Wolf Emphasizes the Importance of Phrasing in Multiple Myeloma

Jeffrey Wolf, MD

In the last few years, many physicians in the oncology space have shortened the name multiple myeloma to myeloma. While this may have been purely for convenience reasons, Jeffrey Wolf, MD, insists that the full name should be reinstated in casual conversation, as it represents the fact that myeloma is not 1 disease, but multiple diseases.

In a lecture during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma and Myeloproliferative Neoplasms, Wolf, clinical professor, Department of Medicine, and director, Multiple Myeloma Program, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, emphasized the importance of identifying risk when diagnosing patients with multiple myeloma.

“I decided it was time that we started calling it multiple myeloma again, the reason being that we are recognizing, more and more, that this disease does have many phenotypes,” said Wolf. “Some patients present with bone lesions, some present with renal failure, and some just present with elevated proteins or light chains. [Additionally] some present with a lot of disease in their marrow and nothing in their bones, or a lot of disease in their bones and nothing in their bone marrow.”

Wolf explained that this is not a homogenous population, as there are many subclones. This is widely known by physicians, as disease recurrence in patients with multiple myeloma is often through drug resistance, signifying there may be a new subclone present.

In 2002, the International Staging System (ISS) was established based on beta2-microglobulin and albumin. The introduction of the ISS was important because it helped identify who would do well and who would do poorly, said Wolf. Patients with a beta2-microglobulin level over 5.5 were stage III; those with a normal albumin were stage I. When the ISS was established, patients with stage I disease had an overall survival (OS) of approximately 5 years, those with stage II had a 4-year OS, and those with stage III disease had about a 2-year OS.

Wolf says that it is important to stage patients so that phase III trials are conducted more successfully. Knowing a patient’s stage may indicate how they will respond to a particular treatment.

“We are discovering different mutations in each of these diseases, and it is becoming more and more important because we are finding drugs that are particularly good for those mutations,” said Wolf. “We now know that not all [patients with multiple myeloma] are the same, and we recognize that we can use mutational analysis.”

The most common mutations found in patients with high-risk myeloma are t(4;14) and 17p deletion. Interphase fluorescence in situ hybridization (iFISH) is used to identify this high-risk population. Wolf says that clinicians need to look for 17p deletion in all patients when the first bone marrow biopsy is taken from them upon presentation. As the disease mutates and the patient relapses, Wolf says that it is a good idea to look for 17p deletion again, as new mutations will show up as others disappear.

The revised ISS that was published in 2015 identified that an elevated log lactate dehydrogenase plus an evaluated beta2-microglobulin classifies the patient as stage III. Three different alterations—17p deletion, t(4;14), or t(14;16)— combined with an evaluated beta2-microglobulin more than 5.5 will place the patient at stage III.

“The new curves look particularly better than the old curves. Stage I patients haven’t even reached a median OS, while stage III patients are now living perhaps 4 years, but that is because of all of the new drugs,” said Wolf. He also emphasized the importance of looking at iFISH in the initial bone marrow at diagnosis.

Another way to identify high-risk patients is through gene expression profiling. There are a number of signatures out there to do this, such as SKY92. This stratifies patients who have standard-risk multiple myeloma from those who are high risk. It is expensive and not yet approved in the United States, but Wolfsaid that it may soon be used in conjunction with iFISH.

Targeted therapies, particularly venetoclax (Venclexta), have been shown to be effective against mutations in myeloma. In a study of the efficacy of venetoclax as targeted therapy for patients with relapsed/refractory multiple myeloma, patients with t(11;14) did particularly well with venetoclax therapy compared with patients who did not have t(11;14). Overall, 21% of patients achieved objective responses to single-agent venetoclax at the time of data cutoff. The objective response rate (ORR) increased to 40% in the subgroup of patients with t(11;14) chromosomal translocation.1

Soon after these single-agent results with venetoclax, a study of venetoclax in combination with bortezomib (Velcade) and dexamethasone in patients with RRMM was published.2 The addition of bortezomib increased levels of BCL-2 and decreased levels of MCL1, both proteins, Wolf said. This resulted in a 68% ORR to the triplet in all patients; those who were not refractory to bortezomib showed a response rate of 89%, and those who were naïve to bortezomib had a 100% ORR.

“We are having particularly good responses with venetoclax and bortezomib these days,” said Wolf. “I believe that [venetoclax] is going to move forward, especially in patients who have t(11;14).” The addition of venetoclax to bortezomib and dexamethasone did not appear to add toxicity and was well tolerated. The antitumor activity observed with this novel combination targeting both BCL-2 and MCL1 supports the ongoing phase III trial with this regimen in patients with relapsed/refractpru disease, Wolf said.

“The final point of this study is that patients who had 1 to 3 prior lines of therapy, were not refractory to bortezomib, and got the triplet had a 97% response rate, which is as good as almost any other combination available,” said Wolf.

Wolf concluded by emphasizing the importance of distinguishing high-risk from standard-risk disease using the revised ISS and conducting iFISH on all patients at the time of diagnosis and time of relapse. Additionally, he advised that most relapses will occur from unknown subclones, and new drugs will need to be introduced into the treatment paradigm.

References

1. Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. In: Proceedings from the 2016 ASH Annual Meeting & Exposition; December 3-6, 2016; San Diego, California. Abstract 488.
2. Moreau P, Chanan-Khan AA, Roberts AW, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. In: Proceedings from the 2016 ASG Annual Meeting & Exposition; December 3-6, 2016; San Diego, California. Abstract 975.