Order Matters: The Art and Science of Myeloma Drug Sequencing

Examining the who, what, when, where, and why of myeloma treatment

In 1844, Thomas Alexander Bean, one of the first documented patients with multiple myeloma (MM), underwent a battery of treatments – blood-letting, cupping, and even leeches for “maintenance therapy.” Amazingly, he lived for a few more years before succumbing to his disease in 1846.1

If he had been diagnosed today and was ineligible for hematopoietic cell transplantation (HCT), Mr. Bean would have had a host of promising MM therapies available to him and likely would have survived years longer.

The field of MM has seen a recent expansion in treatment options: In November 2015, the U.S. Food and Drug Administration (FDA) approved the monoclonal antibodies daratumumab and elotuzumab and the proteasome inhibitor ixazomib for patients with previously treated MM. Earlier that year, panobinostat became the first FDA-approved histone deacetylase inhibitor for MM treatment. (See TABLE for a rundown of all available agents indicated for MM treatment and the potential combinations for each.)

But this wealth of treatment options comes with challenges, as clinicians must determine which drugs to use, as well as when to use them and in what order. ASH Clinical News spoke with myeloma specialists about the “best bets” in therapeutic sequencing for transplant-ineligible patients with newly diagnosed and relapsed disease.

When Transplant May Not Be The Best Option

MM is considered a disease of older individuals: The median age at diagnosis is 69 years and one-third of patients are ≥75 years of age – making many MM patients high-risk for HCT. Non-transplant patients tend to be frailer but are no less deserving of the most appropriate treatment course than younger, fitter patients, according to Andrew J. Yee, MD, and Noopur S. Raje, MD, from the Center for Multiple Myeloma at Massachusetts General Hospital in Boston.2

The goal of the initial MM treatment is to choose a regimen to obtain the deepest response possible with the first round of treatment, which could lead to better survival. The amount of patient and treatment factors to take into consideration can quickly complicate that decision. “For clinicians who don’t see many MM cases, sequencing treatments can be challenging,” Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology at Emory University, told ASH Clinical News. “At our center, we see 16,000 patients each year, but there are clinicians who may only see four or five cases each year. In those instances, the huge amount of data on drugs and sequencing can get quite confusing.”

“Treatment sequencing has become a little easier than it was just a few years ago, when we were dealing with incomplete information,” noted S. Vincent Rajkumar, MD, a hematologist-oncologist at the Mayo Clinic in Rochester, Minnesota, and chair of the Eastern Cooperative Oncology Group Myeloma Committee. “We have several high-quality trials that have given us better data, but the number of options can be a bit overwhelming.”

“What we’ve learned in the last few years is that combination therapies are clearly more effective and attack multiple myeloma from multiple fronts. Given that multiple myeloma can often change or morph and is a genetically complicated disease, hitting it with a single drug, or even a doublet, is almost always going to be a suboptimal approach.”

Sagar Lional, MD

A New Diagnosis

Patients with newly diagnosed disease are starting with a clean slate, so to speak. Because they are treatment-naïve, toxicities and adverse events (AEs) from previous treatments do not need to be factored into the treatment equation. Of course, any sequence will need to be tailored based on various patient factors. As such, the International Myeloma Working Group created a geriatric assessment tool based on age, comorbidities, cognitive condition, and physical condition that categorizes patients as “fit,” “intermediate,” or “frail.”3

Recently, triplet therapies have become a standard for this patient population because they lead to a greater proportion of patients achieving complete remission, tolerating treatment longer, and having longer progression-free survival (PFS). However, the intensity of this treatment regimen precludes some patients from receiving it.

Patients with higher performance status scores who are deemed fit or intermediate can tolerate more aggressive therapy. As the number of therapies increases, the performance status tends to decrease, Dr. Lonial noted, but that decline generally happens much later with newer agents.

“Many people think about sequencing [individual drugs] in lieu of combination therapy. What we’ve learned in the last few years is that combination therapies are clearly more effective and attack MM from multiple fronts,” Dr. Lonial said. “Given that MM can often change or morph and is a genetically complicated disease, hitting it with a single drug, or even a doublet, is almost always going to be a suboptimal approach.”

The triplet combination of lenalidomide, bortezomib, and dexamethasone (known as RVD) is the go-to firstline treatment in patients with MM who are not candidates for transplant. Dr. Rajkumar confirmed that, at the Mayo Clinic, most non-transplant patients receive RVD as frontline treatment, usually for one year, and then receive maintenance therapy, most commonly with lenalidomide and dexamethasone.

According to results from the Southwest Oncology Group (SWOG) S0777 trial, fit and intermediate patients who were treated with RVD had a longer median PFS and overall survival (OS), compared with patients treated with lenalidomide and dexamethasone alone (RD; 43 months vs. 30 months and 75 months vs. 64 months, respectively; p=0.018).4

“Previous trials compared a new regimen to an old regimen or compared two newer regimens, but did not show a survival benefit,” Dr. Rajkumar said. “SWOG was the first to compare modern regimens and show that a triplet is better than the doublet combination.”

Unfortunately, frail patients are likely to experience worse OS with RVD than fit patients (57% vs. 84%; p=0.025) and are prone to experience more toxicity. In these cases, Dr. Rajkumar said he opts for the older RD sequence.

For patients who have worse performance status scores, Drs. Yee and Raje recommend an alternative sequence referred to as “RVD-lite,” in which the drugs are administered on a more “user-friendly schedule” that includes an extended treatment cycle, a lower dose of lenalidomide, and a modified bortezomib schedule.5

If at First You Don’t Succeed …

These regimens are not likely to be curative, though, and as a result relapse (or death from MM or other causes) is almost guaranteed for patients with MM.

“A challenge in sequencing myeloma treatment is the diminishing effectiveness of each successive line of treatment, with a shorter period of disease response with [subsequent] therapy,” Drs. Yee and Raje pointed out. “Furthermore, patients who are refractory to newer agents such as lenalidomide and bortezomib have historically had a poor prognosis.”

Dr. Rajkumar agreed that sequencing in these patients can be difficult and outlined a preferred sequence for relapse in an editorial in the New England Journal of Medicine:6

In first relapse among patients who are not refractory to lenalidomide, use a combination of daratumumab, lenalidomide, and low-dose dexamethasone or carfilzomib, lenalidomide, and dexamethasone.

If patients are deemed too frail for these regimens, then ixazomib or elotuzumab could be used in place of daratumumab or carfilzomib (IRD and ERD, respectively).

For those who are refractory to lenalidomide but not frail, try a combination of daratumumab, bortezomib, dexamethasone or bortezomib, cyclophosphamide, and dexamethasone.

For frail patients, pomalidomide and dexamethasone, with or without ixazomib, is another option.

Recent approvals of monoclonal antibodies, including elotuzumab and daratumumab, have broadened the treatment landscape for all patients with myeloma. The toxicities associated with these agents tend to occur early in treatment. In pivotal trials, infusion reactions were the most common treatment-related AEs, and although these events occasionally can be challenging to treat, the safety profile of these drugs appears to be tolerable after the initial exposure.7,8

Immunomodulatory-based sequences, such as carfilzomib, pomalidomide, dexamethasone plus pomalidomide, ixazomib, and dexamethasone are also under investigation.9,10

Finally, what to do for patients who experience a second or even third relapse? Dr. Rajkumar advocates for using any of the sequences that were not tried after first relapse, such as pomalidomide-based sequences, and including daratumumab in the therapy combinations.

Reading Between the Guidelines

Without a definite set of recommendations to guide treatment sequencing, much of the clinical decision-making comes from experience, Dr. Rajkumar explained.

“There are really no good guidelines for selecting specific treatment sequences,” he said. “The [National Comprehensive Cancer Network] guidelines are essentially a list of options that insurance should cover, rather than a detailed description of how patients should be treated.”

This can be particularly challenging for a practicing physician without expertise in MM. To help fill this need, Dr. Rajkumar and researchers at the Mayo Clinic developed the mSMART (Mayo Stratification of Myeloma and Risk-Adapted Therapy) Consensus Guidelines, an assessment tool for stratifying newly diagnosed and relapsed patients.11

In addition to providing decision support for physicians who don’t have much experience in treating MM, the guidelines allowed the 30 myeloma specialists at the three Mayo Clinic locations to standardize treatment regimens across their centers. The system is designed to evolve as new research becomes available.

“When combined with other factors, such as age, renal insufficiency, comorbid status, and patient preference, risk status is another step toward genuinely individualized therapy for patients with myeloma,” according to the mSMART authors. “This is perhaps more important than ever because, with many new therapeutic options available, dangers of overtreatment or undertreatment abound; indeed, not providing sufficient therapy for a high-risk patient can lead to poor outcomes, and giving too many drugs (be it in combination or in sequence) to a patient with indolent disease will likely result in excess short- and long-term toxic effects.”11

Although the guidelines are extensive, some of the key points include:

  • risk-stratification of patients into high-, intermediate-, and standard-risk categories
  • assessment of biological factors that could influence risk and prognosis, such as tumor biology, tumor burden, and patient-related factors
  • use of therapeutic breaks in the treatment of standard-risk patients who may have an indolent disease course, to limit toxicity
  • use of bortezomib-based strategies for the treatment of intermediate-risk patients
  • use of more aggressive and continuous therapies for high-risk patients

“In mSMART, we start breaking down treatment options by cytogenic abnormalities and other patient characteristics so that you can fine-tune treatment selection,” Dr. Rakjumar said.

Of course, the mSMART sequencing guidelines are just one option; many major MM treatment centers have their own algorithms, including Dr. Lonial and colleagues.

He noted that he takes calls from clinicians worldwide asking about appropriate sequencing. “I base my response on our algorithms [at Emory]. I don’t presume to say that it is the right answer, but I can let them know what we would do in a given situation.”

He cautioned that most sequencing guidelines are consensus opinions and not necessarily evidence-based approaches. “If you are a physician who doesn’t see a lot of these myeloma cases, then get comfortable with the treatment algorithms that your referral center uses, because that is where you are going to be sending your patients if you need help,” he advised.

Managing AEs

Whether it’s a newly diagnosed patient or someone in relapse, the question of how to manage treatment-related toxicities is a matter of “when,” not “if.”

In the relapse setting, Drs. Yee and Raje emphasized the importance of reviewing a patient’s prior treatment history for toxicities before deciding on the next course. Common toxicities that can inform subsequent treatment choices include peripheral neuropathy, deep vein thrombosis, thrombocytopenia, neutropenia, and anemia.

A significant milestone in MM treatment is the shift from induction to maintenance therapy. The optimal choice in this stage will differ based on a patient’s risk level and disease-specific genetic profile.

“When we get into the maintenance phase, we really begin to tailor treatments,” Sagar Lonial, MD, professor and chair of the Department of Hematology and Medical Oncology at Emory University, said, adding that experience with induction therapies can truly inform treatment decisions. “In high-risk patients, one drug is probably not sufficient to maintain their response, whereas standard-risk patients may be able to ‘get away’ with single-drug therapy.”

Below are a few maintenance therapy sequencing options for transplant-ineligible patients with new or relapsed disease:

  • lenalidomide without dexamethasone (10-15 mg for 21 of 28 days)
  • bortezomib every 3 months with prednisone or thalidomide (a 21-day cycle)
  • bortezomib (weekly for 4 of 5 weeks, or every other week)
  • pomalidomide with low-dose dexamethasone (2-5 mg/day for 21 of 28 days)1,2

At the 2016 ASH Annual Meeting, results from the phase III Myeloma XI trial confirmed that lenalidomide maintenance therapy significantly improved PFS, compared with no lenalidomide maintenance in a mixed population of transplant-eligible and -ineligible patients with newly diagnosed MM. However, an analysis of Myeloma XI data found that patients receiving lenalidomide maintenance had a significantly higher risk of developing secondary primary malignancies (SPMs) – though the SPMs reported were largely non-invasive.3


  1. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the phase III Myeloma XI Study. Abstract #1143. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.
  2. Abonour R, Durie BGM, Jagannath S, et al. Health-related quality of life of patients with newly diagnosed multiple myeloma receiving any or lenalidomide maintenance after autologous stem cell transplant in the Connect® MM Disease Registry. Abstract #537. Presented at the 2016 ASH Annual Meeting, December 4, 2016; San Diego, California.
  3. Jones JR, Cairns DA, Gregory WM, et al. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 2016;6:e506.

For instance, renal impairment is a common symptom of MM, with almost half of patients developing kidney failure. Lenalidomide is not a good option for patients with impaired kidney function because it requires dose adjustments and monitoring to avoid exacerbation of symptoms, Dr. Rajkumar explained. “A combination of bortezomib, thalidomide, and dexamethasone may be a better bet in this case.”

Results from some early-phase studies can offer valuable information regarding treatment sequencing, R. Donald Harvey III, PharmD, director of the Phase I Clinical Trials Section at Winship Cancer Institute of Emory University in Atlanta, Georgia, explained to ASH Clinical News. The expansion of treatment regimens to include triplet, or even quadruplet, combinations does not necessarily translate to a corresponding exponential increase in the risk of AEs because “each drug in a combination regimen has a unique mechanism of action and should ideally have non-overlapping toxicities,” he said.

“Today, in the first-in-human trials in MM, it’s not uncommon for us to have patients who have undergone seven or eight prior lines of treatment,” Dr. Harvey added. “If a drug candidate in a phase I trial is going to be effective, it has a higher bar to clear.”

For instance, a phase I trial that adds and escalates another agent to an RVD sequence would examine the optimal dosing for all four agents before evaluating the sequence in a large set of patients. “From a sequencing perspective, that information might help you determine how to get to a four-drug induction regimen,” he noted.

The horizon of treatment sequencing continues to expand with new indications for the BCL2 inhibitor venetoclax, which is approved to treat chronic lymphocytic leukemia with del17p. At the 2016 ASH Annual Meeting, researchers reported that adding venetoclax to bortezomib and dexamethasone led to an overall response rate of 68 percent among all patients with relapsed/refractory MM.13 The triplet was particularly effective in patients who were not refractory to bortezomib and who had been treated with one to three lines of prior therapy, who experienced an overall response rate of 94 percent.

“Cure Versus Control”

Dr. Rajkumar detailed the “fundamental clash of philosophies” of MM treatment in a 2011 Perspective article in Blood; six years later, that clash has taken center stage in debates over treatment sequencing.13

“If you think you can cure a disease, then you are guided by hope and are likely to give aggressive therapy to reach that goal,” he said, alluding to clinics that take this approach and may use seven- or eight-drug sequences. “In turn, telling a patient that you are going to cure them may make them more willing to turn their lives upside down and agree to all those therapies.”

On the other hand, if the clinician and patient agree that the current goal is disease control and not cure, a patient may opt to start with less aggressive treatment, escalating treatment intensity only when it becomes necessary. “In that scenario, we are able to adjust our approach based on the patient’s wishes, and, if the disease is not curable, many patients will go that route,” he said.

Other factors unrelated to treatment can guide sequencing, such as financial concerns, geographic hardships, or even the ability to tolerate a multi-drug treatment course.
If a patient is scheduled to start an RVD regimen, for instance, he or she would also be put on thromboembolic and herpes zoster prophylaxis; if any treatment-related AEs emerge, then the patient would receive medication to manage those. “So, it’s not just the three agents for treatment we have to consider; it’s also the addition of these other drugs and the supportive care needed during treatment,” Dr. Harvey said. This can be challenging, particularly for older patients who are already receiving treatment for comorbidities, he continued. “As clinicians, we have to factor all of those aspects into how we deliver treatment.”

Dr. Rajkumar recalled a recent patient who declined to make the weekly 45-mile drive to the nearest hospital to receive subcutaneous bortezomib. “She took two doses and then stopped because of the travel burden, so, as a reasonable alternative, she took oral ixazomib instead,” he said. “We have to be willing to fine-tune the treatment to address those kinds of patient hardships.”

Financial circumstances also play a large part in patients’ prescription drug usage, and high costs force many cancer patients to skip medication doses, take less medicine, use alternative therapies, or take other cost-saving actions, according to an analysis from the American Cancer Society.14

“This type of financial toxicity has been shown to decrease compliance with treatment,” Daniel A. Goldstein, MD, a senior physician at the Davidoff Cancer Center in Petach Tikvah, Israel, wrote in an editorial accompanying the report.15 “All physicians must recognize that financial toxicity is a serious issue, not to be denied or ignored,” he stated. “Although financial toxicity has become accepted by most, there remain subsections of the medical community that deny its existence. … We must avoid unnecessary testing and treatments; if a test or treatment will not impact management, then it should not be done.”

“The treatment schedule also may play a role, depending on the patient’s ability to travel for treatment, which in turn may be influenced by the patient’s level of fitness and performance status,” Drs. Yee and Raje added.

Ultimately, clinicians need to treat the patient in front of them, rather than relying on a one-size-fits-all regimen. For Dr. Rajkumar, that means first knowing the “default” treatment sequence. “‘If all things were equal, what would my standard treatment option be?’” he posed. “Then from there, you can ask yourself, ‘Under what circumstances would I vary from that default?’”

“It’s hard to create a flowchart that outlines simply, ‘First, do this; if that regimen doesn’t work, do this …’ because there are questions that need to be answered during treatment,” Dr. Lonial offered. “What were some of the patient’s side effects from the first therapy? How far away from the clinic does he or she live? What’s the co-pay for oral drugs? All those answers factor into making drug-sequencing decisions.”—By Shalmali Pal


  1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962-72.
  2. Yee AJ, Raje NS. Sequencing of nontransplant treatments in multiple myeloma patients with active disease. Hematology Am Soc Hematol Educ Program. 2016;1:495-503.
  3. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068-74.
  4. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519-27.
  5. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase II study of modified lenalidomide, bortezomib, and dexamethasone (RVD-lite) for transplant-ineligible patients with newly diagnosed multiple myeloma. Abstract #4217. Presented at the 2015 ASH Annual Meeting, December 8, 2015; Orlando, Florida.
  6. Rajkumar SV, Kyle RA. Progress in myeloma – a monoclonal breakthrough. N Engl J Med. 2016;375:1390-2.
  7. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-31.
  8. Dimopoulos M, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-31.
  9. Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015;126:2284-90.
  10. Voorhees PM, Mulkey F, Hassoun H, et al. Alliance A061202. A phase I/II study of pomalidomide, dexamethasone, and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy: phase I results. Abstract #375. Presented at the 2015 ASH Annual Meeting, December 5, 2015; Orlando, Florida.
  11. Mayo Clinic. Welcome to mSMART: the Risk Adapted Approach to Management of Multiple Myeloma and Related Disorders. Accessed March 6, 2017, from https://www.msmart.org/home.html.
  12. Moreau P, Chanan-Khan AA, Roberts AW, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Abstract #975. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.
  13. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011;118:3205-11.
  14. Zheng Z, Han X, Guy, Jr GP, et al. Do cancer survivors change their prescription drug use for financial reasons? Findings from a nationally representative sample in the United States. Cancer. 2017 February 20. [Epub ahead of print]
  15. Goldstein DA. Financial toxicity in cancer care—edging toward solutions. Cancer. 2017 February 20. [Epub ahead of print]

TABLE. Multiple Myeloma Therapies*
Pharmaceutical Options
Monoclonal antibodies daratumumab
Immunomodulatory drugs (IMiDs) lenalidomide
Proteasome inhibitors ixazomib
Chemotherapy doxorubicin HCL liposome injection, otherwise known as pegylated liposomal doxorubicin
alkylator chemotherapy such as melphalan or cyclophosphamide
Histone deacetylase (HDAC) inhibitor panobinostat
Corticosteroids dexamethasone
Initial Pharmaceutical Therapy Options
Doublets lenalidomide and dexamethasone (RD)
bortezomib and dexamethasone (VD)
Triplets lenalidomide, bortezomib, and dexamethasone (RVD)
bortezomib, cyclophosphamide, and dexamethasone (VCD or CyBorD)
bortezomib, thalidomide, and dexamethasone (VTD)
Quadruplets research ongoing to determine balance of effectiveness and tolerability
Chemotherapy only melphalan-based regimen (infrequently used in the United States)
*As of March 2017

Source: Multiple Myeloma Research Foundation, “Multiple Myeloma Drug Therapies.” The full document can be accessed from https://www.themmrf.org/multiple-myeloma/multiple-myeloma-treatment-options/myeloma-drugs/.