The Beacon is pleased to introduce our newest myeloma thought leader col­um­nist, Dr. Ravi Vij. Every three months, Dr. Vij will share with us a new edition of “The Myeloma Quiz,” which will test your knowledge and under­standing of the myeloma-related research published during the pre­vi­ous several months.

We hope you will join us in welcoming Dr. Vij to the Beacon community, and in thank­ing him for sharing with us his valuable perspectives.

The relentless grind in the battle against myeloma continues. The last several months have seen some major presentations and publications in the arena.

With the deluge of information, it is often difficult to choose what to high­light. However the chatter among my colleagues has certainly brought out some themes.

The MM-020 study, one of the largest randomized trials done to date in myeloma, was highlighted at the plenary session of the American Society of Hematology (ASH) meeting in December 2013. Two large next generation sequencing efforts were published in major scientific journals. We saw the first two publications on a new assay for minimal residual disease. Also, the MM-002 and MM-003 studies that led to the approval of Pomalyst ^[1] (pomalidomide, Imnovid) for multiple myeloma in the United States and Europe, respectively, were published.

There is no better way to ensure that one has grasped and assigned to permanent memory the basic messages from these studies than to ace a short quiz. The patients who read the Myeloma Beacon are among the most informed about their disease and I am sure will breeze through it.

So here goes.

1. The FIRST (MM-020) study presented at the American Society of Hematology annual meeting in December 2013 showed all of the following about patients with newly diagnosed myeloma ineligible for stem cell transplantation except:
1. Patients getting continuous Revlimid ^[2] (lenalidomide) and dexamethasone ^[3] (Decadron) took longer to progress than those getting Revlimid and dexamethasone for 18 months only
2. Patients getting continuous Revlimid and dexamethasone took longer to progress than those getting melphalan ^[4] (Alkeran), prednisone, and thalidomide ^[5] (Thalomid) for 18 months only
3. Patients getting continuous Revlimid and dexamethasone lived longer than those getting Revlimid and dexamethasone for 18 months only
4. Patients getting continuous Revlimid and dexamethasone lived longer than those getting melphalan, prednisone, and thalidomide.

Correct answer: .

The results of the FIRST trial showed that patients who started on the two-drug combination of Revlimid and dexamethasone and received it till disease progression had a longer time to disease recurrence, compared to patients treated with Revlimid and dexamethasone or melphalan, prednisone, and thalidomide for a fixed period of 18 months.

The trial also showed that patients who started on Revlimid and dexamethasone and received the drugs till disease progression lived longer than patients treated with melphalan, prednisone, and thalidomide for a fixed period of 18 months.

The results did not show that patients who started on Revlimid and dexamethasone and received the drugs till disease progression lived longer than patients who received Revlimid and dexamethasone for a fixed period of 18 months. However, follow-up on this study is short and a survival advantage between these two treatment arms of the study may emerge with longer follow-up.

This study is likely to have little impact on the care of patients in the United States, where the two-drug com­bi­nation of Revlimid and dexamethasone is already a popular regimen in this patient population. However, this study will hopefully lead to the approval of Revlimid and dexamethasone in Europe and other countries where its use in frontline setting is still restricted.

2. Which of the following statements is true about large genome sequencing efforts to unravel the biology of myeloma?
1. There are a few genes that are recurrently mutated in tumor cells from different patients
2. Each patient’s tumor is characterized by only a few distinct changes
3. All the tumor cells from a patient’s tumor carry the same mutations
4. The tumor cells of a single patient are made of a mixture of cells with different mutations, and each patient has multiple distinct mutations.

Correct answer: .

The revolution in gene sequencing technology is starting to unravel the genetic make-up of cancers. Find­ings for several gene sequencing efforts in myeloma have also been reported recently.

In contrast to the findings in patients with blood cancers such as some acute leukemias, where it has been found that patients’ tumors share a limited number of recurrent mutations, the tumor cells in myeloma have hundreds of mutations, with few being commonly shared by tumors from different individuals. In this regard, the tumor cells from myeloma resemble more those from patients with solid tumors, such as lung and breast cancer.

However, a common theme that seems to be emerging is that the tumor cells in myeloma, like in other can­cers, are made up of a mixture of cells carrying different mutations, and that at various points in the disease course, the proportion of these various cell populations in the tumor flows like tides, as certain cells respond to a given treatment and others start growing.

Perhaps one day this technology can help us study in real-time the genetic make-up of the tumor and tailor our therapies to the predominant cell population.

3. What is true about minimal residual disease (MRD) testing in patients with myeloma?
1. New techniques are able to detect one residual myeloma cell in a million normal cells
2. MRD testing is routinely done after completion of therapy in all patients being treated for myeloma
3. MRD is the goal for therapy in patients with myeloma
4. There are now well accepted guidelines about how to test for MRD.

Correct answer: .

As our ability to treat patients with multiple myeloma becomes more effective with modern therapies, we con­tinue to raise the bar by aiming to eradicate more of the disease in an attempt to achieve better out­comes for patients.

New techniques based on modern “deep sequencing” technology now allow us to test one residual mye­lo­ma cancer cell among a million normal cells. Though it seems rational to assume eradicating the disease to levels where we cannot detect cancer cells even at this low level will lead to better long-term outcomes, this still needs to be conclusively proven in clinical trials. Currently such testing is done mainly for research purpose.

In addition to sequencing-based tests, there are a variety of multicolor flow cytometry-based assays that are being studied. There is currently still no uniform consensus on the definition of MRD.

4. Which of the following statements is true about Pomalyst?
1. It does not work for patients whose disease is refractory (resistant) to Revlimid
2. It does not work for those whose disease is refractory to both Revlimid and Velcade ^[6] (bortezomib)
3. It can be given without dose reduction even in patients on dialysis due to impaired kidney function
4. Rare cases of lung toxicity have been described.

Correct answer: .

Pomalyst is a welcome addition to our armamentarium of drugs for patients with multiple myeloma. Though structurally similar to Revlimid, the drug, when combined with dexamethasone, produces responses in about 30 percent of patients whose disease is refractory to Revlimid. It seems to work equally well in patients whose disease is refractory to both Velcade and Revlimid, giving these patients an active treatment option.

However, dosing in patients with severe kidney problems requires further study, as the trial that led to the drug’s approval excluded patients with serum creatinine levels of more than 3mg/dl. Trials looking at its dosing in patients with higher levels of kidney malfunction are currently ongoing.

Rare reports of “interstitial pneumonitis,” a serious lung toxicity, have been described.

Dr. Ravi Vij is an associate professor of medicine at the Washington University School of Medicine in St. Louis. Dr. Vij has clinical expertise in the management of hematologic malignancies and stem cell trans­plan­ta­tion. He has a special research interest in multiple myeloma and has been involved in de­vel­op­ment of novel therapies for the disease. He also works closely with basic science researchers engaged in cancer genomics to help translate the findings to the clinical management of patients with myeloma.

References

Facon, T, et al., “Initial Phase 3 results of the FIRST (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT),” ASH 2013 Annual Meeting Abstract 2 (abstract ^[7]) (related Beacon ^[8] news)

Melchor, L, et al., “Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma,” Leukemia, Jan 13, 2014 doi: 10.1038/leu.2014.13 (Epub ahead of print) (abstract ^[9])

Lohr, J.G., et al., “Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy,” Cancer Cell, Jan 13, 2014 25(1):91-101 (full text ^[10])

Martinez-Lopez, J., et al., “Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma,” Blood, Mar 19, 2014 (Epub ahead of print) (full text pdf ^[11]) (related Beacon ^[12] news)

Vij, R., et al., “Deep sequencing reveals myeloma cells in peripheral blood in majority of multiple myeloma patients,” Clinical Lymphoma Myeloma and Leukemia, Apr 2014 14(2):131-139.e1 (abstract ^[13])

Richardson, PG, et al., “Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study,” Blood, Mar 20, 2014 123(12):1826-32 (full text pdf ^[14]) (related Beacon ^[15] news about earlier presentation of trial results)

San Miguel, J, et al., “Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial,” The Lancet Oncology, Oct 14, 2013 (11):1055-66 (abstract ^[16]) (related Beacon ^[17] news).