In the treatment of multiple myeloma (MM), following decades of little progress, the last 10 years have been characterized by more clinical advancements than for any other cancer.

One recent achievement includes encouraging results from a small pilot study of patients with high-risk smoldering multiple myeloma (HR-SMM),

or minimal residual disease (MRD). Another study demonstrated the first evidence of prolonged survival in this population of patients.

In fact, much current research focuses on the myeloma precursor statemonoclonal gammopathy of uncertain significance (MGUS)/SMM&mdash;and how integrating novel biologic markers (still under development), very sensitive molecular imaging, and clinical monitoring could result in the development of successful early treatment strategies that forestall progression from precursor disease to full-blown MM.

Ola Landgren, MD, PhD, is head of the Multiple Myeloma Section, Metabolism Branch, at the NCI, and lead author at the December 2013 meeting of the American Society of Hematology (ASH) of a pilot study in a dozen patients with HR-SMM. In that study, with a 3-drug combination, (carfilzomib, lenalidomide, and dexamethasone [CRd]), 9 patients obtained complete response (CR), 1 patient obtained a stringent complete response (sCR), and 2 patients obtained near CR.2

Landgren called these results a &ldquo;very powerful finding,&rdquo; which he considered even more striking by confirmation via high-quality assays, including multicolor flow cytometry capable of analysis of &ge;3 x 106 events, with a sensitivity detection rate of q x 10-5. Next steps include an expansion of the cohort (initially by 16 more patients), and ongoing monitoring to ensure that patients continue to be MRD negative.

Landgren authored a chapter of the ASH annual Educational Program book,

, in which he further examined this type of state-of-the-art MM research and offered current strategies in patient care.

The following are some research and clinical pearls from that chapter: &ldquo;Monoclonal gammopathy of undetermined significance and smoldering multiple: biological insights and early treatment strategies.&rdquo;

The Molecular Composition of Myeloma Precursor Disease Versus Multiple Myeloma

&ldquo;Based on current standard technologies (eg, fluorescence in situ hybridization [FISH]), the molecular makeup of myeloma precursor disease states and multiple myeloma are strikingly similar, and no defining molecular features unique to multiple myeloma have been identified.&rdquo;

&ldquo;Currently, the serum-free light chain (sFLC) ratio is one of the most promising clinical biomarkers in asymptomatic myeloma. The sFLC ratio has been used as a prognostic indicator both in patients with MGUS and SMM.&rdquo;

&ldquo;&hellip;There is a consensus that bone marrow plasma cell (BMPC) levels &ge;10%, serum M protein levels &ge;3 g/dL, and abnormal sFLC ratios (&le;.125 or &ge;8) increase the probability that SMM will develop into multiple myeloma.&rdquo;

A Note on Current Clinical Management Strategies

&ldquo;In 2013-2014, the cornerstone of managing MGUS/SMM involves a prudent &lsquo;watch and wait&rsquo; strategy. Outside of trials, there are no current standardized treatment options for MGUS or SMM.&rdquo;

&ldquo;Although current evidence does not support the treatment of SMM outside of clinical studies, it seems reasonable to support the development of early treatment trials that integrate molecular monitoring.&rdquo;

On Tools and Technology to Detect End- Organ Damage: From X-ray to Molecular Imaging

&ldquo;According to the most recent consensus guidelines of the International Myeloma Working Group (IMWG), updated in 2011, radiological skeletal survey is still the gold standard for the initial workup of patients with multiple myeloma.&rdquo;

&ldquo;However, conventional x-ray has some important drawbacks.&rdquo;

&ldquo;&hellip;The occurrence of bone destruction is a relatively late event.&rdquo;

&ldquo;Magnetic resonance imaging (MRI) is able to assess the disease in the [bone marrow] BM itself independently from the growth pattern, and therefore can provide information on the actual tumor burden.&rdquo;

&ldquo;&hellip;Dynamic contrast-enhanced MRI and diffusion-weighted imaging MRI comprise the possibility of gaining information regarding disease activity.&rdquo;

&ldquo;&hellip;In SMM or high-risk MGUS patients highly suspicious of harboring bone disease, imaging evaluation may be better served by obtaining MRI or positron emission tomography (PET) rather than skeletal surveys.&rdquo;

In a recent interview, Landgren discussed the major questions that challenge myeloma clinical researchers, questions that are critical to advancing treatments and improving outcomes in patients with MM.

First, he said, knowing &ldquo;when is the right time to start therapy,&rdquo; instead of waiting for a patient to get sick, is a key challenge. What is needed is for researchers to &ldquo;find something that would drive the initiation of therapy.&rdquo;

Second, although the availability of effective drugs, and more effective new drugs, is important, he said, even more important is to have tests that predict which therapies will work. &ldquo;I am not saying that we should stop developing drugs, but we need to have a balance. Tools have been left behind.&rdquo;

The last question that Landgren raised is how to &ldquo;test in a more sophisticated way how well a given therapy is working,&rdquo; and measuring the depth of (patient) response using molecular tools. Now, according to Landgren, the way to evaluate therapy is old and very crude.

Clinicians with a focus on &ldquo;better characterization&rdquo; imaging to determine who is and is not responding to drugs will be able to help patients to a much greater degree, according to Landgren. &ldquo;This may take time,&rdquo; he said, but is likely to have a large impact on patient outcomes.

On the practical side of patient care, Landgren advocates a sharper focus on elderly patients. Myeloma has an average age of 70 years, he said, but &ldquo;People above the age of 70 have been treated with quite inferior drugs.&rdquo;

In studies, Landgren noted, &ldquo;&hellip;all of the driving (advances) in multiple myeloma have involved people up to age 70.&rdquo; But it has been shown that people above age 70 years can have good results, and this is about half of the MM population.

&ldquo;We have treated patients (similarly) in their upper 80s and their 40s,&rdquo; a wide range of ages, with &ldquo;very effective therapy&rdquo; and no age-related differences.

&ldquo;Just by doing this, you could improve survival,&rdquo; he said.

Landgren O. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies. American Society of Hematology.

. 2013:478-487. http://asheducationbook.hematologylibrary .org/

Landgren O, Mailankody S, Kwok M, et al. Clinical and correlative pilot study of carfilzomab, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRdR) in high-risk smoldering multiple myeloma.

Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.

Articles

Clinical Articles

Insights on Multiple Myeloma From Ola Landgren, MD, PhD

Treatment of chronic lymphocytic leukemia (CLL) is complicated by the fact that most patients are diagnosed at a later age, with a median age at diagnosis of 72 years. In the United States, 75% of patients with CLL are more than 65 years of age.

Despite this, the elderly population is typically underrepresented in clinical trial populations, which have age ranges of 58 to 62 years.

The optimal therapy for patients 65 years of age and older with CLL is not known, particularly for less fit patients; accordingly, a number of studies are investigating treatments in this important population.

New developments in this topic were presented at the American Society of Hematology (ASH) 55th Annual Meeting and Exposition (December 2013) in New Orleans.

examined the characteristics, prognosis, and treatment of elderly patients with CLL in a retrospective, single-center study (N = 949; n = 367 defined as ages 70 years or greater). The study found that elderly patients were diagnosed at a more advanced clinical stage (

<.001), and were treated less frequently than were younger patients (39% vs 62%;

<.001); in contrast to younger patients, there was also an equal sex distribution in the elderly. In terms of treatments, compared with younger patients, elderly patients had a higher use of alkylating agents (70%), but a lower use of purine analogues (10%) or chemoimmunotherapy (5%). While no apparent differences in biology of disease were observed between the elderly and younger patients, elderly patients had a lower overall response rate (ORR; 49% vs 69%;

<.001), shorter overall survival (OS; 6.6 vs 13.3 years;

<.001), and a higher incidence of mortality that was unrelated to CLL (at 10 years, 34.9% vs 6.9%;

<.001). The findings of this study, in addition to defining some important characteristics for the elderly population with CLL, also highlight the smaller proportion of elderly who receive treatments, and provide a rationale for exploring new regimens that are both active and well tolerated in this population.

Pentostatin With Cyclophosphamide and Ofatumumab

The standard first-line treatment for CLL (ie, fludaribine/cyclophosphamide/ rituximab; [FCR]) is associated with side effects.

Although FCR may be a viable therapy for older fit patients with fewer comorbidities, it is not known whether or not novel combination therapies may be better suited for less fit patients.

The CLL10 trial compared the efficacy and safety of FCR versus bendamustine/ rituximab (BR). At a median observation time of 27.9 months, the ORR was identical in both arms (97.8%), and no difference in OS was observed (at 2 years, 94.2% vs 95.8%, respectively, for FCR and BR;

= .593). Notably, when comparing progression-free survival (PFS) in patients <65 years and >65 years, a difference was observed between treatments in the <65 group (PFS, 36.5 months BR vs not reached [NR] for FCR;

= .016), but no such difference was seen in the elderly (ie, >65 group) patients (not reached [NR] vs 45.6 months, respectively;

= .757). Moreover, in the FCR arm, a higher rate of severe neutropenia was seen (81.7% vs 56.8%;

<.001), and resulted in a significantly higher rate of severe infection in the elderly patients (47.4% FCR vs 26.5% BR;

= .002). Results of the trial did not allow for a recommendation for one regimen over another for patients with good fitness.

Lenalidomide is an immunomodulatory agent that had previously been shown to have activity in multiple myeloma and CLL.

The phase II REAL07 Trial of the Fondazione Italiana Linfomi (FIL) evaluated the use of lenalidomide with rituximab- CHOP21 in elderly patients with diffuse large B-cell lymphoma (DLBCL).

Previous phase I findings had shown the feasibility of this combination therapy in elderly patients, with 15-mg lenalidomide established as the maximum tolerated dosage with RCHOP21. Fit patients aged 60 through 80 years were included (n = 49, enrolled). Notably, there were no grade IV extrahematologic events and no toxicity-related deaths during the treatment; with 94% (277 of 294) of the planned LR-CHOP21 courses administered. Complete remissions (CR) were observed in some 86% of patients (n = 42), with another 6% (n = 3) having partial remissions (PR); there were three nonresponders (6%) and one additional homicide-related death. At 28 months median follow up, the 2-year OS rate was 92% and the 2-year PFS rate was 80%; event-free survival at 2 years was 70%. The ORR for both germinal center (GCB) and non-GCB patients was 88%, with complete responses observed in 81% and 88%, respectively; corresponding 2-year PFS was 71% and 81%, respectively, at a median 28 months follow up. Overall, the results of this trial demonstrated that LR-CHOP21 was effective in the elderly population, and these results serve as the basis for a future phase III study designed to evaluate LR-CHOP21 versus R-CHOP21 for previously untreated non-GCB patients with DLBCL.

For younger and physically fit patients with CLL, purine analogs in combination with the anti-CD20 antibody rituximab (chemoimmunotherapy) is the standard of care for initial treatment.

But because fludaribine-containing regimens may frequently be inappropriate for elderly patients and for those with comorbid conditions, more tolerable treatment choices are needed.

Ofatumumab is a fully-human anti-CD20 monoclonal antibody with single-agent activity in fludaribine- resistant CLL. Unlike FCR, which may be associated with significant hematologic toxicity, pentostatin, a purine analog, has been noted for its lower myelotoxic profile in use with agents such as cyclophosphamide.

A presentation by Marco Montillo and coworkers examined the use of pentostatin with cyclophosphamide and ofatumumab (PCO) in older (65 years and over; ECOG 0-2) patients (n = 49) with previously untreated CLL in a phase II Italian multicenter study.

Results showed that 94% of patients (n = 30) were able to receive the intended 6 cycles of treatment, with 90% receiving a full dose. Myelosuppression was the main reason for dose reduction or discontinuation of treatment. Neutropenia was the most common adverse event (AE) of grade 3 or higher; a total of 19 patients experienced grade 3 or 4 AEs, and no deaths occurred during treatment. Among the grade 1 or 2 toxicities were fever, hypotension, nausea and vomiting, and skin rash. ORR, the primary endpoint, was 93.7%, with 41% CR. Collectively, the findings of this study demonstrated the activity of the PCO chemoimmunotherapy regimen and showed it to be well tolerated in this older population of patients with CLL. Compared with prior studies evaluating the same chemotherapies with a rituximab backbone, the PCO regimen showed comparable efficacy and more manageable toxicity.

Ofatumumab was also evaluated in a phase III study in combination with chlorambucil (CHL), a standard of care for older, less fit patients, versus CHL alone.

Patients requiring therapy for CLL who were of advanced age or who had comorbidities and were thus considered inappropriate for fludaribinebased therapy were randomized (N = 447). A minimum of 3 with best response up to 12 cycles, was the intended treatment duration. A median duration of 6 cycles of treatment were administered and 82% of patients received 6 or more cycles of the ofatumumab/chlorambucil (O+CHL) regimen. Independent Review Committee (IRC)-assessed PFS was significantly prolonged for patients randomized to O+CHL, at 22.4 months versus 13.1 months (

<.001). A significant benefit of the combination was also seen in ORR (82% vs 69%;

<.001), with more CR observed (12%) compared with the CHL arm (1%). Grade 3 and 4 AEs (start of therapy to 60 days after last dose) occurred in 50% and 43% of patients treated with O+CHL and CHL, respectively; neutropenia (26% vs 14%) was most common among these. Grade 3 or higher infections occurred in 15% and 14% of patients in the respective treatment groups. In both arms, deaths during treatment occurred in 2% of patients. Collectively, the results demonstrated clinically meaningful improvements in disease with ofatumumab/ chlorambucil, and manageable toxicities in this challenging-to-treat population of patients who are inappropriate for fludaribine-based therapy.

These findings highlight the importance of the elderly as a patient group in CLL requiring treatment that is both effective and well tolerated. While no definitive conclusions could be made about the use of standard FCR versus bendamustine and rituximab, the findings of CLL10 highlighted the higher rates of severe neutropenia with FCR, which could contribute to more severe infections, particularly in the elderly.

The FIL trial, on the other hand, has contributed important findings about the combination of lenalidomide with rituximab and CHOP21 in elderly patients with DLBCL, with high rates of complete remissions and with comparable ORRs for both GCB and non-GCB untreated patients; results of a future phase III trial are awaited.

Ofatumumab has demonstrated superiority over rituximab in preclinical findings. This anti-CD20 therapy has demonstrated clinically important activity in combination with pentostatin and cyclophosphamide,

with manageable toxicity in each case. All of these emerging regimens offer promise for this important population of elderly patients.

Tadmor T, Polliack A. Optimal management of older patients with chronic lymphocytic leukemia: some facts and principles guiding therapeutic choices.

Wu M, Akinleye A, Zhu X. Novel agents for chronic lymphocytic leukemia.

Baumann T, Delgado J, Santacruz R, et al. Initial characteristics, treatment, and prognosis of elderly (&ge; 70 years) patients with chronic lymphocytic leukemia (CLL): an analysis of a series of 367 cases. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 4155.

Eichhorst B, Fink A-M, Busch R, et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 Trial, an international, randomized study of the German CLL Study Group (GCLLSG). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 526.

Smolewski P, Witkowska M, Korycka-WoÅ‚owiec A. New insights into biology, prognostic factors, and current therapeutic strategies in chronic lymphocytic leukemia.

Chiappella A, Franceschetti S, Castellino A. Final results of phase II study of lenalidomide plus rituximab-CHOP21 in elderly untreated diffuse large B-cell lymphoma focusing on the analysis of cell of origin: REAL07 Trial of the Fondazione Italiana Linfomi. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 850.

Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 528.

Montillo M, Rossi D, Motta M, et al. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab (PCO) in older previously untreated chronic lymphocytic leukemia (CLL) patients. 55th ASH&reg; Annual Meeting and Exposition. New Orleans, LA, December 7-10, 2013. Abstract 4177.

Treatment of CLL is complicated by the fact that most patients are diagnosed at a later age, with a median age at diagnosis of 72 years. In the United States, 75% of patients with CLL are more than 65 years of age.

Trials Explore Treatments for Elderly Patients With CLL

More than two dozen abstracts at the December 2013 meeting of the American Society of Hematology (ASH) focused on the detection, measurement, or monitoring of minimal residual disease (MRD) in patients with multiple myeloma (MM). This emphasis is &ldquo;very exciting,&rdquo; according to Brian G. M. Durie, MD, founder and chair of the International Myeloma Foundation (IMF) and Hematologist/Oncologist at Cedars-Sinai Medical Center in Los Angeles, California. According to Durie the focus on MRD reflects real progress in what the IMF recently declared as the goal of its Black Swan Research Initiative (BSRI): MRD-Zero.

MRD-Zero will be achieved when tools are available to physicians to successfully determine when patients arrive at, and are able to sustain, the status of MRD. One study reported at ASH showed that it can be done. Ola Landgren, MD, PhD, and colleagues showed in a small pilot study that 11 of 12 patients with high-risk smoldering MM (HR-SSM) achieved and sustained MRD-Zero.

Several other abstracts from ASH examined the expanded possibilities in MRD testing and monitoring with the use of alternative sophisticated models.

In a Spanish study, researchers undertook a first-time characterization of the MRD clone at the biological level, as what they described as a &ldquo;unique model for understanding chemoresistance.&rdquo; This is important work, Durie commented, because there is a need to better understand the nature of resistant subclones in order to achieve MRD-Zero.

There are no black swansuntil there is a black swan.

There is no cure for multiple myeloma. Until there is a cure. Thus, the Black Swan Research Initiative (BSRI) of the International Myeloma Foundation is well-named for what is described as a breakthrough approach to finding a cure for myeloma.

The BSRI is unique as an &ldquo;actual research project aimed at finding a functional cure for myeloma, not an open-access platform to support external research,&rdquo; explained Brian G. M. Durie, MD, in one of his regular online postings, &ldquo;Dr. Durie&rsquo;s Blog.&rdquo;

&ldquo;A core tenet of BSRI is that many patients might be cured [already] and don&rsquo;t know it because previously we have lacked the sophisticated tests necessary to determine that zero minimal residual disease (MRD-Zero) has been achieved.&rdquo;

The most recent ASH meeting featured testing methods for MRD with great near-term potential.

&ldquo;Using the latest procedures involving flow cytometry and full DNA sequencing, we will be able to detect down to less than 1 cell per million of myeloma. Thus, we can identify who has been cured, and what combinations of therapies led to that cure.&rdquo;

Black Swan Research Initiative&rsquo;s distinctly different pathway to a cure.

http://myeloma.org/MtEntryPage. action?source=/imf_blogs/myeloma_voices/

2013/09/black-swan-research-initiativesdistinctively- different-pathway-to-a-cure.html

Complete eradication of all subclones in MM is required to prolong patient survival. Members of the same group from the Universidad de Salamanca, Spain, conducted a sophisticated analysis of subclones with different genetic profiles, clonogenic profiles, and differing drug sensitivities. They found that distinct phenotypic subclones translate into different cytogenetic profiles and clonogenic potential. As the balance between different subclones changes over the course of treatment, so does the extent of specific cytogenetic abnormalities, as well as patient risk. &ldquo;Careful monitoring of specific subclones may have implications toward an adapted therapy to overcome chemoresistant cells,&rdquo; the investigators concluded.

Regarding the clinical implications of this work, Durie said that an understanding of subclones, which persist or emerge despite current novel therapy, &ldquo;is key to developing more successful treatment and achieving MRD-Zero.&rdquo;

A number of abstracts at the ASH meeting compared molecular testing and flow cytometry to assess MRD.

One was a &ldquo;deep sequencing approach&rdquo; to an analysis of bone marrow samples from 133 patients who were treated similarly within the Spanish Myeloma Group trials.

The investigators compared the prognostic value of traditional response criteria to assess MRD with a sequencing-based platform (LymphoSIGHT), multiparameter flow cytometry (MFC), and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) of Ig genes. Their findings established a near equivalence between the MRD studies, at 91%, and the flow cytometry, at 96%. The investigators also found a high correlation between MRD levels by sequencing, by ASO-PCR, and by MFC. Based on these results, &ldquo;MRD assessment by sequencing is a useful method for patient risk stratification and can be used to determine molecular complete response (CR) in MM,&rdquo; the group concluded.

A group from the National Cancer Institute, led by Landgren, compared serum heavy-light chains (HLC) with free light-chains (FLC) as predictors of early CR in newly diagnosed patients with myeloma who were treated with carfilzomib, lenalidomide, and dexamethasone in an ongoing, prospective, clinical trial for patients with MM and HR-SMM.

Early monitoring (after 2 cycles) of HLC patterns, the group found, was an independent predictor of rapid response.

The International Myeloma Foundation. The International Myeloma Foundation launches the Black Swan Research Initiative to develop the very first definitive cure for multiple myeloma.

http://myeloma. org/BSRI/IMF_BlackSwanLaunch_031113_F3.pdf

Landgren O, Mailankody S, Kwok M, et al. Clinical and correlative pilot study of carfilzomab, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRdR) in high-risk smoldering multiple myeloma. American Society of Hematology, 2013. Abstract 1939.

Paiva B, Corchete LA, Gutierrez N, et al. Phenotypic and genomic analysis of multiple myeloma (MM): minimal residual disease (MRD) clonal plasma cells. American Society of Hematology, 2013. Abstract 402.

Paino T, Paiva B, Sayagues JM, et al. Phenotypic identification of subclones in multiple myeloma with different genomic profile, clonogenic potential and drug sensitivity. American Society of Hematology, 2013. Abstract 531.

Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing approach for minimal residual disease (MRD) detection in multiple myeloma patients. American Society of Hematology, 2013. Abstract 1848.

Bhutani M, Costello R, Korde N, et al. Serum heavy-light chains (HLC) and free light chains (FLC) as predictors for early CR in newly diagnosed myeloma patients treated with carfilzomib, lenalidomide, and dexamethasone (CRd). American Society of Hematology, 2013. Abstract 762.

More than two dozen abstracts at the December 2013 meeting of the American Society of Hematology (ASH) focused on the detection, measurement, or monitoring of MRD in patients with multiple myeloma.

Minimal Residual Disease (MRD) Marches to Front Line of Myeloma Research

Table. Smoldering Multiple Myeloma: A Case Study

Asymptomatic, active, 53-year-old woman was found to have an elevated erythrocyte sedimentation rate (ESR) with elevated serum proteins (90 g/L) in routine examination

Complementary studies revealed normal hemoglobin, creatinine, and serum beta-2-microglobulin

M component: 35 g/L; plasma cells (PCs) in bone marrow (BM): 33%

No lytic lesions were detected; magnetic resonance imaging (MRI) showed osteoporosis with 1-2 focal lesions

(The full-panel discussion can be accessed at:

http://www.youtube.com/watch?v=FNw7bctXqfg

The panel was sponsored jointly by the International Myeloma Foundation, the Annenberg Center for Health Sciences, and Clinical Care Options) Before the presentations, audience members voted on whether or not to recommend starting systemic myeloma therapy for the following patient. The result: 61% no, 39% yes. At the conclusion of the presentations and discussion, the vote was essentially unchanged.

Thus, before the opening of the official 55th Annual American Society of Hematology (ASH) meeting in December 2013, two members of an international panel of myeloma experts, one from Spain and one from the United States, presented opposing arguments for the treat versus watch-and-wait approaches for a sample patient case of HR-SMM (

). The panel, which featured three other presentations on current research regarding myeloma, was moderated by Brian G.M. Durie, MD, founder and chair of the International Myeloma Foundation and hematologist/oncologist at Cedars-Sinai Medical Center in Los Angeles, California.

Yes: Initiate Therapy Based on Risk of Progression

A consensus emerged from both sides that while patients with &ldquo;early myeloma or ultra-high-risk SMM require treatment,&rdquo; a better definition of HR-SMM is needed, along with clinical trials that may answer the critical question of whether or not early intervention changes the natural history of the disease.

Results from clinical trials in SMM have been mostly consistent in finding no benefit from early treatment.

In studies of bisphosphonates versus observation, the bisphosphonates have been found to delay the time to skeletal events, but not the time to progression (TTP). More recently, studies with thalidomide plus zoledronic acid (ZOL) versus no ZOL for early versus delayed intervention found no benefit in TTP, in symptomatic disease, or in overall survival (OS).

However, the risk of progressive disease to active disease is &ldquo;heterogeneous,&rdquo; said Jes&uacute;s F. San Miguel, MD, PhD, from Universidad de Navarra, Spain. &ldquo;None of these trials discriminates between low-risk patients who are not likely to benefit from intervention (and) highrisk patients who may well benefit from therapy,&rdquo; San Miguel stated.

One recent trial is an exception. The randomized, phase III trial from the Spanish myeloma group produced the first evidence of an improvement in OS in a group of patients with SMM whose disease met either the Mayo or the Spanish classification criteria for HR-SMM, defined as 50% risk of progression within 2 years. These criteria require 10% or more PCs in the BM plus &ge;3 g/dL of MC

or most of the PCs (>95%) being clonal plus immunoparesis.

In this study, 119 patients were randomized to receive either lenalidomide plus dexamethasone or no treatment for nine cycles, followed by lenalidomide maintenance. Patients who progressed on lenalidomide maintenance could receive low-dose dexamethasone based on biologic progression alone (not clinical progression).

At a median of 40 months, the response rate (RR), TTP, and OS favored the experimental treatment arm. &ldquo;Over 80% of patients (in the lenalidomideplus- dexamethasone arm) responded, with over 15% [experiencing] complete responses,&rdquo; San Miguel said. &ldquo;During the maintenance phase, the sCR plus CR rate increased to 26%.&rdquo;

This RR was clearly different from what has been previously reported for thalidomide, and very similar to the RR that the Spanish group observed with lenalidomide/dexamethasone in symptomatic patients.

&ldquo;The simplest explanation for me is that we are dealing with different populations of patients,&rdquo; said San Miguel.

The primary endpoint of the Spanish study was TTP. Median TTP was significantly longer in the treatment group than in the observation group (the median was not reached at 21 months; hazard ratio [HR] for progression .18; 95% confidence interval [CI] .09-32;

<.001). A total of 76% of patients had already progressed in the observation arm, indicating a veryhigh- risk population, versus only 23% clinical progression in the experimental arm.&rdquo;

What was most striking to myeloma experts was the OS data in the Spanish trial. With a median follow up of 47 months, there was a clear OS advantage for the lenalidomide/dexamethasone arm. &ldquo;At 5 years, 95% of the patients are alive versus 78% of patients in the no treatment arm.&rdquo;

Side effects were primarily grade 2 or lower and less than 10% of grade 3 side effects were seen.

To many, these data provide compelling evidence that early intervention could be beneficial for patients with HRSMM.

SanMiguel conceded that some physicians would argue that a proportion of patients even in the high-risk population will never progress, and, based on this, they would require that better criteria be used to define high risk.

No: Improve Knowledge and Seek Consensus Regarding Definition of High Risk

But, he asked: &ldquo;Can (the risk of) 30% of patient (overtreatment) justify the risk of undertreating the 70% who would benefit from treatment?&rdquo;

Two significant problems persist in the care of patients with MM. The first is that a correct definition of MM is lacking, according to S. Vincent Rajkumar, MD, professor of medicine at the Mayo Clinic, Rochester, Minnesota, speaking on behalf of the &rsquo;no treatment&lsquo; choice of SMM. The second, he said, is that, &ldquo;We are talking about multiple diseases but we are considering them as one disease.&rdquo;

The disease definition of MM is currently based on end-organ damage, and according to Rajkumar and some colleagues, this needs to change.

Rajkumar, along with San Miguel and other myeloma colleagues, identified these subgroups of patients with SMM who have ultra-high-risk disease:

Patients with more than 60% PCs in the BM. Even without end-organ damage, these patients may be considered to have MM because they progress very rapidly

Patients with high free light-chain (FLC) ratio (&ge;100), who progress very rapidly; 80% or more within the first 2 years

Patients with more than 1 focal lesion on MRI; who also progress very rapidly: 80% within the first 2 years

Rajkumar explained: &ldquo;We need to recognize that the various cytogenetic subtypes of SMM progress to MM at different rates, and each subtype may actually represent a distinct disease entity.&rdquo;

Rajkumar described three subgroups of SMM:

Patients with ultra-high-risk features (&ge;80% risk of progression within 2 years). These patients are best treated as patients with MM regardless of the presence or absence of end-organ damage

Patients with high-risk features (~50% risk of progression within 2 years), a population for which clinicians are now debating the value of early therapy

Patients without any high-risk features, about whom there is consensus favoring a watch-and-wait strategy

&ldquo;What we have right now,&rdquo; said Rajkumar, &ldquo;is a small cohort of patients with myeloma who are ultra-high risk. Then we have patients with HR-SMM who have about a 25% high risk per year of progression.&rdquo;

The real debate, according to Rajkumar, is not about the management of ultra-high-risk or low-risk SMM, but rather whether or not clinicians should treat patients in the middle, with HRSMM, who, according to most studies, have shown evidence of progressionfree survival but no survival advantage. Showing an improvement in OS, the Spanish myeloma trial poses the question of whether or not there should still be a debate about treatment of HR-SMM.

Figure. Low-risk, high-risk, and ultra-high-risk smoldering multiple myeloma.

BMPC, bone marrow plasma cells; FLC, free light-chain ratio; PC, plasma cells; SMM, smoldering multiple myeloma.

In other words, the key clinical question is: should not all patients with HRSMM be treated?

Perhaps not, Rajkumar suggested. &ldquo;The first problem with the Spanish trial that we need to address is that it is not generalizable to a large proportion of the (patient population). One-half of the patients in the Spanish trial1 were enrolled based on the results of a flow cytometrybased assay that is not generally available.&rdquo;

The second problem, according to Rajkumar, is that the actual event rate in the Spanish trial is small. &ldquo;The entire survival difference is based on a death rate of 4 deaths (of 57 patients) in the treatment group versus 13 deaths (of 62 patients) in the observation group. Even minor imbalances in the cytogenetics of the patients, such as deletion 17p and t(4;14) at baseline could have skewed the OS difference (between treatment groups).&rdquo;

Another question is whether or not the survival benefit in the Spanish trial could have been conferred by the dexamethasone. This question will be investigated in a study under recruitment, led by Sagar Lonial, comparing lenalidomide versus observation in asymptomatic patients with HR-SMM.

For patients whose disease bears ultra- high-risk features (&ge;60% PCs in BM, FLC ratio &ge;100, and >1 focal lesion on MRI), Rajkumar urged: don&rsquo;t wait, because these patients will progress rapidly or get renal failure very quickly.&rdquo;

&ldquo;This is not (the patient) we are speaking about,&rdquo; he said. &ldquo;We are speaking about the high-risk patients: abnormal immunophenotype, abnormal FLC ratio; &ge;3 g M protein, and &ge;10% plasma cells.&rdquo; For this patient group, &ldquo;We still need to do clinical trials if we are to make this a reality for patients,&rdquo; he said (Figure).

A discussion led by moderator Durie established the contours of a consensus among panel members.

Although the typical clinical manifestations of MM are summarized by the CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone lesions), a significant proportion of patients with MM present with a variety of other clinical manifestations.

among patients with symptomatic MM, 74% presented with CRAB symptoms, 20% presented with non-CRAB manifestations, and 6% had both clinical features.

&ldquo;For patients who already have high risk of progression within 2 years (&ge;80%), there is no reason to wait for the other shoe to drop&hellip;and have some catastrophic problems before we initiate therapy. We basically have to take the 15% to 20% or so of patients who we currently call smoldering and treat them as early as possible, at pre-CRAB myeloma. The remaining 80% should be enrolled in clinical trials that will seek to answer the question whether early intervention changes the natural history of the disease,&rdquo; Durie stated.

&ldquo;The major issue is to update CRAB criteria (taking into account) the new criteria and new technology available to define early myeloma, and to better (discriminate) the benign tumor from the malignant tumor that is myeloma, taking out the gray zone that is the mix of the malignant and the benign,&rdquo; Durie said.

Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monocloncal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter cytometry analysis of bone marrow plasma cells.

Rajkumar SJ, Merlini G, San Miguel JF. Hematologic cancer: redefining myeloma.

ClinicalTrials.gov. Lenalidomide or observation in treating patients with asymptomatic high-risk smoldering multiple myeloma. http://clinicaltrials. gov/ct2/show/NCT01169337.

Talamo G, Farooq U, Zangari M, et al: Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma.

In most malignancies, early detection and intervention are prerequisites for a possible cure. Consequently, why is the standard of care for myeloma a watch-and-wait approach, with no treatment until progression?

March 2014 | Targeted Therapies in Oncology

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