­vid­ual drugs.

The most common side effects of all grades in­cluded gastro­in­tes­ti­nal symp­toms (31 per­cent of patients), and metabolic disorders (31 per­cent). The most common severe side effects in­cluded anemia (24 per­cent), low platelet count (21 per­cent), low white blood cell count (24 per­cent, in­clud­ing patients with low white blood cell counts accompanied by fever), and shortness of breath (10 per­cent).

For more in­for­ma­tion, please see the study by Hietz, F. et al., “Nelfinavir and lena­lido­mide / dexa­meth­a­sone in patients with lena­lido­mide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10),” in Blood Cancer Journal, August 27, 2019 (full-text) and the description of the nelfinavir-Revlimid clin­i­cal trial at clin­i­caltrials.gov.

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).

The number of new treat­ments under devel­op­ment for multiple myeloma is greater than it ever has been, and this creates tremendous hope in the myeloma com­munity. In just a few years, a number of new drugs are likely to be approved for the treat­ment of myeloma, and patients have the option of exploring many of those options now by par­tic­i­pating in clin­i­cal trials.

At the same time, the ex­panding number of poten­tial treat­ments for multiple myeloma makes it dif­fi­cult to stay informed about all the dif­fer­en­t options. For this reason, The Myeloma Beacon is starting a new “Getting To Know” series of occasional articles to introduce myeloma patients and care­givers to treat­ments physicians and researchers are investigating.

In this, the first of the “Getting To Know” series, the focus is on a drug known as TNB-383B.

TNB-383B: A Bispecific Antibody Targeting BCMA And CD3

TNB-383B is an in­fused drug that is just starting clin­i­cal trial testing. Like the approved myeloma ther­a­pies Darzalex (dara­tu­mu­mab) and Empliciti (elotuzumab), TNB-383B is a mono­clonal anti­body. TNB-383B differs from the two approved mono­clonal anti­body myeloma ther­a­pies, how­ever, in several im­por­tant ways.

First, Darzalex and Empliciti work by targeting one specific protein found on myeloma cells. In the case of Darzalex, the targeted protein is known as CD38. In the case of Empliciti, the targeted protein is SLAMF7 (also known as CD319 and CS1).

TNB-383B, on the other hand, targets two proteins: BCMA (an abbre­vi­a­tion for “B-cell maturation an­ti­gen”) and CD3. Mono­clonal anti­bodies like TNB-383B that have two targets often are called “bispecific anti­bodies.”

In the body, BCMA is found mainly on myeloma cells, and the initial step in the way TNB-383B is designed to work is by attaching itself to the BCMA on myeloma cells.

Once a TNB-383B molecule is attached to a myeloma cell, the drug’s second target, CD3, comes into play. The CD3 attracts and then binds T-cells to the drug and to the myeloma cell, after which the T-cells attack and, if all goes well, kill the myeloma cell.

Another Bispecific Antibody Targeting BCMA And CD3: AMG 420

TNB-383B is not the only BCMA- and CD3-targeting bispecific anti­body being tested as a poten­tial new treat­ment for multiple myeloma. There are, in fact, several. The best known of them is AMG 420 (BI 836909), cur­rently under devel­op­ment by Amgen. Results of AMG 420’s Phase 1 clin­i­cal trial have been presented at medical conferences as recently as this past summer.

Patients in the Phase 1 trial of AMG 420 had a median of 4 prior lines of ther­apy, and all had been treated with at least one immuno­modu­la­tory drug like Revlimid (lena­lido­mide) or Pomalyst (poma­lido­mide, Imnovid) and at least one pro­te­a­some in­hib­i­tor, such as Velcade (bor­tez­o­mib) or Kyprolis (car­filz­o­mib). About a quarter of the patients had been treated at some point with Darzalex.

Among the 10 patients in the Phase 1 trial who were given the dose of AMG 420 that is going to be tested in future trials of the drug, seven (70 per­cent) achieved at least a partial response, and five (50 per­cent) became minimal residual dis­ease neg­a­tive. Myeloma specialists generally have been im­pressed by these responses given how heavily pre­treated the patients in this trial were.

TBN-383B’s Unique Structure

TNB-383B differs somewhat from AMG 420, how­ever, in a way that also dif­fer­en­ti­ates the drug from Darzalex and Empliciti.

In particular, TNB-383B consists of two immuno­glob­u­lin heavy chains and just one immuno­glob­u­lin light chain, as depicted in Figure 1 above. Darzalex and Empliciti, in contrast, have the standard two heavy and two light chains one ex­pec­ts in immuno­glob­u­lin molecules (similar to part (a) of Figure 2, below). AMG 420 consists of the com­bined heavy chain and light chain tips of two dif­fer­en­t anti­bodies fused together (Figure 2).

TNB-383B’s structure is relevant primarily in terms of what its efficacy and safety may be like in comparison to a drug like AMG 420 that also targets both BCMA and CD3. The fact that the TNB-383B molecule has two full immuno­glob­u­lin heavy chains means it could stay longer in patient’s bodies, in­creas­ing its efficacy. The drug’s developers also believe TNB-383B’s design could reduce how likely it is to cause the side effect known as cytokine release syn­drome, a poten­tially serious immune sys­tem reac­tion that has occurred in AMG 420 and other ther­a­pies that affect the immune sys­tem.

It is worth noting that, in addi­tion to AMG 420, several other well-known inves­ti­ga­tional ther­a­pies for multiple myeloma are targeting the BCMA protein, in­clud­ing the CAR T-cell ther­apy bb2121 and the anti­body-drug con­ju­gate be­lan­ta­mab mafo­dotin (GSK2857916).

The Phase 1 Trial Testing TNB-383B In Multiple Myeloma

There cur­rently is one clin­i­cal trial underway exploring the efficacy and safety of TNB-383B in multiple myeloma patients. It is a Phase 1 trial in­tended, in part, to estab­lish­ the optimal dose of the drug. The trial is taking place in the United States, and it eventually will be open to patients at a minimum of six dif­fer­en­t locations. Two locations, one in North Carolina and one in Wisconsin, already are enrolling patients.

To par­tic­i­pate in the TNB-383B trial, patients must have re­lapsed multiple myeloma, and they must pre­vi­ously have been treated with an immunodulatory ther­apy, a pro­te­a­some in­hib­i­tor, and a CD38-targeted ther­apy.

Immunodulatory ther­a­pies in­clude Revlimid (lena­lido­mide), Pomalyst (poma­lido­mide), and thalido­mide. Proteasome in­hib­i­tor ther­a­pies in­clude Velcade (bor­tez­o­mib), Kyprolis (car­filz­o­mib), and Ninlaro (ixazomib). CD38-targeted ther­a­pies in­clude Darzalex and the inves­ti­ga­tional agent isatuximab.

More details about the TNB-383B trial, in­clud­ing trial locations and eligibility criteria, can be found at the trial’s page at clin­i­caltrials.gov.

The Com­panies Developing TNB-383B

TNB-383B is being devel­oped through a col­lab­o­ration involving two com­pa­nies, TeneoBio and AbbVie. Neither of those com­pa­nies have provided financial or any other form of sup­port or com­pen­sa­tion to The Myeloma Beacon or its employees. To ensure the objectivity of the in­for­ma­tion it pro­vides the myeloma com­munity, The Beacon neither seeks nor accepts financial sup­port from pharma­ceu­tical com­pa­nies or or­ga­ni­za­tions sup­ported by them.

The five busiest U.S. centers in terms of au­tol­o­gous trans­plants for mul­ti­ple myeloma carried out an average of 236 such trans­plants per center in 2017, the latest year for which data are pub­licly avail­able. That is a pace equal to almost one trans­plant per weekday at each of the five centers.

In contrast, across the other 134 other U.S. centers that per­formed au­tol­o­gous trans­plants in mul­ti­ple myeloma patients in 2017, the average num­ber of such trans­plants per center was 47, or less than one trans­plant per week.

The statistics compiled by The Beacon also reveal that allo­geneic (donor) stem cell trans­plants for people with mul­ti­ple myeloma are very rare. In 2017, just 49 U.S. cancer centers per­formed allo­geneic stem cell trans­plants in patients with mul­ti­ple myeloma, and only three centers carried out more than 10 such pro­ce­dures during the entire year.

Across the 49 centers that per­formed allo­geneic trans­plants for mul­ti­ple myeloma patients in 2017, the average num­ber of such trans­plants for the year was less than 4 per center.

The stem cell trans­plant statistics compiled by The Beacon can be found in the re­port “Number Of Stem Cell Transplants Carried Out At U.S. Multiple Myeloma Treatment Centers,” which The Beacon pub­lished earlier to­day. The re­port features an inter­active table with trans­plant statistics for 149 U.S. cancer centers. Results in the table are likely to be of sig­nif­i­cant interest to patients, care­givers, and med­i­cal professionals in the U.S. and inter­na­tionally.

Autologous Stem Cell Transplants

Table 1 below lists in descending order the 20 U.S. cancer centers that in 2017 per­formed the most au­tol­o­gous (own) stem cell trans­plants for mul­ti­ple myeloma patients. The data in the table are a subset of the data in the broader Beacon re­port mentioned above.

The column in Table 1 labeled “MM” lists the num­ber of au­tol­o­gous trans­plants carried out at each center for patients with mul­ti­ple myeloma.

The column in Table 1 labeled “MM + Others” lists the num­ber of au­tol­o­gous trans­plants carried out at each center in patients with either mul­ti­ple myeloma, Hodgkin lym­phoma, or non-Hodgkin lym­phoma. From 2012 to 2106, au­tol­o­gous trans­plants for patients with these three dis­eases accounted for 89 per­cent of all au­tol­o­gous trans­plants carried out in the United States.

Table 1
U.S. Cancer Centers Performing The Most
Autologous Stem Cell Transplants
For Multiple Myeloma Patients In 2017

Many of the entries in Table 1 are centers one would ex­pec­t to be among the most active U.S. cancer centers when it comes to per­forming au­tol­o­gous stem cell trans­plants for people with mul­ti­ple myeloma. There are some entries, how­ever, that may come as a surprise to many Beacon readers, such as Northwestern Uni­ver­sity (Illinois), the Uni­ver­sity of Kansas, Barnes Jewish Hospital (Missouri), Froedtert Memorial Lutheran Hospital (Wisconsin), and the Colorado Blood Cancer In­sti­tute.

In general, the num­ber of trans­plants per­formed at a center will de­pend on

1. The number of myeloma patients regularly under the care of physicians at the center
2. How often physicians at the center recommend that their patients undergo autologous stem cell transplantation
3. How many transplants a patient at the center typically receives when they undergo autologous stem cell transplantation (that is, does the center typically perform single or tandem stem cell transplants?)

Of these three factors, the third is par­tic­u­larly im­por­tant. A center that prefers tandem stem cell trans­plan­ta­tion, which is two stem cell trans­plants carried out within a short period of time, can have double the num­ber of trans­plants each year com­pared to other centers with com­parable num­bers of myeloma patients and spe­cialists.

It should not come as a surprise, there­fore, that sev­er­al hos­pi­tals find themselves in Table 1 precisely because they are more likely than other centers to carry out tandem, rather than single, stem cell trans­plants. This is cer­tainly the case with the very first entry in the table, the Uni­ver­sity of Arkansas for Medical Sciences (UAMS), which has a long history of en­cour­ag­ing tandem stem cell trans­plan­ta­tion in myeloma patients under its care.

Tandem trans­plan­ta­tion also is likely to play a role in the re­­sults for Northwestern Medicine, Hackensack Uni­ver­sity Medical Center, and Mount Sinai Medical Center, which are centers with myeloma spe­cialists also more inclined to tandem trans­plan­ta­tion than spe­cialists at other centers.

Allogeneic Stem Cell Transplants

Table 2 below lists in descending order the 10 U.S. cancer centers that in 2017 per­formed the most allo­geneic (donor) stem cell trans­plants for mul­ti­ple myeloma patients. Once again, this table is a subset of the data in the broader Beacon re­port mentioned earlier.

The column in Table 2 labeled “MM” lists the num­ber of allo­geneic trans­plants carried out at each center for patients with mul­ti­ple myeloma.

The column in Table 2 labeled “MM + Others” lists the num­ber of allo­geneic trans­plants carried out at each center in patients with either mul­ti­ple myeloma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lym­phoma, myelo­dys­plastic syn­dromes (MDS), non-Hodgkin lym­phoma, or severe aplastic anemia. From 2012 to 2016, allo­geneic trans­plants for patients with these seven dis­eases accounted for 80 per­cent of all allo­geneic trans­plants carried out in the United States.

Table 2
U.S. Cancer Centers Performing
The Most Allogeneic Stem Cell Transplants
For Multiple Myeloma Patients In 2017

It’s clear from Table 2 that allo­geneic trans­plants for mul­ti­ple myeloma are rare, and just two or three U.S. cancer centers are per­forming such trans­plants reg­u­larly. Indeed, most of the centers in Table 2 are carrying out just single digit num­bers of allo­geneic trans­plants each year for mul­ti­ple myeloma patients.

This does not mean that allo­geneic trans­plants are generally rare at U.S. cancer centers. Indeed, sev­er­al of the centers listed in Table 2 are per­forming more than 200 allo­geneic trans­plants each year for dis­eases other than mul­ti­ple myeloma. The ex­peri­ence that comes from carrying out so many allo­geneic trans­plants in general may be a con­sid­er­a­tion when someone with mul­ti­ple myeloma is con­sidering where to have an allo­geneic trans­plant carried out.

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For au­tol­o­gous and allo­geneic stem cell trans­plant statistics for all U.S. cancer centers that per­formed trans­plants for mul­ti­ple myeloma patients in 2017, please be sure to consult the Beacon's detailed online re­port, "Number Of Stem Cell Transplants Carried Out At U.S. Multiple Myeloma Treatment Centers."

The authors report on a case series of 16 patients who devel­oped either blepharitis or chalazia after starting treat­ment with Velcade (bor­tez­o­mib) or Kyprolis (car­filz­o­mib).

Blepharitis is the medical term for chronic inflammation of the eyelid, and a chalazion is a cyst in the eyelid caused by a blocked oil gland.

Both blepharitis and chalazia have pre­vi­ously been reported as occurring in patients treated with Velcade, and both Velcade and Kyprolis are in the pro­te­a­some inhibitor class of ther­a­pies, which also in­cludes Ninlaro (ixazomib).

There were 11 women and 5 men in the researchers’ sample of 16 patients, suggesting that eyelid com­pli­ca­tions may be more likely to occur in female myeloma patients.

Fourteen of the 16 patients had one or more episodes of chalazia, and 10 of the patients had one or more episodes of blepharitis. It was common for patients to develop both of the eyelid-related com­pli­ca­tions. This occurred in 60 per­cent of the patients who devel­oped chalazia and 80 per­cent of the patients who devel­oped blepharitis.

The average time from the start of Velcade or Kyprolis treat­ment to the devel­op­ment of an eyelid com­pli­ca­tion was 103 days (3.4 months).

Because the researchers’ report was a retro­spec­tive­ analysis, the patients in their case series did not have their eyelid-related com­pli­ca­tions addressed in a con­sis­tent way. The ap­proach to addressing the com­pli­ca­tions depended on the choice of the patients and their physicians.

In many cases, the eyelid com­pli­ca­tions were addressed solely with what the researchers describe as “ocular ther­apy.” This is treat­ment of the com­pli­ca­tion with warm compresses, oral or in­fused (“systemic”) antibiotics, antibiotic eye drops or ointments, or steroid eye drops or ointments.

In episodes where the researchers were able to document the treat­ment out­come, ocular ther­apy alone suc­cess­fully re­solved the eyelid-related com­pli­ca­tion 70 per­cent of the time.

Another ap­proach to the eyelid-related com­pli­ca­tions was to start ocular ther­apy while also dis­con­tin­u­ing treat­ment with the pro­te­a­some inhibitor the patient was on when the com­pli­ca­tion devel­oped. In episodes with known out­comes, this ap­proach suc­cess­fully re­solved the com­pli­ca­tion 73 per­cent of the time.

Recommendations For Prevention And Treatment

Based on their findings, the researchers propose an algorithm for the prevention and treat­ment of eyelid-related com­pli­ca­tions in patients being treated with Velcade.

As a first step, they rec­om­mend that patients starting treat­ment with Velcade be referred to an ophthalmologist for a base­line screen­ing. They also rec­om­mend that patients be given in­for­ma­tion about eyelid hygiene and the poten­tial for eyelid-related com­pli­ca­tions while being treated with Velcade.

If a patient being treated with Velcade develops chalazia or blepharitis, the researchers rec­om­mend im­medi­ate referral to an ophthalmologist, two months of ocular ther­apy, but no change in myeloma treat­ment. As initial ocular ther­apy, the study authors suggest hot compresses in com­bi­na­tion with at least one topical antibiotic and/or steroid drop.

If this initial ap­proach to the com­pli­ca­tions is not suc­cess­ful, the researchers rec­om­mend that ocular ther­apy be con­tinued, Velcade ther­apy be dis­con­tinued, and con­sid­er­a­tion be given to switching the patient to an alter­na­tive pro­te­a­some inhibitor such as Kyprolis or Ninlaro.

If the com­pli­ca­tions persist even after switching to alter­na­tive myeloma ther­apy, the authors rec­om­mend a prolonged course of the antibiotic doxycycline, admin­istered orally. They also rec­om­mend that a biopsy be carried out to more accurately de­ter­mine the nature of com­pli­ca­tion.

If the com­pli­ca­tions finally re­solve after the patient has been switched to a dif­fer­en­t myeloma ther­apy, the authors suggest that the option of switching the patient back to Velcade be con­sidered.

Study Design And Results

The case series compiled by the study authors in­cluded data for 16 patients seen at Mount Sinai Hospital in New York City. All of the patients had either multiple myeloma (14 patients) or AL amyloidosis with MGUS (2 patients), and they devel­oped eye com­pli­ca­tions be­tween January 2010 and January 2017 while being treated with a pro­te­a­some inhibitor.

The average patient age was 62 years. Median follow-up time was 17 months.

All but one of the 16 patients was receiving a Velcade-containing com­bi­na­tion ther­apy when they devel­oped their first eyelid com­pli­ca­tion. The one non-Velcade patient was on a Kyprolis-containing treat­ment regi­men.

Four of the patients (25 per­cent) devel­oped their first eyelid com­pli­ca­tion during the first cycle of treat­ment. Average time from treat­ment exposure to the onset of the first eyelid com­pli­ca­tion was 3.4 months.

Overall, 14 patients (87.5 per­cent) devel­oped chalazia, 10 patients (62 per­cent) devel­oped blepharitis, and 8 patients (50 per­cent) devel­oped both.

Of the 14 patients who had chalazia, 11 (79 per­cent) devel­oped two or more concurrent lesions. Female patients were more likely to develop concurrent lesions.

The researchers observed 34 episodes of eyelid com­pli­ca­tions in total; 23 of those cases (68 per­cent) were chalazia and 11 cases (32 per­cent) were blepharitis.

The two most common ap­proaches to dealing with these com­pli­ca­tions were ocular ther­apy alone and ocular ther­apy com­bined with stopping the patient’s treat­ment with Velcade.

The most common ocular ther­a­pies were warm compresses (18 episodes), antibiotic eye drops and/or ointments (12 episodes), sys­temic antibiotics (9 episodes), and steroid eye drops and/or ointments (4 episodes).

When ocular ther­apy alone was able to suc­cess­fully address an eyelid-related com­pli­ca­tion, the average time until com­pli­ca­tion resolution was 55 days (1.8 months).

When the com­pli­ca­tion was suc­cess­fully addressed through a com­bi­na­tion of ocular ther­apy and dis­con­tin­u­ing the patient’s original pro­te­a­some inhibitor, the average time until com­pli­ca­tion resolution was 93 days (3.1 months) after dis­con­tinu­a­tion of the patient’s original pro­te­a­some inhibitor.

Five of the 34 episodes of eyelid-related com­pli­ca­tions tallied in the study were not suc­cess­fully re­solved by the time the researchers carried out their analysis of the study results. The authors of the study point out, how­ever, that this was not entirely unexpected because the study follow-up time was just 17 months. The authors there­fore speculate that some of the unresolved episodes may eventually be re­solved.

For more in­for­ma­tion, please see the study by Sklar, B. A. et al., “Management and out­comes of pro­te­a­some inhibitor asso­ci­ated chalazia and blepharitis: a case series,” in BMC Ophthalmology, May 14, 2019 (full text).

In particular, the researchers found that myeloma patients who ex­peri­enced heart-related side effects while being treated with Kyprolis had sig­nif­i­cantly higher blood pressure, left ventricular mass, and pulse wave velocity before starting Kyprolis treat­ment than patients who did not ex­peri­ence heart-related side effects.

Blood pressure, left ventricular mass, and pulse wave velocity are well estab­lish­ed markers of heart and blood vessel health and can be measured in a physician’s office.

The researchers’ findings are based on data from a pro­spec­tive­ single-center study that in­cluded 70 multiple myeloma patients, most of whom (90 per­cent) had re­lapsed / refractory disease.

In the journal article summarizing their findings, the Italian researchers note that addi­tional studies are needed to con­firm their results. If the results are con­firmed, the researchers suggest that the markers they identified be in­cluded in patient evaluations prior to the start of Kyprolis treat­ment. This would help identify patients who could benefit from closer monitoring and more aggressive blood pressure treat­ment during Kyprolis ther­apy.

Global sales of Kyprolis have been flat for the past 12 months as physicians in­creas­ingly turn to alter­na­tives such as Darzalex (dara­tu­mu­mab), Pomalyst (poma­lido­mide, Imnovid), Empliciti (elotuzumab), and Ninlaro (ixazomib) when choosing treat­ments for their myeloma patients. Kyprolis sales in the past six months were up just 0.2 per­cent com­pared to the pre­vi­ous six months, while the four com­pet­ing drugs just mentioned ex­peri­enced double digit growth over the same period.

Safety con­cerns have been one reason Kyprolis sales have been lagging, particularly con­cerns about the drug’s impact on the heart. The new Italian study could address some of these con­cerns by helping physicians identify patients who could benefit from in­­creased heart monitoring and/or preventative use of heart medications to avoid heart-related side effects that might occur during Kyprolis treat­ment.

At the same time, the study may highlight the risks involved with Kyprolis treat­ment, given that a third of the patients in the study ex­peri­enced heart-related side effects.

Background

Kyprolis belongs to the pro­te­a­some inhibitor class of drugs, which also in­cludes Velcade (bor­tez­o­mib) and Ninlaro. Research dating back more than a decade has shown that there is some risk of heart-related side effects during treat­ment with Velcade, the first and most widely used pro­te­a­some inhibitor. Of the three drugs in the pro­te­a­some inhibitor class, how­ever, it is Kyprolis that is particularly known for having a risk of heart-related side effects, which can be severe, even fatal.

It is not cur­rently known why Kyprolis has “cardiovascular toxicity,” as the Italian researchers describe it. The researchers note, how­ever, that the way pro­te­a­some inhibitors work may interfere with the normal functioning of heart muscle cells, and it also may de­crease nitric oxide levels in artery and vein walls, which leads to higher blood pressure.

No predictive factors have been identified yet for the devel­op­ment of heart-related side effects with Kyprolis, according to the study authors. They there­fore sought to de­ter­mine whether parameters commonly used to assess heart damage and heart function might predict the risk of devel­op­ing heart-related side effects during treat­ment with Kyprolis.

Study Design

Between April 2017 and April 2018, the researchers enrolled 70 multiple myeloma patients in their pro­spec­tive­ study. All patients were seen at the Myeloma Unit of the “Città della Salute e della Scienza” medical campus in Turin, Italy. The mean patient age was 60 years.

The majority of patients in the study (90 per­cent) had re­lapsed / refractory multiple myeloma and had received a median of 2.5 prior ther­a­pies, in­­clud­ing alkylating agents such as mel­phalan (84 per­cent of patients), Velcade (80 per­cent), and immuno­modu­la­tory agents such as Revlimid (60 per­cent).

More than one third of patients (37 per­cent) had a history of high blood pressure; many patients showed other risk factors for devel­op­ing heart disease, such as obesity (31 per­cent), high lipid levels in the blood (11 per­cent), and diabetes (10 per­cent).

Patients underwent a com­pre­hen­sive heart-related evaluation before starting treat­ment with Kyprolis. The evaluation in­cluded office and 24-hour blood pressure mea­sure­ments, electro­cardio­grams, trans­thoracic echo­car­dio­grams, and evaluation of carotid-femoral pulse wave velocity. Trans­thoracic echo­car­dio­grams were per­formed to assess heart damage, and carotid-femoral pulse wave velocity was measured to assess arterial stiffness.

Optimal office blood pressure control was defined as blood pressure below 140/90 mmHg.

The results of the blood pressure monitoring before the start of Kyprolis ther­apy revealed that half of the patients did not have optimal blood pressure control, and these patients were required to either start blood pressure medication or make ad­just­ments in their current medication.

The median follow-up time was 9.3 months.

Study Results

The Italian researchers found that one third of the patients in their study ex­peri­enced heart-related side effects a median of 3.6 month after starting treat­ment with Kyprolis. Most of the heart-related side effects were classified as mild to mod­er­ate in nature (78 per­cent); the remaining 22 per­cent were severe in nature.

The most common heart-related side effect was excessive blood pressure (91 per­cent), requiring either an intensification of blood pressure medication (74 per­cent) or temporary dis­con­tinu­a­tion of Kyprolis treat­ment (17 per­cent).

The two other heart-related side effects observed among the patients in the study were heart attack (myocardial infarction) and ab­nor­mal heart rhythm (arrhythmia); there was one instance of each of these side effects (2 patients total, or 3 per­cent of the total study par­tic­i­pants).

The researchers found that patients who ex­peri­enced heart-related side effects while receiving Kyprolis treat­ment had sig­nif­i­cantly higher blood pressure, left ventricular mass, and pulse wave velocity before starting Kyprolis treat­ment than patients who did not ex­peri­ence these side effects.

The average blood pressure before the start of Kyprolis treat­ment was 141/82 mmHg for patients who ex­peri­enced heart-related side effects while receiving Kyprolis treat­ment com­pared to 127/74 mmHg for patients who did not ex­peri­ence heart-related side effects.

Similarly, the share of patients who had optimal blood pressure control (below 140/90 mmHg) before Kyprolis treat­ment was sig­nif­i­cantly higher among patients who did not ex­peri­ence heart-related side effects than among patients who did (60 per­cent versus 30 per­cent).

Left ventricular mass (indexed to body size) was 98 g/m2 for patients who ex­peri­enced heart-related side effects while receiving Kyprolis treat­ment com­pared to 85 g/m2 for patients who did not ex­peri­ence them. The left ventricle is the chamber of the heart responsible for pumping blood out to the rest of the body after it has come from the lungs to the heart. When pumping blood out to the body be­comes dif­fi­cult due, for example, clogging of the arteries and veins, the muscles surrounding the left ventricle grow larger, in­creas­ing left ventricular mass.

Pulse wave velocity was 8.5 m/s for patients who ex­peri­enced heart-related side effects while receiving Kyprolis com­pared to 7.5 m/s for patients who did not ex­peri­ence them. Pulse wave velocity is a measure of how stiff a person’s arteries are. It is the speed at which a blood pressure pulse travels from the heart through the arteries, and this speed is lower when arteries are flexible and higher when they are stiff.

For more in­for­ma­tion, please see the study by Bruno, G. et al., “Cardiovascular Organ Damage und Blood Pressure Levels Predict Adverse Events in Multiple Myeloma Patients Undergoing Carfilzomib Therapy,” in Cancers, May 3, 2019 (full text).

The results are based on in­for­ma­tion for 78,095 multiple myeloma patients from the United States whose data were reported to the National Cancer Data Base be­tween 2004 and 2015.

For their retro­spec­tive­ analysis, the authors of the new study divided the 78,095 patients in their sample into two groups.

One group in­cluded the patients who were found to have undergone “upfront” radiation ther­apy, which the study authors defined as radiation ther­apy carried out after a myeloma diag­nosis and within 90 days before, or up to 14 days after, a patient started drug-based myeloma ther­apy.

The second group in­cluded the patients who did not receive up­front radiation ther­apy.

Because the study in­cludes data for patients diag­nosed up to 15 years ago, survival out­comes are worse than would be ex­pec­ted in data for more recently diag­nosed patients.

Nevertheless, there was a noticeable dif­fer­ence in survival be­tween the two groups of patients. Overall survival for patients who received up­front radiation ther­apy was 3.6 years com­pared to 4.2 years for patients who did not receive up­front radiation ther­apy.

Across all patients in the study, 17 per­cent received up­front radiation ther­apy. Interestingly, patients were almost 25 per­cent more likely to receive up­front ther­apy if they were diag­nosed in a com­munity hospital rather than an academic hospital.

The authors of the new study are not able to conclude from their data why up­front radiation ther­apy is asso­ci­ated with lower over­all survival.

One poten­tial explanation is that radiation ther­apy is more likely to be needed in myeloma that is more aggressive, as it may be more likely to cause bone damage, or in patients whose disease is more ad­vanced due to a comparatively delayed diag­nosis.

Another explanation is that bone-related com­pli­ca­tions that require radiation ther­apy may limit the extent to which a patient’s disease can be treated.

The authors also explore the possibility that radiation ther­apy may be more common in patients who, for socioeconomic reasons, have more limited treat­ment options com­pared to other patients.

Background

Bone disease is a common com­pli­ca­tion of multiple myeloma. Approximately 80 per­cent of multiple myeloma patients show evi­dence of bone lesions at the time of their diag­nosis. Bone-destroying cells are more active in the bones of myeloma patients than bone-forming cells, which ultimately leads to bone destruction and skeletal com­pli­ca­tions such as lesions, fractures, and spinal cord compression.

Radiation ther­apy is one ap­proach to addressing some of the bone-related issues caused by multiple myeloma. It is used primarily to reduce bone pain and to prevent or treat bone fractures that can occur in myeloma patients.

Researchers have long known that the more bone lesions a myeloma patient has at diag­nosis, the poorer their prognosis tends to be. Prior research has not explored, how­ever, whether up­front radiation ther­apy has any association with patient prognosis.

Thus, the authors of the new study sought to examine up­front radiation treat­ment in multiple myeloma patients, in­­clud­ing patterns of its use, factors asso­ci­ated with its use, and its poten­tial impact on survival.

Study Design And Results

The authors analyzed data from 78,095 multiple myeloma patients whose in­for­ma­tion was reported to the National Cancer Data Base be­tween 2004 and 2015. The median patient age in the study sample was 65 years.

Of the 78,095 patient in­cluded in the analysis, slightly less than one fifth (17 per­cent) received up­front radiation ther­apy. Among the up­front ther­apy patients, 70 per­cent received radiation ther­apy before the start of their drug-based myeloma ther­apy, and 30 per­cent started it within 14 days after the start of the drug-based ther­apy.

Radiation ther­apy was predominantly admin­istered to the spine (59 per­cent) and the hip / pelvis area (12 per­cent).

Factors Affecting The Use Of Upfront Radiation Therapy

The odds of receiving up­front radiation ther­apy were sig­nif­i­cantly higher for younger patients, male patients, white non-Hispanic patients, uninsured patients, patients with lower incomes, patients treated at a com­munity hospital rather than an academic hospital, patients who live close to a hospital, and patients who had few or no health issues ("comorbidities") other than their myeloma.

Being treated at a com­munity hospital (rather than an academic hospital) was the strongest factor asso­ci­ated with up­front radiation ther­apy.

The use of up­front radiation ther­apy also appears to have declined over time. Among patients in the sample from 2004 to 2009, 18.6 per­cent underwent up­front radiation ther­apy. In the patients from 2010 to 2015, in comparison, 16.5 per­cent underwent up­front radiation ther­apy.

The study authors speculate that this decline in the use of up­front radiation ther­apy may be a reflection of physicians becoming more confident over time in the ability of drug-based myeloma ther­a­pies to address bone-related issues.

Upfront Radiation Therapy And Survival

Overall survival among the patients in the sample who underwent up­front radiation ther­apy was 3.6 years versus 4.2 years for the other patients. The three-year over­all survival rate was 55.5 per­cent in the up­front radiation ther­apy group versus 59.7 per­cent in the other patients.

The researchers also explored the poten­tial sig­nif­i­cance of the timing of up­front radiation ther­apy. They found that survival was noticeably lower in the up­front patients who received radiation ther­apy within 14 days after the start of their drug-based ther­apy, com­pared to the survival seen in the up­front patients who received their radiation ther­apy prior to the start of their drug-based ther­apy.

The authors also checked whether they still could find an association be­tween up­front radiation ther­apy and survival when they looked only at patients who survived at least a year after diag­nosis, and also when they looked only at patients who underwent a stem cell trans­plant.

In both these smaller samples of patients, the researchers con­tinued to find an association be­tween up­front radiation ther­apy and survival.

To the authors, this speaks in favor of the association be­tween early radiation ther­apy and over­all survival being due to patients with more aggressive myeloma being more likely to need early radiation ther­apy.

For more in­for­ma­tion, please see to the study by Orcutt, X. et al., “Prognostic sig­nif­i­cance of up­front radiation ther­apy in patients with multiple myeloma,” in The American Journal of Hematology, April 21, 2019 (full text).