Myeloma Study Makes the Case for a New Standard for Predicting Long-Term Outcome


  • Researchers propose using a less-than-one-in-a-million level—or the absence of minimal residual disease (MRD)—as a new standard.
  • According to the study, MRD status can be used to evaluate patients’ response to therapy at all stages of treatment.

As new treatments for multiple myeloma have extended patient survival—from an average of three years to more than 10 in some cases—physicians and researchers face a new challenge: how to predict a drug’s long-term effectiveness? How to tell, early on, whether one drug is likely to extend patients’ lives more than another?

At Dana-Farber’s Jerome Lipper Multiple Myeloma Center, researchers have identified one such sign. In a study published in the journal Blood, investigators found that, after treatment, patients with no myeloma cells within 1 million bone marrow cells were more likely to have a lengthy remission than those with higher myeloma cell counts. They propose that the less-than-one-in-a-million level—formally known as an absence of “minimal residual disease” (MRD)—be adopted as the new standard for managing myeloma and evaluating myeloma drugs.

Nikhil Munshi, MD.
Nikhil Munshi, MD.

“The success of new agents in extending the lives of patients with multiple myeloma has created the need to identify biomarkers of drugs’ effectiveness,” says study senior author Nikhil Munshi, MD, director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center. “Our findings show that MRD status can be such a biomarker—not only in clinical trials of potential new therapies but inpatients treated with standard therapies. It has the potential to change the practice of myeloma treatment.”

The traditional criterion of myeloma drugs’ effectiveness is whether they generate a complete response, defined as an absence of any myeloma cells within 100 bone marrow cells. Even at such low concentrations, however, myeloma is rarely vanquished: Virtually all patients who achieve a complete response eventually relapse, Munshi notes.

With the development of next-generation DNA sequencing, it has become possible to detect myeloma cells at a much deeper level. This September, in fact, the U.S. Food and Drug Administration (FDA) authorized the first test based on next-generation sequencing to detect very low levels of cancer cells in patients with myeloma or acute lymphoblastic leukemia.


Researchers propose that the less-than-one-in-a-million levelformally known as an absence of “minimal residual disease” (MRD)be adopted as the new standard for managing myeloma and evaluating myeloma drugs.


MRD status versus complete response

The study explored whether MRD status is a better predictor of a long-lasting remission than complete response is. Data for the investigation came from a collaborative study between Dana-Farber and the French Myeloma Group that enrolled 700 patients with multiple myeloma between 2010 and 2012. Patients received either a standard chemotherapy regimen or a shorter, more intense round of chemotherapy followed by a transplant of their own stem cells. Bone marrow samples were collected from all patients at the beginning and end of maintenance therapy—a 12-month period of follow-up treatment intended to prevent or delay the cancer’s return – and were analyzed for MRD.

The analysis showed that 127 of the patients were MRD-negative (had no minimal residual disease) at least once during their maintenance therapy. Researchers found that patients who were MRD-negative were likely to survive for a much longer time before the disease worsened than were patients with the presence of MRD. The overall survival of MRD-negative patients—the percent alive more than two years after finishing maintenance therapy—was far higher, as well.

“We showed that when patients have deep responses to therapy, they have much better outcomes: they relapse later and live longer,” Munshi comments. “The effect is so great, that patients with high-risk myeloma who achieve MRD negativity have essentially the same rate of relapse as patients with standard-risk myeloma.”

MRD status can be used to evaluate patients’ response to therapy at all stages of treatment, he continues—prior to a stem cell transplant (to judge the effectiveness of pre-transplant chemotherapy); after transplant (to gauge the success of the transplant); and during and after maintenance therapy.

“MRD is one of the most promising biomarkers identified to date and has long been used in patients with lymphoma and chronic myelogenous leukemia, Munshi observes. “It will now inform our therapy in myeloma with the eventual goal of achieving MRD-negative status.”

Multiple Myeloma


For me, the top story for multiple myeloma in 2018, is venetoclax. Venetoclax represents the culmination of efforts to develop a therapeutic agent tailored to work in certain genetic subtypes of the disease. How did we get here? How can this development be the most important one for 2018, when everyone is talking about CAR T-cell therapies and bispecific antibodies? How can this development be so important given that we have the results of phase III trials showing improvement in disease control with daratumumab-based combinations? How could this be the story of the year when we have the possible addition of new drugs such as selinexor? The answer is simple. This is the first time that a truly targeted therapeutic has been developed for multiple myeloma. Let me explain.

Myeloma has been, for several years, one of the best understood tumors when it comes down to disease biology and genetic changes. Description of the major subtypes of the disease and secondary genetic changes dates back now close to 15 years. Although we have had important refinements to this knowledge framework, the basic genetic groups are the same. The addition of novel tools, such as gene-expression profiling and mutation analysis with next-generation sequencing, has increased the depth of our understanding of the genetic nature of the disease. Myeloma is divided into two broad subgroups, the hyperdiploid and the non-hyperdiploid variants.

One of the hallmarks of myeloma is that the non-hyperdiploid variant is enriched for chromosome translocations involving the immunoglobulin heavy-chain locus. Although the translocation t(11;14) could be detected through cytogenetic analysis, it was not until molecular genetic studies performed by Bergsagel, Kuehl, and Chesi identified the presence of the translocations t(4;14) and t(14;16). Despite having this detailed knowledge of the disease, genetics had been predominantly used to stratify patients into risk categories and to propose different treatment pathways. However, none of these treatments has directly targeted the consequence of genetic aberrations. Previous efforts to target the FGFR3 gene, associated with t(4;14), have failed. Genetic understanding did not provide to myeloma the opportunity that was fully realized in chronic myelogenous leukemia.

Nevertheless, genetics in myeloma did help with a better understanding of the prognostic categories of disease. This has allowed for a more tailored conversation with patients regarding the likelihood of better outcomes. Furthermore, the knowledge about high-risk genetic features changed the paradigm upon which we recommend maintenance therapy in the post–stem cell transplant setting. Knowing that patients with high-risk genetic features derive greater benefit from the use of proteasome inhibitors became important practical knowledge. Arguably, the natural history of patients with t(4;14) was changed because of the addition of bortezomib to treatment. At the same time, great strides were made in the fight against multiple myeloma by the incorporation of medications that target “normal plasma cell differentiation” and protein metabolism. The introduction of proteasome inhibitors and IMIDs, followed by the introduction of monoclonal antibodies, greatly improved the survival for myeloma patients. Nevertheless, genetics have not augmented our treatment armamentarium. However, that will change with venetoclax!

Although there is still significant room for a better understanding of the mechanism of action of venetoclax in multiple myeloma, it is now very clear that this drug seems particularly effective for patients with the translocation t(11;14). Even if better biomarkers are developed for the selection of the right patients, venetoclax provides options for patients with this translocation and for whom no treatments have been available. We are all hoping that venetoclax will be approved by the FDA soon. Patients have been treated with venetoclax, often in combination with steroids or with proteasome inhibitors, off-label when no further treatment options were available to them. Several clinical trials have now demonstrated a very high rate of response to combination strategies that use venetoclax, particularly in patients with t(11;14). We have seen patients who have been heavily pretreated and who have achieved a complete response with venetoclax and dexamethasone alone.

The obvious corollary questions are as follows. Should venetoclax be used as maintenance therapy in patients who have the translocation t(11;14)? What is the role of venetoclax in patients who have light-chain amyloidosis (50% have this translocation) and in patients with primary plasma cell leukemia (50% also have this translocation)? Should venetoclax be used earlier in the course of the disease in patients with this genetic abnormality as a part of combination strategies? If venetoclax can treat effectively the 15% of patients with this genetic abnormality, what about MCL-1 inhibitors?

Recent data from the Mayo Clinic has shown that, although survival for most myeloma patients has improved over the past 15 years, these improvements have lagged among patients with the translocation t(11;14). Perhaps this has been because t(11;14) plasma tends to be more lymphoid and their cytoplasm contains fewer proteins. Accordingly, the protein stress associated with the use of proteasome inhibitors and IMIDs is lessened in patients with t(11;14).

CAR T-Cell Therapy Shows Durable Activity in Heavily Pretreated Multiple Myeloma


B-cell maturation antigen most promising myeloma target for CAR T-cell therapy

Immunotherapies are becoming the next-generation therapies for multiple myeloma.

The immune microenvironment is immunosuppressive, which makes this disease susceptible to cellular therapy with chimeric antigen receptor (CAR) T-cell therapy. CD-19 targeted CAR T-cell therapy has shown activity in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The most promising target in multiple myeloma is B-cell maturation antigen (BCMA).

“BCMA is a good target because it is expressed on normal and malignant plasma cells and promotes multiple myeloma cell survival,” said Adam D. Cohen, MD, director of myeloma immunotherapy at the University of Pennsylvania Abramson Cancer Center in Philadelphia.

In a presentation at the American Society of Hematology annual meeting, he explained that BCMA-targeted therapies, including CAR T cells, show preclinical and early clinical activity in myeloma. The BCMA CAR T-cell trial he reported divided multiple myeloma patients into three cohorts, including CAR alone with no lymphodepletion, with cyclophosphamide first, and with lower and higher doses of CAR cells. The patients had a median of seven prior lines of therapy, and almost all (95%) had high-risk genetics.

At the time of the analysis, 24 patients, mean age of 58, had been treated (nine in cohort 1, five in cohort 2, and 10 in cohort 3). All have successfully manufactured at least minimum target dose.

A total of 11 of 24 patients (46%) achieved an objective response, and median duration of response is 4 months. Two patients had a complete response (CR) — one in cohort 1 for 24 months, and one in cohort 3 for 6 months.

Toxicities remain cytokine release syndrome (CRS) in six patients and neurotoxicity in six, but there was no increased toxicity with cyclophosphamide, Cohen reported.

“CAR T-BCMA has activity in heavily pretreated multiple myeloma. Lymphodepletion is not required for robust expansion and response. Cyclophosphamide may increase the frequency of patients with strong expansion.”

Two other multicenter trials of CAR T-cell therapy in multiple myeloma also show durable responses, with some approaching 1 year, he noted.

At the 2017 American Society of Clinical Oncology annual meeting, Chinese researchers presented the results of treatment with a novel, proprietary CAR T-cell product, LCAR-B38M, targeting BCMA. All 19 patients with relapsed/refractory multiple myeloma responded, and 14 of 19 (74%) followed for a median of 4 months achieved a stringent CR and have not recurred. The majority (14 patients) experienced mild or manageable CRS, and five patients were even free of diagnosable CRS.

In another presentation at ASH17, durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma were reported with bb2121 anti-BCMA CAR T-cell therapy.

BB2121 is a second-generation CAR construct targeting BCMA, consisting of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB co-stimulatory motif to promote proliferation and persistence, and a CD3-zeta T cell activation domain.

The phase I study, conducted at nine sites in the United States, is the first U.S.-based multicenter study of a CAR T-cell therapy engineered to target BCMA. The study included 21 evaluable patients, median age of 58, who were enrolled in the dose-escalation phase. All had relapsed/refractory disease after a median of seven prior treatments, including a stem cell transplant. The patients had received three or more prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or were double-refractory, and had at least 50% BCMA expression on malignant cells.

A one-time infusion of this investigational CAR T-cell therapy elicited an 86% overall response rate. Among 18 patients who received higher, active doses of infused CAR T cells, the response rate increased to 94%, with manageable adverse effects, reported researchers led by James Kochenderfer, MD, of the National Cancer Institute’s Center for Cancer Research.

Among these 18 patients, 10 (56%) had a CR, and nine of 10 evaluated for minimal residual disease (MRD) using sensitive genetic tests achieved an MRD-negative response. After a median follow-up of 40 weeks, the median progression-free survival had not been reached; four patients have progressed.

The duration of ongoing response is more than 1 year with no additional myeloma therapy, the researchers reported, noting that responses deepened over time — PFS at 6 months was 81% and at 9 months, 71% — and responses continued to improve as late as month 15, from a very good partial response to CR.

The CAR T-cell therapy was generally well-tolerated, and no dose-limiting toxicities were observed in dose escalation, the team noted. Cytopenias were mostly related to cyclophosphamide/fludarabine lymphodepletion. Patients recovered to less than Grade 3 cytopenias by month 2.

Five patients died, three due to disease progression. Two patients were being treated at active doses in CR at the time of death. Fourteen patients had one or more serious adverse events. Four patients had CRS grade 1-2 that required hospitalization, and two patients developed pyrexia.

Kochenderfer et al said they believe that specific targeting with this CAR T-cell therapy is safe and a logical way to attack multiple myeloma.

Cohen summed up: “BCMA is the most promising target for immunotherapy in multiple myeloma. CAR T-cell therapy leads to high response rates. We are in the early days for CAR T-cell therapy for multiple myeloma, but the future is bright.”

Still, he added, many questions and challenges remain, including determining optimal patient populations, how to manage toxicities, and assessing sequencing or combining immunotherapies with current therapies.

Popular “Diet” Ingredient Now Linked to Leukemia and Lymphoma in New Landmark Study on Humans


As few as one diet soda daily may increase the risk for leukemia in men and women, and for multiple myeloma and non-Hodgkin lymphoma in men, according to new results from the longest-ever running study on aspartame as a carcinogen in humans. Importantly, this is the most comprehensive, long-term study ever completed on this topic, so it holds more weight than other past studies which appeared to show no risk. And disturbingly, it may also open the door for further similar findings on other cancers in future studies.

aspartameee

 The most thorough study yet on aspartame – Over two million person-years

For this study, researchers prospectively analyzed data from the Nurses’ Health Study and the Health Professionals Follow-Up Study for a 22-year period. A total of 77,218 women and 47,810 men were included in the analysis, for a total of 2,278,396 person-years of data. Apart from sheer size, what makes this study superior to other past studies is the thoroughness with which aspartame intake was assessed. Every two years, participants were given a detailed dietary questionnaire, and their diets were reassessed every four years. Previous studies which found no link to cancer only ever assessed participants’ aspartame intake at one point in time, which could be a major weakness affecting their accuracy.

 

One diet soda a day increases leukemia, multiple myeloma and non-Hodgkin lymphomas

The combined results of this new study showed that just one 12-fl oz. can (355 ml) of diet soda daily leads to:

– 42 percent higher leukemia risk in men and women (pooled analysis)
– 102 percent higher multiple myeloma risk (in men only)
– 31 percent higher non-Hodgkin lymphoma risk (in men only)

These results were based on multi-variable relative risk models, all in comparison to participants who drank no diet soda. It is unknown why only men drinking higher amounts of diet soda showed increased risk for multiple myeloma and non-Hodgkin lymphoma. Note that diet soda is the largest dietary source of aspartame (by far) in the U.S. Every year, Americans consume about 5,250 tons of aspartame in total, of which about 86 percent (4,500 tons) is found in diet sodas.

Confirmation of previous high quality research on animals

This new study shows the importance of the quality of research. Most of the past studies showing no link between aspartame and cancer have been criticized for being too short in duration and too inaccurate in assessing long-term aspartame intake. This new study solves both of those issues. The fact that it also shows a positive link to cancer should come as no surprise, because a previous best-in-class research study done on animals (900 rats over their entire natural lifetimes) showed strikingly similar results back in 2006: aspartame significantly increased the risk for lymphomas and leukemia in both males and females. More worrying is the follow on mega-study, which started aspartame exposure of the rats at the fetal stage. Increased lymphoma and leukemia risks were confirmed, and this time the female rats also showed significantly increased breast (mammary) cancer rates. This raises a critical question: will future, high-quality studies uncover links to the other cancers in which aspartame has been implicated (brain, breast, prostate, etc.)?

There is now more reason than ever to completely avoid aspartame in our daily diet. For those who are tempted to go back to sugary sodas as a “healthy” alternative, this study had a surprise finding: men consuming one or more sugar-sweetened sodas daily saw a 66 percent increase in non-Hodgkin lymphoma (even worse than for diet soda). Perhaps the healthiest soda is no soda at all.

Three drug combo slows progression of multiple myeloma


An interim analysis from the multinational phase III CASTOR trial, presented recently at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that adding daratumumab to the standard two-drug regimen of bortezomib and dexamethasone (Vd) markedly improved outcomes of patients with recurrent or refractory multiple myeloma (RRMM). [ASCO 2016, abstract LBA4]

“Daratumumab is a human CD38 selective monoclonal antibody with direct and indirect anti-myeloma activity that has been approved in the US and Europe for RRMM. It depletes CD38+ immunosuppressive regulatory cells and promotes expansion of cytotoxic and helper T cells,” said lead author Dr. Antonio Palumbo from the University of Torino, in Torino, Italy. “We’ve suspected for a long time that CD38 is the major treatment target for multiple myeloma, but these results are unprecedented in this cancer.”

CASTOR was a multicentre open-label trial that randomized RRMM patients who had received one or more prior lines of therapy to receive daratumumab plus bortezomib and dexamethasone (DVd; n=251) or Vd (n=247) for 8 cycles, followed by daratumumab maintenance in the DVd arm. Baseline demographics and disease characteristics were well balanced between study arms. The primary endpoint was progression-free survival (PFS), with secondary endpoints for response rates, overall survival (OS), time to response and duration of response.

“At a median follow-up of 7.4 months, daratumumab significantly improved PFS, with an unprecedented 61 percent reduction in the risk of progression [p<0.0001]. Median PFS was 7.2 months in the standard treatment arm and not yet reached in the experimental arm,” reported Palumbo. “The estimated 1-year PFS was doubled from 26.9 percent with the standard regimen to 60.7 percent with the addition of daratumumab.”

The PFS benefits of daratumumab were consistent in all patient subgroups regardless of age, disease stage, prior stem cell transplantation or type of prior therapy. “According to the subgroup analysis, patients who had had only one prior line of therapy benefited the most, suggesting that early intervention can maximize the benefit of DVd,” Palumbo emphasized.

Response rates were also significantly improved with daratumumab, including overall response (83 vs 63 percent with Vd, p<0.0001), very good partial response (59 vs 29 percent, p<0.0001) and complete response (19 vs 9 percent, p=0.0012). Time to response was relatively shorter in the DVd arm than in the Vd arm, with about 80 percent of the patients on daratumumab achieving partial response at 1 month.

”Importantly, adding daratumumab does not substantially increase toxicity. The rates of common adverse events such as thrombocytopenia, anaemia, and neutropenia, were only slightly higher in the daratumumab arm,” remarked Palumbo. “Given the encouraging results, this three drug regimen with daratumumab can potentially be considered a new standard of care for RRMM patients.”

A longer follow-up of CASTOR will help to determine the impact of adding daratumumab on patient OS. Ongoing trials are also evaluating daratumumab in combination with another standard therapy for RRMM and testing various daratumumab-based regimens in newly diagnosed multiple myeloma.

Aplidin® Improves Progression-Free Survival in Multiple Myeloma


The addition of the investigative agent Aplidin® (plitidepsin) to dexamethasone appears to significantly reduce the risk of cancer progression or death compared to dexamethasone alone among patients with multiple myeloma that has progressed following prior therapies.

Multiple myeloma is a type of blood cancer that affects certain immune cells called plasma cells. Healthy plasma cells produce proteins called antibodies that are an important part of the immune system’s defense for fighting bacteria and viruses.

Cancerous plasma cells tend to replicate at a fast pace, crowding out other healthy immune cells, as well as producing malfunctioning antibodies. These antibodies tend to cause damage to the kidneys, in addition to reducing the immune system’s ability to efficiently fight infection.

Researchers continue to evaluate novel treatment options for multiple myeloma, particularly among patients whose disease has progressed or returned despite prior therapies (referred to as recurrent or refractory disease). Novel therapeutic agents that do not tend to create the severity of side effects associated with chemotherapy continue to be developed for the treatment of various types of cancers, including multiple myeloma. Studies are ongoing to explore optimal combinations and sequences of regimens containing these novel compounds.

Plitidepsin, originally derived from the marine animal ascidian Aplidium albicans, is the first agent in a class that targets a protein referred to as eEF1A2. This particular protein enhances a cancer cell’s ability to replicate and spread. By specifically targeting eEF1A2, plitidepsin reduces the effects of eEF1A2 and therefore, decreases cancer growth caused by the protein.

The recent clinical trial evaluating plitidepsin in multiple myeloma was an international phase III clinical trial referred to as ADMYRE. This trial included 255 patients in 82 medical centers across 19 countries. Patients had multiple myeloma that had progressed or returned following at least 3, but less than 6, prior therapies.

Patients in this trial were divided into two groups: one group was treated with plitidepsin plus dexamethasone, and a second group was treated with dexamethasone only (a standard treatment approach for multiple myeloma). Results from the two groups were directly compared.

  • Overall, patients who were treated with the combination of plitidepsin and dexamethasone experienced a 35% reduction in the risk of cancer progression or death, compared to those who were treated with dexamethasone only.

These results demonstrate a significant improvement with the addition of plitidepsin to dexamethasone among patients with relapsed or refractory multiple myeloma. More detailed data and results of this trial will be submitted for presentation at an upcoming medical conference.

Reference: PharmaMar. Press release March 31, 2016. Aplidin® shows positive results in pivotal Phase III clinical trial for multiple myeloma. Available at: https://www.pharmamar.com/2016/03/31/aplidin-shows-positive-results-in-pivotal-phase-iii-clinical-trial-for-multiple-myeloma/. Accessed April 14, 2016.

Daratumumab Combo: New Standard of Care in Multiple Myeloma


A three-drug regimen that includes the novel agent daratumumab (Darzalex, Janssen Biotech) was declared a new standard of care in relapsed multiple myeloma after a presentation during the plenary session here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

This is “one of the most exciting presentations of the entire meeting,” said Richard Schilsky, MD, ASCO chief medical officer and former chief of the section of hematology–oncology at the University of Chicago.

 The presentation revealed initial findings from the pivotal phase 3 CASTOR trial of 498 patients with relapsed or refractory multiple myeloma who were randomized to receive daratumumab added to a regimen of bortezomib (Velcade, Millennium) plus dexamethasone or a two-drug regimen of bortezomib plus dexamethasone.

Data from this trial were released early after the primary end point of progression-free survival was met at the interim analysis (median follow-up, 7.4 months).

The median progression-free survival was not reached in the three-drug daratumumab group, although it was in the two-drug group (not reached vs 7.16 months; hazard ratio [HR], 0.39; P < .001).

Dr Antonio Palumbo

This hazard ratio of 0.39 is “unprecedented in randomized studies that compare novel treatments in refractory multiple myeloma,” said lead study author Antonio Palumbo, MD, chief of the myeloma unit at the Department of Oncology, University of Torino, in Italy.

“This translated to a 61% reduction in the risk of progression or death,” he reported.

In addition, response rates doubled with the addition of daratumumab. For very good partial response, the rate in the three-drug group was 59% and in the two-drug group was 29%. For complete response, rates were 19% and 9%, respectively.

“Daratumumab plus bortezomib and dexamethasone should be considered a new standard of care for relapsed or refractory multiple myeloma patients currently receiving bortezomib/dexamethasone alone,” Dr Palumbo said.

“The three-drug regimen with daratumumab significantly improved progression-free survival and the overall response rate, and this benefit was maintained across clinically relevant subgroups,” he noted.

This is one of the most exciting presentations of the entire meeting.

This will become the new standard of care, said Paul Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, in Boston.

“It will become a new standard of care once approvals are through, and both CASTOR and the POLLUX study are game changers in my view,” he told Medscape Medical News.

However, another expert is a little more cautious.

“The results were very impressive when comparing daratumumab, bortezomib, dexamethasone with bortezomib and dexamethasone for relapsed/refractory multiple myeloma,” said Philip McCarthy, MD, professor of oncology and director of the Blood and Marrow Transplant Center, Roswell Park Cancer Institute, in Buffalo, New York.

“However, the daratumumab was continued, whereas the bortezomib dexamethasone arm did not continue any therapy,” he told Medscape Medical News. “We would expect the daratumumab to have continued activity versus no therapy.”

Although these findings are impressive, it would have been better to have some form of continued therapy for the control group. “We look forward to the upfront studies with this drug in combination with an immunomodulatory drug and a proteasome inhibitor,” Dr McCarthy added.

Toxicities were consistent with those previously reported with daratumumab monotherapy and with bortezomib plus dexamethasone.

Adverse events that affected more than 25% of the three- and two-drug groups were thrombocytopenia (59% vs 44%), peripheral sensory neuropathy (47% vs 38%), diarrhea (32% vs 22%), and anemia (26% vs 31%).

Grade 3/4 events that affected more than 10% the of the three- and two-drug groups were thrombocytopenia (45% vs 33%), anemia (14% vs 16%), and neutropenia (13% vs 4%). Discontinuation related to treatment was similar in the three- and two-drug groups (7% vs 9%).

First Antibody for Myeloma

Daratumumab is a human IgG1k monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through apoptosis, as well as through other multiple immune-mediated mechanisms.

It is the first monoclonal antibody to be approved for multiple myeloma by the US Food and Drug Administration). The current indication is for use as a monotherapy in heavily pretreated patients with multiple myeloma.

The CASTOR study shows that daratumumab can be combined with bortezomib and dexamethasone. A similar study, known as POLLUX, has shown that it can be combined with lenalidomide and dexamethasone.

The POLLUX study was unblinded last month and, at the preplanned interim analysis, the primary end point of improved progression-free survival was met. The POLLUX data will be presented during the Presidential Symposium at the annual meeting of the European Hematology Association, to be held in Copenhagen on June 12 (Abstract LB2238), and will be reported at that time by Medscape Medical News.

This is unprecedented in randomized studies that compare novel treatments in refractory multiple myeloma.

A number of other drugs have been approved recently for myeloma, including panobinostat (Farydak, Novartis Pharmaceuticals Corporation), ixazomib (Ninlaro, Takeda Pharmaceutical Company, Ltd.), and elotuzumab (Empliciti, Bristol-Myers Squibb Company).

Replacing Transplants?

Currently, high-dose chemotherapy and autologous stem cell transplantation (ASCT) is still the standard of care for younger, fit patients with multiple myeloma, but this is being called into question as the newer drugs push responses ever higher, Dr Schilsky told Medscape Medical News.

For the time being, however, ASCT remains the standard of care. Another study presented at the meeting showed that up-front transplantation significantly reduced the risk for progression, compared with a bortezomib-based drug regimen.

However, Dr Schilsky said he believes that it is unlikely that those results will settle the wider debate of whether ASCT is needed in the era of novel targeted agents.

“This won’t settle the issue, mostly because there is a whole slew of newer agents that have been introduced since bortezomib that are even more effective. How those drugs compare with a transplant-based regimen remains to be seen,” he said.

Another expert agreed that the field of myeloma treatment is in flux.

In the CASTOR study, it wasn’t “surprising that the three-drug regimen did better, but we will have to wait and see what the progression-free survival is,” said Noopur Raje, MD, associate professor of medicine at Harvard Medical School and director of the Center for Multiple Myeloma at the Massachusetts General Hospital Cancer Center in Boston.

“The P value is quite significant,” Dr Raje said told Medscape Medical News. “We are going to see a difference in progression-free survival, compared with bortezomib. It’s not surprising, as we’ve seen this result with all of the new drug approvals from last year.”

For now, ASCT is here to stay for younger patients who want to go that route. “Younger patients should have that option,” she said. “But this is going to be evolving with new drugs.”

Genetically Engineered T-cells Show Promise in Treating Multiple Myeloma


Genetically-engineered t-cells can cure multiple meyloma

If genetic engineering sounds a little creepy to you, akin to lab-produced glow-in-the-dark worms and mutant humans with superpowers, I know some really cool researchers who might change your mind.

These researchers, led by Dr. Aaron P. Rapoport , the Gary Jobson Professor in Medical Oncology and Director of Gene Medicine/Lymphoma at the University of Maryland in Baltimore, are using genetic engineering to get some pretty impressive results for people suffering with difficult-to-treat multiple myeloma (MM), a type of cancer that starts in bone marrow.

Although about 35 percent of patients benefit from standard treatment, i.e. longer life, less pain and fewer complications, there is virtually no cure for multiple myeoma. Rapoport says standard treatment is effective — at least for a while, but in many MM patients it eventually stops working and there is a recurrence of disease.

Unfortunately, standard treatment is less effective for people with aggressive MM, who realize limited benefits for short intervals. The disease is marked by a high prevalence of infections such as pneumonia, bone pain, hypercalcemia (elevated calcium in the blood), renal failure and spinal cord compression.

That’s where genetic engineering comes in.

Genetic engineering, technically known as recombinant DNA technology, is a fairly new concept that’s increasingly becoming an important tool in treating HIV-AIDS and cancer. Perhaps, in the future, conditions such as hemophilia, Parkinson’s disease, diabetes and a form of inherited high cholesterol (hypercholesterolemia).

Researchers are investigating right now to determine whether or not recombinant DNA technology will slow or cure these diseases.

There are two main ways in which genetic engineering is being used.

In the first, researchers pluck genes from one type of organism, say algae or sheep for example, and combine them with genes from a second organism — like you and me.

We’re not talking science fiction animal-human hybrids here.

These engineered genes can be coaxed to make human hormones such as insulin, or human proteins capable of fighting hard-to-treat hepatitis and the AIDS virus.

The second option is gene therapy. Doctors replace defective or missing genes with normalized genes capable of slowing or stopping the disease progression—and in a best-case scenario, curing them.

In the phase-II clinical trial , Rapoport’s team has engineered T-cells in 13 patients with difficult-to-treat multiple myeloma, or in people with recurrent or high-risk disease.

“Gene therapy is taking the bull by the horns and retraining the cells rather than relying on standard vaccine treatments alone with less response rate,” Rapoport said.

“Four of the patients in the study had previous stem cell transplants without getting results. So while this treatment is still in the early stages, we are feeling encouraged by the outcome.”

Cancers can develop when T-cells — specialized “killer cells” produced by the human immune system — lose their ability to target harmful “invader” cells (in this case, cancer cells) they are designed to seek out and destroy, in keeping the body disease-free.

Rapoport and his team add a new gene to each patient’s T-cells and infuse the immune system with vaccines. The new gene effectively retrains the existing T-cells to recognize a new target present on the myeloma cells and do their job, that is, attacking cancer cells. It also builds an army of new potent T-cells equipped to destroy or neutralize the cancer cells.

Days later, the supercharged genes are injected back into patients. At day 100 after treatment, 10 of the 13 patients in the trial are in remission or very close to it — a 77 per cent response rate — and the others showed drastic reduction in their cancer, Rapoport said. By contrast, standard MM treatment alone gives a response rate of between 33 and 69 percent.

Rapoport said that the clinical trial is still recruiting patients.

Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma


Abstract

Purpose: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell–mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu.

Experimental Design: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138+ multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti–multiple myeloma immune response and tumor cell growth.

Results: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression.

Conclusions: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti–multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy.

Bortezomib- and Thalidomide-Induced Peripheral Neuropathy in Multiple Myeloma


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